Dynamic transfer of chirality in photoresponsive systems

University of Groningen

Dynamic transfer of chirality in photoresponsive systemsPizzolato, Stefano Fabrizio

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2017

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecularphotoswitches in catalysis. University of Groningen.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 21-08-2022

https://research.rug.nl/en/publications/565e2fe1-19b8-4efc-8c88-6f85ba346314

Dynamic Transfer of Chirality in Photoresponsive Systems

Applications of Molecular Photoswitches in Catalysis

Stefano Fabrizio Pizzolato

Dynamic Transfer of Chirality in Photoresponsive Systems: Applications of Molecular Photoswitches

in Catalysis


PhD Thesis

University of Groningen

ISBN: 978-94-034-0249-9 (printed version)

978-94-034-0248-2 (electronic version)

Print: Ipskamp drukkers B.V., Enschede, The Netherlands

The work described in this thesis was carried out at the Zernike Institute for Advanced Materials and

Stratingh Institute for Chemistry, in compliance with the requirements of the Graduate School of Science

(Faculty of Mathematics and Natural Sciences, University of Groningen)

This work was financially supported by the Netherlands Organization for Scientific Research (NWO).

Dynamic Transfer of Chirality in Photoresponsive Systems

Applications of Molecular Photoswitches in Catalysis

PhD thesis

to obtain the degree of PhD at the University of Groningen on the authority of the

Rector Magnificus Prof. E. Sterken and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Friday 1 December 2017 at 14.30 hours

by


born on 17 March 1988 in Garbagnate Milanese, Italy

Supervisor

Prof. B.L. Feringa

Assessment Committee

Prof. S. Harutyunyan

Prof. H. Hiemstra

Prof. J.G. de Vries

To my wife Susanna,

for her support during the seemingly endless time dedicated to write this manuscript.

Table of Contents

1. Photoswitchable Systems for Dynamic Transfer of Chirality 1

1.1 Chirality 2

1.2 Organic photoswitchable molecules 2

1.3 Dynamic stereochemistry and molecular motors 5

1.3.1 Chirality sets the way 5

1.3.2 Control of single-molecule motion 5

1.3.3 Liquid crystal and supramolecular structure morphology 7

1.3.4 Polymers morphology 10

1.3.5 Stereoselective catalysis 16

1.3.6 Host-guest interaction and chiral recognition 19

1.3.7 Photocontrol of biological systems 22

1.4 Conclusions 25

1.5 Aim and outline of the thesis 26

1.6 References 28

2. Spectroscopic and Theoretical Identification of Two Thermal Isomerization Pathways

for Bistable Chiral Overcrowded Alkenes 33

2.1 Introduction 34

2.1.1 Photo- and thermally-responsive molecular switches 34

2.1.2 Second generation molecular motors 34

2.2 Results and discussion 35

2.2.1 Design 35

2.2.2 Synthesis 36

2.2.3 Photochemical and thermal isomerizations 39

2.2.4 Computational results 47

2.2.5 Photoswitching process 50

2.2.6 Full experimental study of stable E-isomer isomers 52

2.3 Conclusions 56

2.4 Acknowledgements 56

2.5 Experimental section 57

2.6 References 69

3. Bifunctional Molecular Photoswitches based on Overcrowded Alkenes for Dynamic Control

of Catalytic Activity in Michael Addition Reactions 71

3.1 Introduction 72

3.1.1 Photocontrol of catalytic functions 72

3.1.2 Unique features of molecular motors 73


3.2.1 Design 75

3.2.2 Synthesis 76

3.2.3 Photoswitching process 80

3.2.4 Catalytic activity 84

3.2.5 Computational study 87

3.3 Conclusions 88



3.6 References 115

4. Studies towards a Trifunctionalized Molecular Switch for Light-assisted Tandem Catalytic

Processes 119

4.1 Introduction 120


4.2.1 Design 126

4.2.2 Preliminary testing of bifunctional overcrowded alkenes as switchable catalysts 131

4.2.3 Attempted synthesis of alternative bifunctionalized switches 132

4.2.4 Investigation of catalytic performance in alternative organocatalyzed transformations 136

4.3 Conclusions 142



4.6 References 147

5. Central-to-Helical-to-Axial-to-Central Transfer of Chirality with a Photoresponsive

Catalyst 151


5.2 Results and Discussion 153

5.2.1 Design and modeling calculations 153

5.2.2 Synthesis 157

5.2.3 NMR spectroscopy and atropisomer assignment 159

5.2.4 Atropisomerization process 164

5.2.5 Photochemical isomerization 171

5.2.6 Switchable asymmetric catalysis 175

5.3 Conclusions 177



5.6 References 194

6. Phosphoramidite-Molecular Switches as Photoresponsive Ligands Displaying Multifold

Transfer of Chirality in Dynamic Enantioselective Metal Catalysis 197


6.2 Results and Discussion 199

6.2.1 Design 199

6.2.2 Synthesis 201

6.2.3 Photochemical isomerization 202

6.2.4 Assignment of 1H NMR absorptions of (M) and (P) isomers of L2 via 1D-2D NMR

techniques 205

6.2.5 X-ray crystallography 209

6.2.6 Switchable asymmetric catalysis 210

6.3 Conclusions 214



6.6 References 233

7. Studies towards a Photoswitchable Chiral Organic Phosphoric Acid based on an Overcrowded

Alkene for Organocatalyzed Asymmetric Transformations 235



7.2.1 Design 238

7.2.2 Synthesis 242

7.2.3 NMR spectroscopy 242

7.2.4 Photochemical isomerization. 244

7.2.5 Switchable asymmetric catalysis. 244

7.2.6 Attempted synthesis of 3,3‘-distituted biaryl switch core 246

7.3 Conclusion 251


7.5 References 257

8. Study towards a Photoswitchable Chiral Bidentate Phosphine Ligand based on an

Overcrowded Alkene for Metal-catalyzed Asymmetric Transformations 259


8.1.1 Design of natural and artificial metal complexes 260

8.1.2 Asymmetric transformation of stereodynamic biaryls 260

8.1.3 Photoswitchable metal complexes for asymmetric catalysis 262


8.2.1 Design 265

8.2.2 Retrosynthetic analysis 268

8.2.3 Derivatization of resolved bisphenol derivative 269

8.2.4 Metal-catalyzed phosphorylation 270

8.2.5 Phosphine oxide reduction 272

8.2.6 Attempted second metal-catalyzed phosphorylation 275

8.2.7 Development of photoswitchable chiral Brønsted acid 278

8.3 Conclusions 283


8.5 References 289

Summary 293

Samenvatting 299

Abbreviations and Acronyms 305

Acknowledgements 307

Chapter 1

Photoswitchable Systems for Dynamic Transfer of

Chirality

In this chapter, the concept of photo-controlled dynamic transfer of chirality is presented. After a general

introduction of various versatile classes of photochromic molecules, illustrative examples using light-

triggered molecular switches and motors to illustrate the concepts of dynamic transfer of chirality are

discussed. Various approaches towards the chemistry of smart materials are presented, including the most

relevant applications of chiral photoresponsive systems to molecular motion, liquid crystals, polymers,

catalysis, host-guest complexes, and biological structures.

Chapter 1

2

1.1 Chirality

Since the pioneering work of Pasteur,1 Le Bel and van‘t Hoff,

2 stereochemistry

3,4 has evolved to a

multifaceted and interdisciplinary field that continues to grow at an exponential rate. Today, we know that

chirality can indeed be encountered at all levels in nature – in the form of elementary particle known as the

helical neutrino, inherently chiral proteins, carbohydrates and DNA, or helical bacteria, plants and sea

shells, up to the shapes of spiral galaxies.5–7

Pasteur realized that chiral objects exist as a pair of

enantiomorphous mirror images that are non-superimposable and related to each other like a left-handed

and right-handed gloves.1 At the molecular level, enantiomeric species can exhibit striking differences in

chemical and physical properties when interacting with a chiral environment.5 Many biologically active

compounds, ranging from pharmaceuticals, agrochemicals, flavor, fragrances, and nutrients are chiral.8 The

social and economic relevance acquired by our ability of controlling chirality can be hardly overestimated.

The increasing demand for enantiopure chemicals has been accompanied by significant progress in

asymmetric synthesis and catalysis, and by the development of analytical techniques for the determination

of the stereochemical purity of chiral compounds. Stereoselective analysis usually entails chiroptical

measurements, NMR spectroscopic and mass spectrometric methods, electrophoresis, chiral

chromatography or UV and fluorescence sensing assays. Furthermore, in depth stereoselective analysis can

provide invaluable information about the stability of chiral compounds.

1.2 Organic photoswitchable molecules

The desire to control and manipulate molecular structures by an external stimulus such as light has been

inspired by the photoinduced movements and morphogenesis frequently encountered in nature. A

prominent example is the visual excitation in retina based on light-induced cis-trans isomerization of 11-

cis-retinal to all-trans-retinal.9 This process essentially converts a single photon into molecular motion

through conformational changes, triggering an enzymatic cascade and subsequently a nerve pulse. Retinal

isomerase then regenerates cis-retinal which basically serves as photoresponsive biomolecular switch.

During the last decades, chemists have developed various classes of artificial responsive systems and

switches. Important properties of a molecular switch are bistability and fast, effective and reproducible

responsiveness to a photochemical, thermal, electrochemical or chemical stimulus. A bistable system

consists of two stable states that undergo reversible interconversion controlled by an external signal. Other

criteria for the usefulness of a switch are detectability and non-destructive read-out, stability to

photochemical and thermal degradation, and stability to interconversion and concomitant loss of

information over a wide range of temperatures.

The photochemistry of fulgides, azobenzenes, spiropyrans, diarylethenes and sterically overcrowded

stilbenes that undergo photochemically controlled cis-trans isomerization, cyclization, electron transfer,

and tautomerization has been exploited for the same purpose. A typical photochemical process starts with

the absorption of a photon, causing the excitation of an electron from an occupied orbital, often the highest

in energy (HOMO), to an unoccupied orbital, often the one lowest in energy (LUMO). From this excited

state the system can relax back to its ground state via radiative processes (fluorescence or phosphorescence)

or thermal processes (internal conversion). Photochromism is an alternative photochemical reactivity that

has interested chemists for decades.10,11

It is defined as the reversible photochemically driven

transformation between two isomers displaying different UV-vis absorption spectra. Photoreversible

switching relies on selective interconversion of distinct isomers that absorb at different wavelengths. Chiral

photochromic compounds are susceptible to selective diastereomerization and enantiomerization induced

by irradiation at different wavelengths or circularly polarized light, respectively. Attractive features of

chiroptical switches commonly include facile non-destructive read-out and detectability by ORD or CD

spectroscopy at wavelengths remote from absorption maxima. Compounds exhibiting this behavior

attracted much interest as they can be used as molecular switches12,13

and applied in more complex systems,

such as in organic electronic devices14

or optical data storage.15,16

The most relevant classes of organic

photochromic molecules are depicted in Scheme 1.1.

Photoswitchable Systems for Dynamic Transfer Of Chirality

3

Scheme 1.1. Photochemical and thermal reactivity of main classes of photochromic molecules: a)

spiropyrans; b) azobenzenes; c) diarylethenes; d) hemithioindigos; e) overcrowded alkenes (here an

example of second generation molecular motor is displayed; f) diaryl-N-alkyl imines.

Spiropyrans consist of two fused heterocyclic rings, one of which is a pyran derivative (Scheme 1.1a).17,18

Irradiation of UV-light induces the conversion of a spiropyran into a zwitterionic merocyanine isomer,

which absorbs strongly in the visible region. The reverse isomerization process towards the starting pyran

form can be achieved by irradiation with visible light. Alternatively, the conversion of the merocyanine

isomer can also proceed thermally, although thermally stable merocyanine isomers have been described.19

Azobenzenes consist of two phenyls attached to a central azo moiety (Scheme 1.1b).20,21

The typically more

energetically favored trans-isomer can be converted to the more sterically hindered cis-isomer upon

irradiation with UV light. The reverse isomerization process can be induced either by irradiation with

visible light or thermally. The UV-vis absorption spectra as well as the thermal stability of azobenzenes is

strongly dependent on the electronic properties of the substituents and the substitution pattern on the phenyl

rings.

Similar to azobenzenes, diarylethenes consist of two aromatic groups connected to a central double bond

(Scheme 1.1c).22,23

However, the structure of a cyclic olefin cannot accommodate a cis-trans isomerization

upon photochemical excitation. Instead, the compounds undergo a conrotatory six-electron

electrocyclization yielding a ring-closed isomer. As opposed to spiropyrans and azobenzenes, the photo-

generated closed isomer is thermally stable and requires irradiation with visible light to obtain the initial

open-ring isomer. The most popular design for diarylethenes features two thiophene rings and is referred to

as dithienylethenes.

Chapter 1

4

Hemithioindigos switches consist of a hemithioindigo moiety and a hemistilbene moiety joined at the

central olefin (Scheme 1.1d).24–26

The Z-isomer, typically lower in energy, can be converted to the

corresponding E-isomer, higher in energy, by irradiation with UV-light. The isomerization takes place with

concomitant bathochromic shift of the UV-vis absorption band, which allows reversing the isomerization

bias by irradiation at longer wavelength. In some systems the reverse E-Z isomerization can also take place

thermally.

Overcrowded alkenes represent a unique class of chiroptical photochromic compounds, displaying rotation

around a sterically hindered central olefinic bond.13

They are able of repetitive photoinduced E-Z

isomerization as their molecular structure, i.e. steric properties and substitution pattern, effectively suppress

the competing electrocyclization process that affects simpler stilbene systems.27

With the introduction of

stereogenic center(s), this type of chiroptical switches is capable of making a complete rotation around the

central olefin (Scheme 1.1e).28

The stereogenic causes the product of the photochemical E-Z isomerization

(PEZI) to lie higher in energy (metastable or unstable form) and adopt an opposite helicity. This is due to

the steric hindrance which impedes the two halves to complete a full 180° rotation relative to each other.

Forward and backward isomerization can generally be obtained by irradiation with UV-light of different

wavelength or UV-light and visible light, respectively, depending on the absorption spectra of the distinct

stable and metastable isomers. Depending on the structural design of the switch, thermally induced

relaxation of the metastable state can proceed via reverse thermal E-Z isomerization (TEZI), yielding the

starting isomer with net 0° rotation, or via thermal helix inversion (THI), yielding a second stable form with

net 180° rotation and same helicity of the starting stable isomer upon structural deformation and slipping of

one half other the other. The energy barrier for THI is mainly influenced by the flexibility of the

overcrowded alkene structure.29

Repeating the E-Z isomerization and subsequent helix inversion cause the

system to return to its original state at which point one full rotation has been made. Systems displaying this

behavior are referred to as molecular motors. Depending on the number of stereogenic centers and

symmetric of the rotating units, molecular motors are divided into first (two),30

second (one)31

and third

generation (zero).32

The unique photochromic and thermochromic properties of overcrowded alkenes

originate from significant ground state distortion, molecular twisting and bistability of stereoisomeric

states. The equilibrium of cis- and trans-isomers at the photostationary state is determined by the ratio of

the molar absorption coefficients of the two diastereoisomers at the wavelengths used and the ratio of the

quantum yields of each diastereoisomerization reaction. Since the interconverting isomers of overcrowded

alkenes exist as mixtures obeying Boltzmann distribution and reversible reaction kinetics, molecular motors

do not in fact rotate in an exclusively monodirectional sense. However, the discrete and synergic

photochemical and thermal isomerization reactions of the diastereomeric mixtures result in an overall

unidirectional rotary motion observed from the stator.

More recently, an analogous type of rotary molecular motor based on imine syn–anti isomerization has

been developed .33

Similar to alkenes, imines may undergo both photochemical and thermal isomerization.

Directionality can be forced on these processes by introducing a stereogenic center on the N-substituent of

the imine functionality, yielding unidirectional molecular motors (Scheme 1.1d).34,35

The design is based on

diaryl-N-alkyl imines, which are stable towards thermal E–Z isomerization at ambient temperatures.

Irradiation of a diastereomeric mixture leads to photoisomerization at the C=N bond and a shift of the

equilibrium towards the (M)-isomer. The original diastereomeric ratio was restored after a thermal

relaxation. This thermal reaction was proposed to proceed through two different mechanisms. Inversion at

the nitrogen (NI) moves the substituent back to its original position. Alternatively, the system can release

the steric strain via ring inversion (RI) of the less energetically favored (M)-form, regenerating the more

stable (P)-form through an effective 180° rotation. Via the ring inversion mechanism, the system described

is able to able to undergo a complete unidirectional 360° rotation in four steps similarly to overcrowded

alkenes-based motors.


5

1.3 Dynamic stereochemistry and molecular motors

1.3.1 Chirality sets the way

Stereochemistry embraces a broad variety of closely intertwined static and dynamic aspects that are all

related to the three-dimensional structure of molecules. While static stereochemistry deals with the spatial

arrangement of atoms in molecules and the corresponding chemical and physical properties, dynamic

stereochemistry emphasizes structural change and comprises asymmetric reactions as well as

interconversion of configurational and conformational isomers.36

Dynamic stereochemistry plays a

fundamental role across the chemical sciences, ranging from asymmetric synthesis to drug discovery and

nanomaterials. It is also a distinctive feature encountered in biological systems, crucial for precise

regulation of numerous chirality-dependent metabolic processes (e.g. DNA-helix, protein α-helix,

conformation of sugars, bacterial flagella, etc.).6 The unique stereodynamics of chiral compounds have

paved the way to artificial machines and other molecular devices that lie at the interface of chemistry,

engineering, physics, and molecular biology.37

The design of molecular gears, rotors, switches, bevel gears.

scissors, brakes, shuttles, turnstiles, sensors and even motors showing unidirectional motion has certainly

been inspired by the coordinated movement in biological systems such as muscle fibers, flagella and cilia or

in macroscopic conventional machines.38–41

Feringa and co-workers developed light-driven molecular

motors derived from sterically overcrowded chiral alkenes exhibiting thermal bistability and non-

destructive read-out.42

Among the various examples of photoresponsive molecular systems, molecular

motors certainly stand out for their unique motion mechanism governed by the interaction of fixed and

dynamic chirality.43,44

The subtle interplay between the stereogenic center and the inherently helical

conformation of this type of light- and heat-responsive selectors provides control of the rotation and helicity

about the central carbon-carbon double bond. Both chirality and conformational flexibility are essential for

unidirectional motion of the rotor around the stator. Their dynamic chirality based on cis-trans

photoisomerization and thermally induce helix inversion provides a versatile and powerful tool for

induction of chiral information in a reversible fashion.45

In the next sections, popular examples of

applications of molecular switches and motors for control of dynamic transfer of chirality will be discussed.

The dynamic chirality of such systems is exploited to selectively induce a reversible and reproducible non-

symmetrical response, which is, for instance, directional motion, a specific chiral supramolecular

morphology, asymmetric catalytic outcome, chiral recognition or a biological activity. Further details on

this topic are summarized in comprehensive subject-related reviews.37,41,46–49

1.3.2 Control of single-molecule motion

Nature provides many wonderful examples of molecular machines including motor proteins that perform a

variety of tasks like chromosome segregation,50

cellular trafficking,51

and locomotion.52

By contrast our

current technology, with the exception of liquid crystals, is still far from utilizing productively the

nanoscale motion of molecules.39

Indeed, the ability to control molecular motion by means of non-invasive

stimuli represented a prominent challenge since the birth of artificial chiroptical switches.13

Often inspired

by the mechanical elements of conventional machine engineering, devices like molecular gears, rotors,

shuttles, etc. have been developed with the future prospect of combining each of their specific function to

eventually build complex and efficient supramolecular machines.53

Molecular motors constitute themselves

a clear example of internal dynamic transfer of chirality, for which the fixed point chirality of the

stereogenic center(s) dictates the sense of unidirectional motion around the olefinic bond through multiple

states with selectable helicity.54

Their rotative isomerization mechanism makes them excellent candidates

for achieving transport at nanoscale by directional motion on surfaces. Their rotation mechanism relative to

an adsorbed surface can be considered a dynamic transfer of chirality, as a preferential direction of

translational motion is stereospecifically achieved upon isomerization of the embedded photoresponsive

core along a defined sense of rotation. Nanovehicles are molecules resembling a regular car, containing

wheels, axes and a chassis.55

The group of Tour developed various classes of nanoscale vehicles, ranging

from a car,56

to a dragster,57

and a train58

that could be deposited and pushed using an STM tip. The group

Chapter 1

6

realized the first nanocar propelled by a photoswitchable overcrowded alkene incorporated in the central

chassis and featuring four carborane wheels 1 (Figure 1.1a).59

The proposed motion mechanism entailed

moving the car over the surface with a skipping motion. Despite the rotational properties of the motor

embedded in the nanocar were found to be very similar to the parent motor in solution, the strong

interaction between the nanocar and the adsorbed copper surface impede any lateral motion induced by

light or STM tip pushing. Movement of the motorized nanocar across the surface was eventually induced

by pulses from the STM tip. Subsequently, the group of Tour demonstrated light-induced movement of a

motorized ‗nanoroadster‘ 2 on the surface (Figure 1.1b).60

The roadster consists of a fast unidirectional

overcrowded alkene based second generation molecular motor attached to an axle with two adamantane

wheels. At temperatures above 150 K, the roadsters start to diffuse across the Cu(111) surface. Irradiation

causes the molecular motor to skip across the surface and increase the speed of diffusion. However, the

direction of movement displayed by these roadsters is random.

Figure 1.1. Schematic representation of structure and envisioned dynamics of motion across the metal

surface of nanocar (a) and nanoroadster (b) developed by Tour and co-workers.

Feringa, Ernst and co-workers reported a nanocar 3 that is capable of unidirectional motion over a copper

surface powered by electrons from the tip of a scanning tunneling microscope (STM) (Figure 1.2).61

Feringa and co-workers carefully constructed the nanocar with four switchable wheels that had different

chirality on opposite sides of the molecule. This provided the necessary asymmetry and yielded motion

only in the forward direction, as in all the four wheels were sequentially rotating in accordance to provide

the same translational motion. Notably, only the meso-(R,S-R,S)-isomer is capable of directional

movement, provided that the nanocar underwent the correct asymmetric ‗landing mode‘. Ernst‘s group used

voltage-dependent experiments in which tunneling electrons of different energies were used to excite the

molecule, while its motion was measured by STM imaging before and after excitation. These studies

revealed that the motors inched forward through a sequence of lower energy (ca. 20 kJ mol-1

) helix

inversions driven by vibrational excitation and higher energy (ca. 50 kJ mol-1

) C=C isomerizations induced

through an electronically excited state of the motor. Only molecules with the correct chirality of wheels

exhibited directional (almost completely straight) motion whereas molecules in which the wheels on

opposite sides of the chassis turned in opposite directions resulting in spinning and random motion [(R,R-

R,R)-isomer]. Although the temperatures at which the nanocar operates make this type of system far from

being useful in practical devices and the system was operated by electronic stimuli rather than by light-

irradiation, it is one of a small number of studies that offer insight into how energy is transferred into

motion at the single-molecule level by operating stimuli-responsive chiroptical switches.


7

Figure 1.2. Schematic representation of the nanocar‘s structure and dynamics of its motion across the metal

surface, developed by Feringa and Ernst and co-workers. Reproduced with permission from Ref. 61.

Additional investigation on the possibilities of controlling molecular motion on surfaces with third

generation molecular motors can be found in the work of Štacko62

and Heideman.63

The design of third

generation molecular motors, each composed of two rotating ‗wheels‘, allows simplifying the nanovehicle

synthesis and reducing its molecular weight. Upon selection of the appropriate size of olefin-bridged

cycloalkenes and substituents in the fjord region, applications at room temperatures and under light-

irradiation have been explored. The reader is strongly invited to consult their theses and manuscripts for

further details.

Notably, the synthesis of the four-wheeled motorized nanocar required 13 synthetic steps and chiral HPLC

separation, with an overall yield of 1.3%. No practical application of such systems can be considered

readily feasible or interesting for practical applications. Therefore, for larger scale applications, chemists

need to rely on other methods, such as cooperativity and synchronization between clusters of dynamic

molecules and amplification of motion. Such properties are more likely to be featured by systems based on

supramolecular assemblies, polymer chemistry or surface functionalization. Functionalization of surfaces

with responsive units64–66

represents an alternative approach, providing smart control of surface related

properties; for instance wettability or adhesion based on dynamic interaction with objects incapable of

autonomous motion. However, this alternative would require a highly ordered placement of the interacting

layer, possibly harnessing the amplification effects provided via self-assembling of supramolecular systems

and neighboring chiral induction by responsive dopants.

1.3.3 Liquid crystal and supramolecular structure morphology

Transmission of chiral information from single-molecule to macromolecular levels67

is a powerful

mechanism adopted in nature for the controlled self-assembly of chiral subunits into complex

superstructures. This results in well-defined architectures capable of regulating highly specific biological

functions due to their unique three-dimensional molecular shapes (e.g. DNA-helix, enzymes, hormone

receptors, ion-channels, etc.).6 Helical domain(s) in macromolecules such as starch, protein, and DNA may

thus be generated,68,69

while H-bonding, electrostatic, π-π, and van der Waals (vdW) interactions are the

major molecular forces involved in triggering these self-assembly processes. As inspired by Nature,

synthetic systems offer a diverse array of opportunities to control the properties of materials in a dynamic,

Chapter 1

8

modular and even reversible manner. By taking advantage of these molecular forces, one can also trigger

the self-assembly of custom-designed small molecules into large supramolecular aggregates, liquid crystal

domains or gel networks.70

The ordered arrangement in such complex systems made by physical interplay

can be perturbed by forces including heat, light, chemical additives, and mechanical action.71

A dominant theme within the research on two-dimensional chirality is the sergeant–soldiers principle,72

wherein a small fraction of chiral molecules (sergeants) is used to direct the handedness of achiral

molecules (soldiers) to generate a homo-chiral structure.73

The general principles of supramolecular

chemistry have proven particularly useful for understanding the different aspects of light-responsive chiral

induction phenomena.74

Conversely, the handedness of a supramolecular aggregate can also be used as a

probe to comprehend the fundamentals of amplification of chirality in supramolecular aggregates.75

Feringa, Eelkema and co-workers described the unidirectional rotation of a macroscopic glass rod deposited

on a light-responsive liquid crystal film (Figure 1.3).76

A cholesteric liquid crystal film was doped with an

enantiopure second generation molecular motor 4 (1 wt%). Continuous irradiation of the fast-rotating

molecular motor around the central alkene bond causes a repeated change in its helicity. When the motor is

used as a dopant, the liquid crystal adopts the same helicity through a ‗sergeants-and-soldiers‘ principle.72

Upon irradiation of the sample, rearrangement of the liquid crystal occurring in a clockwise fashion is

observed. A microscopic glass rod, deposited on top of the liquid crystal layer was used to visualize the

moving liquid crystal pattern. Irradiation with 365 nm light caused the rod to rotate in a clockwise manner.

The movement was observed over 10 min of continuous stimulus, after which period the response gradually

halted. The motion resumed in an anti-clockwise direction upon removal of the irradiation source. A control

experiment using the opposite enantiomer induced rotation in the opposite direction. After an in depth

investigation, it was concluded that the rotation of the glass rod is a direct result of the switching helicity of

the dopant, rather than the unidirectionality of the rotation of the motor.77

Figure 1.3. Unidirectional rotation of a macroscopic glass rod driven by pattern reorganization in a liquid

crystal (only two stages of the rotary cycle are shown for simplicity) described by Feringa and co-workers.

a) Structure of the molecular motor dopant 4. Microscope images depicting initial orientation of glass rod

on liquid crystal surface (b) and subsequent orientations after continuous irradiation: 28°, 15 s (c); 141°, 30

s (d); 226°, 45 s (e). Reproduced with permission from Ref. 76.

Chen and co-workers developed photoswitchable helicenes 5 as conformation modulable photochromes

capable of transferring their reversible, complementary helicities in chiral liquid-crystalline materials upon


9

light-induced switching (Figure 1.4).78

The structure of such helicenes comprises a C2-symmetric

dibenzosuberane (DBS) stator featuring two chiral centers and a biaryl-functionalized rotor joined at the

central olefin. Similar to overcrowded alkene-based switches, the fixed chirality on the stereogenic centers

dictates the dynamic structural helicity adopted in the two addressable states. The helicenes incorporated

aromatic amide (―aramide‖) moieties in the top DBS unit. In addition to H-bonding and π-π interactions,

extra vdW forces were introduced by appending long-chain alkyl groups at the aramides substituents to

effect interchain alignment, further facilitating organogel formation. Furthermore, a phenyl ring was

introduced at the C8′ position of the bottom unit template to enhance the π-π interactions and thus the

helical nature of the resulting organogels. Highly diastereoselective and complementary switching

selectivities could be achieved in n-hexane or CH2Cl2 upon photoirradiation of (M)-5 at 270 nm [(M)-5:(P)-

5 = <1:>99] and (P)-1′ at 335 nm [(M)-5:(P)-5, 90:10] (Figure 1.4a). Notably, a pseudoracemic mixture

[(M)-5:(P)-5 = 50:50] was obtained upon irradiation at 308 nm. (M)-5 and (P)-5 remained dissolved in

apolar solvents (n-hexane, cyclohexane, benzene, and toluene) even at relatively high concentration (0.01

M) at ambient temperature but formed gels in more polar solvents (CH2Cl2, CHCl3, and CH3CN) at a

minimum concentration of 1×10−3

M. The resulting gels were stable at ambient temperature, and the gel-to-

sol interconversion was reversible upon repetitive heating (≥35 °C) and cooling cycles. Notably, (M)-5 and

(P)-5 helicenes led to the corresponding (M)- and (P)-form helical fibers. Thus, the absolute chirality of the

helicene dictates the overall helical chirality of the self-assembled helical fibers, presumably through

intermolecular H-bonding and π-π interactions. In a series of TEM images taken from these

photoisomerization experiments, only either pure (M)- or (P)-form bundled fibril tubes were observed when

the overall composition ranged from (M):(P) = >99:<1 to 70:30 and 25:75 to <1:>99, respectively (Figure

1.4b). Notably, increasing amounts of micelles or vesicles were observed for the intermediate gel and sol

states.

Figure 1.4. Photoisomerization profiles of C2-symmetric dibenzosuberane-based helicenes 5 as tunable

units in chiral liquid-crystalline materials developed by Chen and co-workers. b) TEM images of the

bundled superstructures of xerogels from (M)-5 (left) and (P)-5 (right). Reproduced with permission from

Ref. 78.

In order to apply photoinduced cholesteric helix inversion to the creation of new materials and devices,

photoactive enantiopure dopants will have to be conveniently accessible in reasonable quantities.

Consequently, researchers have investigated the possibility to use other classes of molecules as

photoswitchable chiral dopants, most of them based on cis-trans isomerization of locally achiral

photochromes incorporated in chiral structures (Figure 1.5). The groups of Feringa and Spada reported

Chapter 1

10

light-induced helix inversion in cholesteric mesophases by using a BINOL-based azobenzene as a dopant.

Feringa and co-workers reported that a binaphthyl-based core ensuring chiral induction, symmetrically

functionalized by two azobenzene moieties, 6 yields reversible helix-inversion in a nematic host (Figure

1.5a).79

Spada and co-workers reported a binaphthyl substituted with one azobenzene 7 (Figure 1.5b)

displaying a reverses in sign of helical twisting power under UV irradiation in a nematic host.80

Reversible

helix inversion was also achieved via a combination of photochemical and thermal isomerizations of chiral

azobenzenophane derivatives 8 (Figure 1.5c) dissolved in nematic hosts.81

However, a drawback of

azobenzene derivatives lies in their lack of thermal stability. The search for versatile and efficient dopants

allowing helix inversion, with high helical twisting powers, remains an on-going challenge.

Figure 1.5. Photo-responsive dopants promoting helix inversion in cholesteric liquid crystals featuring

azobenzene moieties.

1.3.4 Polymers morphology

Several synthetic polymers have been developed that exhibit a strong optical activity due to the helical

conformation, with an excess of one particular handedness adopted by their backbone.82,83

These systems

have provided valuable insight into cooperative processes and the amplification of chirality in

macromolecules.84

The amplification of chirality via transfer of chiral information through non-covalent

interactions to helical polymers has now been well studied, experimentally and theoretically.85–87

For a

number of these polymers (e.g. polyisocyanides or polymethacrylates bearing bulky side-groups) this

helical conformation is completely locked due to strong steric interactions experienced by the side-groups

of the neighboring monomeric units. However, much interest is recently devoted to macromolecules in

which the helical conformation is dynamic, and rapidly inverts at ambient temperatures: the low helix

inversion barriers of these polymers result in their helical conformation being thermodynamically

controlled.88,89

Moreover, due to the favorable interactions between the monomeric units in the helical

conformation of these macromolecules they exist as long strands of one particular handedness, only rarely

interrupted by a helix reversal along the chain. Therefore a strong preference for a particular handedness

can readily be biased by a small chiral input.

In order to obtain photochemical control of the chirality of a dynamically helical polymer,90,91

Zentel and

co-workers introduced azobenzene photochromic groups containing two stereocenters in the side-chains of

co-polyisocyanate 9 (Figure 1.6a).92

The polymer was prepared with all of the azobenzene moieties

adopting the trans configuration, and this polymer was shown to have a significant CD and ORD signal,

indicating a preferred helical twist sense of the polymer. Irradiation with UV-light (365 nm) resulted in a

trans-cis isomerization of the azobenzene groups, and resulted in a clear inversion of the CD and ORD

signals (Figure 1.6b), indicating an inversion of the preferred helical twist sense of the polymer chain. The

reason for this effect is not clear (the stereocenters do not change upon photoisomerization): the change in


11

interactions of the stereocenters at the azobenzene with the polymer backbone upon photoisomerization are

proposed to cause the helical inversion.93

Figure 1.6. a) Co-polyisocyanate 9 containing a photochromic azobenzene group in the side chains (avg.

content: 8%) developed by Zendel and co-workers. b) CD spectra of the polymer before and after the

photochemically induced trans-cis isomerization of the azobenzene units. Reproduced with permission

from Ref. 92.

In the last system, the chiral information of multiple photochromic units randomly distributed along the

polymer chain is transferred to the polymer backbone. Alternatively, the presence of one chiral unit situated

at the terminus of the polymer chain, introduced by the use of an optically active initiator for the

polymerization, can induce a preferred helical twist sense of the polymer.94

Reverse of polymer chain

handedness can be induced upon isomerization of a chiral photo-responsive selector installed at the chain-

end of the polymer. Here, the extent to which the chiral unit influences the polymer depends on the

persistence length of the polymer chain: the chiral information will be transferred along the polymer

backbone until a helix reversal is encountered, after which the chiral influence is lost. Therefore, the optical

rotation of these helical polymers depends greatly on their chain length and temperature.

Feringa, Pijper and co-workers reported polyisocyanate 10, in which a single chiral photochromic unit — a

light-driven four step rotary molecular motor — is situated at the terminus of an intrinsically dynamically

racemic helical poly(n-hexylisocyanate) (Scheme 1.2).95

Due to the helical structure of the sterically

overcrowded motor molecule, a chiral environment is created at the terminus of the polymer chain, which is

introduced at its fluorenyl lower half. Through the four subsequent stages of the rotation process, the

stereoinduction towards the macromolecule, which is generated by the cyclopentane-naphthyl upper half of

the motor molecule, strongly changes (Scheme 1.2a). In this system, a single chiral photochromic switch

unit attached at the terminus of a helical polymer allows the reversible induction and inversion of the

preferred helical twist sense of the polymer‘s backbone and a three state switching cycle with racemic, P

and M helicity of the polymer (Scheme 1.2b).

Chapter 1

12

Scheme 1.2. Dynamic transmission of chirality from a light-driven rotary molecular motor to the

macromolecular level of a polyisocyanate 10, as described by Feringa and co-workers. a) Unidirectional

rotation cycle of chain-end motor. b) Schematic illustration of the reversible induction by chain-end motor

and inversion of the helicity of a polymer backbone. Reproduced with permission from Ref. 95.

A drawback of the parent system 10 is the fact that controlling of the exact composition of the mixture of

isomers of the motor molecule, and the associated chiral induction towards the polymer chain, upon

irradiation at room temperature is a highly complex process. This is caused by the non-perfect

photostationary states at the photochemical steps, and the fact that the thermal isomerization steps proceed

relatively fast at room temperature. In order to obtain better control over the chiral induction towards the

helical polymer, the photochromic unit attached at the polymer chain‘s terminus was redesigned into a

photochemically bi-stable chiroptical switch with two thermally stable states, achieved via a slight

structural modification of the molecule, and attachment of the polymer to its upper half. With this system

11 (Scheme 1.3), the magnitude and sign of the supramolecular helicity of the polymeric cholesteric LC

phase can be fully controlled using two different wavelengths of light (365 nm and >480 nm).96


13

Scheme 1.3. Schematic representation of the full photocontrol of the magnitude and sign of the

supramolecular helical pitch of a cholesteric LC phase generated by a polyisocyanate 11 with a single

chiroptical molecular switch covalently linked to the polymer‘s terminus developed by Feringa and co-

workers. Reproduced with permission from Ref. 96.

Recently, Feringa, van Leeuwen and co-workers investigated the transfer of chirality from a molecular motor

to a dynamic helical polymer via ionic interactions.97

A dopant with photoswitchable chirality is able to induce a

preferred helicity in a poly(phenylacetylene) polymer and the helicity is inverted upon irradiation. Irradiation at

312 nm of a sample of polymer doped with the (P,P)-(Z)-isomer of the motor resulted in an inversion of the CD

signal and hence, the inversion of the handedness of the polymer. In sharp contrast, when a sample of polymer

doped with the (P,P)-(E)-isomer of the motor was irradiated, no inversion of the CD signal was observed, only a

decrease in intensity in the CD spectrum.

Alternatively, the polymer can respond to the isomerization of embed chiral inductors and consequent

alteration of chain coiling with a change of material shape or size, rather than a preferred strand helicity.

Depending on the polymer design, an expansion or contraction of the fibers can lead to a three-dimensional

rearrangement of the whole structure. These functional materials were shown to be capable of converting

light energy into mechanical work at the macroscopic scale, which could lead to potential applications in

micromechanical systems, soft robotics and artificial muscles.

Katsonis and co-workers developed liquid-crystal polymer networks that can selectively form either right-

handed or left-handed macroscopic helices at room temperature (Figure 1.7).98

These versatile materials

consist of molecular azobenzene-based photochromic switches 12 (Figure 1.7a, concentrations up to 10

wt%) embedded in a liquid-crystalline polyacrylate material containing chiral dopants (Figure 1.7b),

resulting in spring-like strings (Figure 1.7c). In these springs, reversible light-induced trans-cis

isomerization of azobenzene units (λ = 365 nm and >420 nm) is converted and amplified stereospecifically

into controlled and reversible twisting motions. Liquid-crystal polymer networks display a strong coupling

between orientational order and mechanical strain, which is why they undergo deformations when

submitted to a stimulus-induced decrease of order. Upon photoinduced deformation, the springs display

complex motion, which includes winding, unwinding and helix inversion, as dictated by their initial shape

which in turn depends on the direction in which they are cut (Figure 1.7c). Shape and photo-actuation

modes of the polymer springs are in function of the angular offset, which is defined as the angle between

the orientation of the molecules at mid-plane and the cutting direction. Under irradiation with ultraviolet

light, the ribbons contract along the director and expand in the perpendicular directions, as is consistent

with an ultraviolet-induced increase of disorder. The ribbons deform to accommodate the preferred

distortion along the main axis of the ribbon, and this preferred distortion is determined by the orientation of

the molecules. Importantly, they can produce work by moving a macroscopic object and mimicking

mechanical functions such as those used by plant tendrils to help the plant access sunlight.

Chapter 1

14

Figure 1.7. Photoresponsive liquid crystal in a twist-nematic molecular organization, as developed by

Katsonis and co-workers. a) Photoisomerization process of azobenzene actuator 12, incorporated in liquid-

crystalline polyacrylate springs upon copolymerization. b) Chiral dopants used to induce preferential

helicity to the spring. c) Spiral ribbons irradiated for two minutes with ultraviolet light (λ = 365 nm) display

isochoric winding, unwinding and helix inversion as dictated by their initial shape and geometry. Reverse

motion can be achieved upon irradiation with visible light (λ > 420 nm). Reproduced with permission from

Ref. 98.

Giuseppone and co-workers have developed a polymeric gel including second generation overcrowded

alkene based molecular motors, which contracts upon irradiation with UV light (Figure 1.8).99

The polymer

motor conjugates consist of fast second generation motors (rotation frequency in the order of MHz) cross-

linked with PEG chains. On performing copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions

under high-dilution conditions (Figure 1.8a), 8-shaped macrocyclic motor conjugates 13 are formed (Figure

1.8b). The macrocycles can be coiled up by light activation, thus reducing their size to that of nanoscopic

objects which can be identified by AFM as isolated coiled 8-shaped polymers on mica surfaces (Figure

1.8d). When the CuAAC reaction is carried out at much higher concentrations (Figure 1.8a), the result is

mechanically activated entangled gels 14 in which the polymer chains become coiled up by the UV-light-

activated rotations of the entrapped motors (Figure 1.8c), reducing the overall dimensions of the millimeter-

sized gels (Figure 1.8e). It is hypothesized that this shrinking is the result of increasingly tighter coiling of

the polymeric chains, induced by the continuous rotation of the motor units. At higher tensions the

contraction slows down, until the gel ruptures and subsequently recovers its original size and shape.

Complimentary fluorescence experiments indicate that the rupture is the result of simultaneous oxidation of

the central double bonds of the motors, followed by unwinding of the coils. Using bidirectional rotating

units, one could envision selectively shrinking or expanding the gel structure upon rotation in opposite

direction. Therefore, a dynamic transfer of chirality from a specific rotational motion to a consequential

three-dimensional size regulation can be recognized. Potential practical applications of such systems may

include energy storage, smart materials and artificial muscles.


15

Figure 1.8. Size-reduction of nanoscopic objects 13 and macroscopic entangled gel 14 contractions driven

by artificial molecular motors developed by Giuseppone and co-workers. a) Reaction schemes and

conditions for incorporating artificial molecular motors into an 8-shaped polymer and into mechanically

activated entangled gels. b,c) Graphical illustrations showing the 8-shaped polymer and the mechanically

activated entangled gels coiling up under light activation. d) AFM images before (top) and after (bottom)

light activation of the 8-shaped polymer. e) Snapshots of a movie (taken at 0, 60, 120, and 170 min after

light irradiation, respectively) illustrating macroscopic gel contractions over time. Reproduced with

permission from Ref. 99.

The same group also reported that by connecting subunits made of both unidirectional light-driven rotary

motors and modulators, which respectively braid and unbraid polymer chains in cross-linked networks, it

Chapter 1

16

becomes possible to reverse their integrated motion at all scales.100

The photostationary state of the systems

can be tuned by modulation of frequencies using two irradiation wavelengths. Under this out-of-

equilibrium condition, the global work output (measured as the contraction or expansion of the material) is

controlled by the net flux of clockwise and anticlockwise rotations between the motors and the modulators.

1.3.5 Stereoselective catalysis

Enzymes and synthetic asymmetric catalysts exercise tight stereochemical control over the reactions they

catalyze, producing, for the most part, single enantiomers. Reversing the chiral preference of a catalytic

system is a non-trivial task (for enzymes, directed evolution using genetic engineering has been used).101

During the last decades, chemists have developed striking examples of reversal of stereoselectivity

provided by artificial catalyst by means of externally-induced changes of local chirality.47,102,103

The use of

light to induce a change in catalyst state is particularly attractive as it is non-invasive stimulus, offers

excellent temporal and spatial control, and can be precisely regulated with an appropriate light source. In

photo-modulated stereoselective catalysis, the stereodynamic properties of chiral photoswitches and their

contributions of interconverting configurational and conformational isomers are exploited to achieve

control over catalytic selectivity, reactivity, and substrate recognition.47

In order to proceed at reasonable

rate, most catalytic reactions require concentrations that exceed by several orders of magnitude the usual

condition employed in photochemistry. However, the use of photoresponsive catalysts allows lowering the

concentration of the active chromophore in the reaction mixture.47

Moreover, the photoswitching of

catalytic activity and/or selectivity in facts constitutes an amplification of the light stimulus and chirality,

since the information triggered upon light irradiation is amplified towards multiple asymmetric catalytic

events.47

Most of the photoswitchable catalyst systems reported to date focus on the modulation of catalytic

activity by triggering a change of the catalyst structure between two forms. Control over cooperative

effects,104–106

competing effect,107,108

steric shielding of the active site,109,110

and modulation of pH111–113

or

electronic properties114,115

are amongst the most relevant and successful approaches.

Much more limited in number and therefore more impressive in their achievements are the examples of

photoswitchable catalysts capable of providing selectivity control. The first successful approach to

photochemically alter the stereoselectivity of a catalyst was reported by Branda and co-workers (Scheme

1.4).116

Through cooperative interactions, they successfully controlled the stereochemical outcome of the

cyclopropanation of styrene using a photoswitchable chiral copper-based catalyst 15. Their ligand consists

of a dithienylethene-based chiral bis(oxazoline) which, in its open form (o-15), binds Cu(I) ions in a

bidentate fashion. This results in a rigid chiral environment for the metal ion that subsequently catalyzes the

cyclopropanation reaction with significant enantioselectivity (30–50% ee). In contrast, the closed form of

the ligand (c-15), formed upon irradiation at 313 nm, is only able to form monodentate complexes with

Cu(I) due to the rigidity of the ligand. The chiral environment is less well expressed in this complex and

results in negligible enantioselectivity in the cyclopropanation reaction (5% ee). Irradiating the sample with

visible light led to recovery of the original chiral information and gave an ee of 11–37%. A limitation of

this catalytic system is the low photocyclization efficiency in the presence of Cu(I), with only 23% of the

closed form present at the photostationary state at 313 nm, meaning that switching the catalyst state only

results in a small disruption in the stereoselectivity of the catalyzed reaction.


17

Scheme 1.4. Photoswitching of a dithienylethane-based oxazoline ligand 15 that shows different

stereoselectivities in the copper-catalyzed asymmetric cyclopropanation of styrene developed by Branda

and co-workers.

Feringa and Wang have risen to the challenge by integrating a catalytic system with a light-driven first

generation molecular motor 16, which allows controlling of catalytic activity and configuration of the

product (Figure 1.9a).117

The motor is functionalized on its rotor segment with a dimethylaminopyridine

unit (Brønsted base, A) and on its stator segment with a thiourea function (hydrogen-bond donor, B) that

can act cooperatively as a bifunctional catalyst for a conjugate thiol addition to enone (Figure 1.9b). When

the motor is activated to undergo photochemically and thermally induced steps, counter-clockwise rotation

of the rotor around the overcrowded alkene bond controls the backbone helicity (M or P) and relative

distance the catalytic groups, A and B, producing catalysts I, II and III in sequence with different activities

(Figure 1.9c) and enantioselectivities (Figure 1.9d). The catalytic system displays low catalytic activity and

almost no chiral preference when A and B are far apart (I). The catalytic activity is increased significantly

when A and B are close together, as in II and III, while the chiral preference is reversed when the rotor has

(M) and (P) helicities. Indeed, the catalyzed reaction yielded the addition product with different e.r. and

yield (comparison after 15 h) upon tuning of the catalyst, going from R:S = 51:49 and 7% yield (I), to R:S =

25:75and 50% yield (II), and R:S = 77:23 and 83% yield (III). The concept of application molecular motors

in photoresponsive stereoselective catalysis was further extended by Vlatkovic to an analogous

dimethylaminopyridine-thiourea functionalized organocatalysts 17 to control a Henry reaction118

(Figure

1.10a) and by Zhao to a bis(diphenylphosphine) ligand 18 for palladium-catalyzed enantioselective allylic

substitution (Figure 1.10b).119

Chapter 1

18

Figure 1.9. Reversal of enantioselectivity controlled by a unidirectional rotary motor 16 by Feringa and co-

workers. a) Graphical representation of the motor motion (top) and structural formula of the artificial

switchable catalyst in its (2R,2‘R)-(P,P)-trans form (bottom). A and B stand for the rotor and stator

components, respectively. Unidirectional step-wise rotation around central alkene leads to the molecule

adopting three geometries, namely, I, II, and III, with different catalytic performances. b) Reaction Scheme

1.and conditions for the thiol addition to enone catalyzed by 16. c) Reaction kinetics by 1H NMR

spectroscopy show that the motor functions effectively only when portion A and B are close enough in its

(M,M)-cis form (II) and (P,P)-cis form (III). d) Chiral HPLC traces illustrate the variation of

enantioselectivity upon catalyst isomerization (catalyst form, e.r. R:S of reaction product: I, 51:49; II,

25:75; III, 77:23, from top to bottom, respectively). Reproduced with permission from Ref. 117.


19

Figure 1.10. Bifunctional first generation molecular motor derivatives 17 and 18 for stimuli-responsive

control of catalytic activity and enantioselectivity in organo- and metal-catalyzed transformations: a) Henry

reaction;118

b) Palladium-catalyzed enantioselective allylic substitution.119

Chen and co-workers reported a pseudo-enantiomeric pair of optically switchable helicenes 19 composed of

a C2-symmetric dimethoxymethyl-dibenzosuberane stator and a catalytic 4-N-methylaminopyridine (MAP)

rotor joined by a switchable olefin (Figure 1.11).120

They underwent complementary photoswitching at with

UV-light (P:M, <1:>99 at 290 nm; 91:9 at 340 nm) and unidirectional thermal relaxation similarly to the

helicenes previously described by the same group (see Figure 1.4). They were utilized to catalyze

enantiodivergent Steglich rearrangement of O- to C-carboxylazlactones, with formation of either

enantiomer with up to 91% ee (R) and 94% ee (S), respectively. Based on control experiments, the authors

proposed that the catalytic process may proceed through an initial and reversible nucleophilic carboxyl

substitution of the substrate carbonate moiety by catalyst, resulting in the formation of a stabilized ion pair

(P)-19’ between the enolate-anion of the substrate and phenoxycarbonyl-pyridinium-cation of the catalyst.

Subsequently, an irreversible C-carboxylation of enolate-anion takes place with pyridinium-cation in high

enantiocontrol.

Figure 1.11. Photoisomerization profiles of catalytic C2-symmetric dibenzosuberane-based helicenes 19 for

the stereoselective Steglich rearrangement of O-carboxylazlactone developed by Chen and co-workers.

Chapter 1

20

1.3.6 Host-guest interaction and chiral recognition

The vast majority of biomolecules is chiral and the ability of proteins to distinguish between enantiomers is

of fundamental importance to various biological processes, for example, signal transduction, drug binding,

and biocatalysis.121

Consequently, chemists have been highly active in the area of chiral recognition and

especially enantioselective discrimination.122,123

In principle, the enantiopreference of any biological or

chemical receptor is fixed by the chiral building blocks that it is made from. Yet, it is intriguing to develop

chirality-switchable receptors that could selectively bind a given enantiomer in one state, whereas in the

other state it prefers binding the opposite enantiomer. Such receptors could be used to dynamically control

the ratio between enantiomers or selectively transport an enantiomer of choice. Knowing that opposite

enantiomers of chiral substrates can produce entirely different effects,124

this may be applied eventually

also to exert unique control over chirality-responsive biological and chemical processes.

Aida and co-workers designed a chiral photoresponsive host 20 capable of light-induced scissor-like

conformational changes (Scheme 1.5).125

The system can give rise to mechanical twisting of a non-

covalently bound bidentate guest rotor molecule. To realize this coupling of molecular motions, they uses a

previously designed system:126

a ferrocene moiety with an azobenzene strap, each end of which is attached

to one of the two cyclopentadienyl rings of the ferrocene unit, acts as a pivot so that photoisomerization of

the strap rotates the ferrocene rings relative to each other and thereby also changes the relative position of

two ‗pedal‘ moieties attached to the ferrocene rings. This effect is translated into intermolecular coupling of

motion by endowing the pedals with binding sites, which allow the host system to form a stable complex

with a 4,4‘-biisoquinoline guest 21. Exposure of trans-20 to UV light (λ = 350 nm) at 20 °C induces trans-

cis isomerization of the azobenzene unit to give a molar ratio for trans-20:cis-20 of 22:78. Irradiation of the

isomerized mixture with visible light (λ = 420 nm) resulted in the backward cis-trans isomerization, giving

a molar ratio for trans-20:cis-20 of 63:37. Using circular dichroism spectroscopy, they demonstrated that

the photoinduced conformational changes of the host are indeed transmitted and induce mechanical twisting

of the rotor molecule.

Scheme 1.5. Schematic representation of light-powered molecular pedal 20 capable of inducing

conformational changes via host-guest interaction, developed by Aida and co-workers. Reproduced with


Feringa, Wezenberg and co-workers reported a chiral bis-urea anion receptor 22, derived from a first

generation molecular motor, which can undergo photochemical and thermal isomerization operating as a

reconfigurable system (Scheme 1.6).127

The two possible cis configurations in the isomerization cycle are

opposite in helicity. They demonstrated that the (P)- and (M)-helical cis-isomers hold opposite

enantioselectivity in the binding of BINOL phosphate, while anion complexation by the intermediate trans-

isomer is not selective. Thus, the enantio-preferred substrate binding in this receptor can be inverted in a

dynamic fashion using light and heat. Irradiation of a solution of stable (P,P)-cis-22 with UV-light (λ =

312 nm) resulted, via generation of (P,P)-trans-22 isomer as intermediate, in conversion to (M,M)-cis-22.


21

Upon subsequent heating of the sample, regeneration of the initial stable (P,P)-cis-22 was observed. Fitting

of the 1H NMR spectroscopy titration data of a sample of (P,P)-trans-22 and [Bu4N]

+[(R)-23]

- or

[Bu4N]+[(S)-23]

- to a 1:1 binding model revealed a strong preference for binding of the (R)-enantiomer over

the (S)-enantiomer (KR/KS = 4.2). To determine a stability constant for complexation of 23 by (M,M)-cis-22,

competitive titrations to the photostationary state (at λ = 312 nm) mixture (PSS312: cis:trans = 80:20) were

carried out under the same conditions. It was found that now the (S)-enantiomer of 23 binds the strongest

(KR/KS = 3.2). However, in addition to stereoselective inversion, a decrease in binding strength was noted

when going from (P,P)-cis-23 to (M,M)-cis-23. On the other hand, titrations to (P,P)-trans-23 revealed

poor binding (Ka < 20 M-1

) and no enantioselectivity. Binding tests with more sterically hindered guest 24

displayed less efficient enantiodiscriminating performances.

Scheme 1.6. Schematic representation of bis-urea receptor 22 controlled by light and heat for dynamic

inversion of stereoselective phosphate binding developed by Feringa and co-workers. Reproduced with


Dynamic control over helicity of chiral metal-ligand complexes has also been described. Taking inspiration

from Cu-helicates by Lehn and others,128,129

Feringa, Zhao and co-workers reported that unidirectional

rotary motors with connecting oligo-bipyridyl ligands 25 and 26 (Figure 1.12a), which can dynamically

change their chirality upon irradiation, assemble into metal helicates that are responsive to light.130

The

motor function controls the self-assembly process as well as the helical chirality, allowing switching

between oligomers and double-stranded helicates with distinct handedness (Figure 1.12b). Coordination

oligomers of bipyridine-Cu(I) complex can be formed by treating the trans-molecular motor bearing

oligobipyridines with Cu(I). These oligomers can split into monomers with P’-helicity due to the

unidirectional rotation of the molecular motor from the stable (P,P)-trans-state to the metastable (M,M)-cis-

state with light. Analysis by UV–vis, CD and 1H NMR spectroscopy demonstrated that the inversion of the

chirality of the Cu-helicate from P’ to M’ is governed by a subsequent thermal helical inversion [from

(M,M) to (P,P)] of the molecular motor core structure. Photoisomerization of stable (P,P)-cis-state to stable

(M,M)-cis-state through the rotary cycle via the metastable trans-oligomeric-state will invert the chirality of

the Cu-helicate back from M′ to P′. In this system, the achiral guests (i.e. the Cu(I) ions) support the chiral

photoresponsive selector to construct out of the polydentate ligand strands a supramolecular helical

structure with dynamic helicity. The unidirectionality of the light-induced motion governs the sequence of

programmable steps, enabling the highly regulated self-assembly of fully responsive helical structures.

Chapter 1

22

Figure 1.12. Dynamic control of chirality and self-assembly of double-stranded helicates 25 and 26 with

light and heat developed by Feringa and co-workers. a) First generation molecular motors bearing

oligobipyridines ligand strands 25 and 26. b) Schematic representation of the concept of the dynamic

double-stranded helicates with coordinated Cu(I) ions. Reproduced with permission from Ref. 130.

1.3.7 Photocontrol of biological systems

The ability to control the conformation and activity of biomolecules in a reversible manner is a fascinating

goal48,131–133

that has an outstanding potential for the study of and interference with complex processes in

living cells.134,135

Spatial and temporal control of cellular processes could provide unparalleled

opportunities for elucidating biological events or disease progression.136,137

Light is considered an ideal

external control element for in situ chemical and biological manipulation because it offers a high level of

spatio-temporal resolution, its energy and intensity can be precisely regulated, is generally non-invasive

within specific a range of wavelengths, is orthogonal toward most elements of living systems, and does not

cause the chemical contamination of the sample.138

Many strategies for the reversible photocontrol of

biomolecules have been explored with a wide variety of chromophores. A promising approach along this

line features site-specific anchoring or chain-insertion of a photoswitch onto a target protein, peptide or

DNA structure. The photoinduced isomerization between the cis- and trans-isomers (e.g. azobenzenes,

overcrowded alkenes) or interconversion between closed and open forms (e.g. spiropyrans,

dithienylethenes) results in a net change in geometry, polarity or charge distribution of the chromophore.

Examples of photo-regulation of DNA structure139

and conformation,140

ligand binding to nuclei acids,141

peptide conformation142,143

and functional protein structure and folding (e.g. for control of receptors

function,144

enzyme activity,145–147

ion channel,148

and ligand binding149

) have been reported. It should be

noted that most of these examples imply reversible interaction of chiral biological molecules with

photoresponsive motifs not characterized by enantioselective switching mechanisms, like azobenzenes or

dithienylethenes. The concept of dynamic transfer of chirality is therefore not easy to delineate in this field,


23

as most systems entail up-down regulation of biological processes by inclusion of artificial photo-actuators

without any clear reversal of chiral outcome.150

For instance, various groups have used light to alter the

structure and binding properties of nucleic acids and nucleic acid analogs by employing photochromic

molecules introduced in diverse structural positions, including the phosphate backbone, the nucleobase, and

ribose moiety in native nucleic acids.48

The resulting photosensitive oligomers have allowed, for instance,

the initiation or inhibition of nucleic acid hybridization simply by using the proper wavelength of light.

However, photoinduced destabilization and interconversion of inherently chiral biological structures do

involve dynamic interactions between chiral elements.151

For example, peptides are known to be good

synthetic analogs of protein motifs and can exist in disordered or regularly folded structures, such as

random-coil, β-sheet, and α-helix structures, depending on reaction medium, pH, and temperature.152

Incorporating photoresponsive amino acid residues into peptide structures allows for photochemical control

of molecular recognition and organization. Some of the most remarkable examples will be described herein.

Due to the large number of articles on analogous concepts and approaches, we refer to specialized

comprehensive reviews for further details.48,131–133

Woolley and co-workers achieved photocontrol over α-helix folding by introducing two cysteine (Cys)

residues into peptides and cross-linking these with a photoresponsive bridging unit, an iodoacetamide-

modified azobenzene 27 (Figure 1.13a).153

The distance of the cysteine residues at i, i+7 spacing was

designed to match the linker length of the switch in the cis-conformation (Figure 1.13b). As indicated by

CD measurements, the isomerization of the azobenzene switch from the trans-cis configuration increased

helical content from 12% to 48% (Figure 1.13d). Alternative Cys spacing was also investigated in this

study. Peptides with alternative spacing i, i+11 (Figure 1.13c) showed the reverse behavior , with

significant helical content for the trans isomer (66%).154

Figure 1.13. Photo-control of helix content in a short peptide reported by Woolley and co-workers. a)

Photisomerization of iodoacetamide-modified azobenzene linker 27. Primary sequences of the cross-linked

peptides: b) azobenzene reacted via Cys residues spaced i, i+7; c) azobenzene via Cys residues spaced i,

i+11. d) Model showing the increased helicity induced in the peptide upon trans-cis isomerization of the

attached azobenzene cross-linker. Reproduced with permission from Ref. 154.

Moroder and co-workers demonstrated photoresponsive folding and unfolding of triple-helix structures in

collagen model peptides (Figure 1.14). In the initial approach,155

mercaptoproline residues were

incorporated in the sequence and cross-linked with an azobenzene chromophore 28 (Figure 1.14a). Trans-

cis isomerization at ambient temperatures unfolded or distorted the triple-helix structure, and thermal

relaxation induced refolding (Figure 1.14b). Subsequently, a different approach related to Woolley‘s was

used to cross-link the peptide sequence with the azobenzene chromophore. Unfolding in response to

photoinduced isomerization of the triple helix was limited and only observed in the region spanned by the

azobenzene switch.156

Chapter 1

24

Figure 1.14. Schematic illustration of the unfolding/distortion of triple-helix structure upon trans-cis

isomerization of cross-linked azobenzene actuator 28 reported by Moroder and co-workers. Reproduced

with permission from Ref. 155.

Clayden and co-workers reported the conformational photoswitching of a synthetic peptide foldamer 29

bound within a phospholipid bilayer akin to a biological membrane phase (Scheme 1.7).143

The described

photoswitchable helical molecules contain an azobenzene unit, which could be tuned with appropriate

substituents to affect its switching performances and bi-stability. The chromophore is attached to a helical

oligoamide that both promotes membrane insertion and communicates conformational change along its

length. Isomerization of the initial E-form could be achieved selectively and reversibly (λ = 365 nm, E:Z up

to 14:86; λ = 455 nm, E:Z up to 71:29). Light-induced structural changes in the chromophore are translated

into global conformational changes, which propagate over several nanometers within a membrane

environment through helical structures with selectable twisting-sense. Upon sequence of irradiation, the

population distribution of the peptide helixes varied from the initial left-handed helicity (dark), to a large

extent of right-handed form (λ = 365 nm) with up to 66% of the equilibrium population, and back to

original left-handed form (λ = 455 nm).

Scheme 1.7. Conformational photoswitching of a synthetic peptide foldamer 29 bound within a

phospholipid bilayer, as described by Clayden and co-workers. Reproduced with permission from Ref. 143.


25

Feringa, Poloni and co-workers described the use of a first generation molecular motor to control a model

β-hairpin peptide.157

Photoswitchable β-hairpins are also considered for their ability to form hydrogels: they

can be useful in tissue engineering, drug delivery and biosensing.158

Simple β-hairpins, bearing an

azobenzene unit, have been used to modulate viscoelasticity of a peptide hydrogel.158

Notably, the light-

and heat-responsive unit in 30 undergoes a large conformational change between a thermally stable trans-

isomer (stable trans-30) and two thermally bi-stable cis-isomers featuring opposite helicity (metastable cis-

30 and stable cis-30) (Scheme 1.8). This dynamic chiral induction has major influence on the secondary

structure and the aggregation of the peptide, permitting the photo-triggered formation of amyloid-like

fibrils. The β-hairpin sequence used in this design is called trpzip. The trpzips are stable β-hairpins which

fold in a monomeric form without requiring metal binding, due to the stabilization by cross-strand pairs of

indole rings.159

The switching properties of 30 were investigated in methanol and water, using HPLC, CD,

UV-vis and NMR spectroscopy. The irradiation of stable trans-30 to metastable cis-30 afforded

photostationary state of 7:93, respectively. Subsequent thermal isomerization of metastable cis-30 yielded

stable cis-30, was achieved at 40–50 °C within 6 h. Inversion of supramolecular helicity was suggested

upon inversion in CD signal of the band corresponding to interacting indole rings of the β-hairpin. From the

in depth analysis, it was concluded that trans-30 does not seem to adopt any secondary structure and exists

in a monomeric state. Metastable and stable cis-30 both form aggregates, and the decrease in temperature

promotes this process. The aggregation properties were studied by TEM and cryo-TEM, which allowed to

identify in each state more than one type of aggregate (sheet-like structures, vesicles and fibers), which is

the characteristic behavior of peptides adopting a β-hairpin structure. Additionally, some of the aggregate

could be disrupted by irradiation.

Scheme 1.8. Light and heat control over secondary structure of an overcrowded-alkene-modified Trp

zipper 30, as described by Feringa and co-workers. Reproduced with permission from Ref. 157.

1.4 Conclusions

The complex interplay between the fixed chirality and flexible chirality embedded within the components

of (supra)molecular assemblies has given access to a playground full of remarkable nanosystems capable of

displaying controllable dynamic transfer and amplification of chirality. Among the several described

approaches exploited to achieve external control over responsive molecular systems, this chapter focuses on

the use of light as non-invasive input to drive asymmetric responses by photoisomerization of embedded

chiral molecular switches or motors. Most remarkable examples are based on sterically overcrowded

alkenes, azobenzenes and dithienylethenes derivatives that confer helix inversion and motion capabilities to

nanovehicles, liquid crystals, polymers, gelators, catalysts, and biological derivatives. The exponential

increase in examples showing amplification of chirality in covalent and supramolecular systems over the

last decade may eventually lead to an increased understanding of the factors responsible for the delicate

Chapter 1

26

chiral interplay. However, the detailed studies over chirality transfer and amplification in dynamic

photoresponsive systems have also highlighted many critical factors, such as light-induced decomposition,

limited penetration depth and wavelength window of irradiating light, excitation/inhibition of neighboring

chromophores, sub-optimal switching selectivity, and concentration-dependent balance between overall

switching efficiency and asymmetric response. The constant improvement of photochromic switches and

their structurally related switching performances is providing chemists with higher precision triggering and

more robust tools to finally meet the expectations of diverse applications.160

As a matter of fact, predicting

sensible practical applications of responsive molecular systems is far from being easy at the current state of

the art. Based on the overwhelming number of recent reviews on responsive molecular switches and

nanosystems,40,41,54,102

research into wholly synthetic molecular machines appears to have reached a peak

point, which culminated with the Noble Prize for Chemistry awarded in 2016.161

If this point in the rise of

molecular machines162,163

has indeed been reached, then the questions which arise are what next and where

next?164

Looking back at the history of science, applications which find their way into our everyday lives

are a prerequisite for the development of a new field of technology research. With the rise of molecular and

cellular biology during the past half century, biologists have led us to believe that, although living systems

are extremely complicated, there are strong interdependent relationships between small and large molecules

that work in unison to produce, store, and consume energy so that life can be sustained across a wide range

of length scales. For just over a couple of decades, chemists have started to design and synthesize wholly

synthetic molecules capable of performing some of the tasks of their biological counterparts.38

Thus far, the

greatest obstacle of nanomachines has been to overcome Brownian motion,165,166

for which cooperation of

multiple responsive units and chiral amplification towards adaptable supramolecular systems are likely to

be an important strategy. Careful planning ought to be dedicated to the matters of length scales, robustness,

reproducibility and efficiency. It would seem to us that, although there is surely room to go in search of

applications across all length scales, we do need to devote much more time and effort in working out how

to harness and amplify the output of molecular motors operating collectively and efficiently away from

equilibrium167

in robust settings within sustainable surroundings.168,169

Once again, Nature inspires

scientists by providing an excellent example. One of them is the ability of fire ants (Solenopsis Invicta) to

construct bridges, rafts and even temporary shelters using their own bodies as building material, with no

main head in charge and through a continuous reorganization of their structure to maintain stability.170

Much more complex in design and high-aimed target is the treatment of illnesses and dysfunctions, often

regarded as one the long-term goals of nanotechnology when applied to medicine. The importance of this

subject cannot be underestimated. After all, the concept of nanotechnology and nanorobots have in fact

found place in plenty of science fiction book and movies for more than half a century,171

providing bright

ideas for real applied research groups to dream and work on. After giving our personal contribute to this

field, I can safely say that my young colleagues of the Feringa molecular machines research group and

myself cannot wait to see it come true.

1.5 Aim and outline of the thesis

The work described in this thesis explores how of second generation molecular motors/switches can be

tuned, modified and applied in photoswitchable catalysis. The final aim is to develop alternative designs of

switchable catalysts which could display improved thermal stability and more advanced catalytic

performance when compared with previously described systems based on first generation molecular

motors. We envisioned these novel responsive scaffolds to be tailored for applications via multiple modes

of catalytic activity (e.g. metal-catalysis, organocatalysis, activity control, dual stereocontrol) and in wider

range of reaction conditions (e.g. temperature, reaction time). Particular attention was dedicated to the

development of stereoselective catalytic systems, harnessing the distinctive switchable helicity of molecular

motors via dynamic transfer of chirality. Conventional classes of photochromic molecules, such as

azobenzenes, spiropyrans and dithienylethens, are not suited for such applications, as they cannot provide a

strong and reversible enantiomorphous induction upon photoswitching. Moreover, the characteristic

structure of second generation molecular motors was also hypothesized to be a promising candidate for the

http://en.wikipedia.org/wiki/Red_imported_fire_ant

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093451/


27

development of the first trifunctionalized switchable catalyst featuring two orthogonal catalytic sites for

application in light-assisted tandem catalysis. Such systems could ensure high spatio-temporal control of

catalytic functions by means of non-invasive input, improving the catalyst efficiency and reducing the

number of purification steps required in multi-step synthesis. An example of ultimate application of

stereoselective switchable catalysis could the industrial production of polymers with tailored tacticity, on

which their physical and mechanical properties are highly dependent. However, the systems and properties

disclosed in this work hold great promises also for other applications in the wide field of smart materials, in

particular where dynamic control of chirality could provide superior control of chemical functions and

molecular architecture. Important aspects that will hereby be addressed are how certain modifications to the

molecular structure affects the photochemical behavior and thermal stability of metastable species, and

which catalytically active functions are successfully implemented in chiral tunable catalyst based on

overcrowded alkenes.

Chapter 2 describes the synthesis of four chiral overcrowded alkenes and the experimental and

computational study of their photochemical and thermal behavior. Kinetic studies on metastable isomers

using CD spectroscopy and HPLC analysis revealed two pathways at higher temperatures for the thermal

relaxation, namely thermal E–Z isomerization (TEZI) and a thermal helix inversion (THI). Overall, the

alkenes studied showed a remarkable and unprecedented combination of switching properties including

dynamic helicity, reversibility, selectivity, fatigue resistance, and thermal bistability. The switches

described herein have been used as central switchable units for the development of various photoresponsive

catalysts in the following chapters.

Chapter 3 focuses on the development of two bifunctionalized molecular switches featuring a thiourea

substituent as hydrogen-donor moiety in the upper half and a basic dimethylamine group in the lower half.

This combination of functional groups offers the possibility for application of these molecules in

photoswitchable organocatalytic processes. Control of catalytic activity in the Michael addition reaction

between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione is achieved upon irradiation to the metastable

state, providing systems with the potential to be applied as ON/OFF catalytic photoswitches.

Chapter 4 describes the study towards a trifunctionalized molecular photoswitch based on an overcrowded

alkene for light-assisted tandem catalytic processes. We proposed a two-step sequence of Morita–Baylis–

Hillman (MBH) reaction and enamine catalyzed aldol reaction by merging two pairs of orthogonal

bifunctional catalytic groups. Alternative designs aimed to improve the catalytic activity in the MBH

reaction and related attempted syntheses are presented. Lastly, screening of other transformations that could

be mediated by the initially proposed photoswitchable catalysts design is reported.

Chapter 5 presents the synthesis and characterization of a photoresponsive chiral 2,2‘-bisphenol-substituted

molecular switch, exhibiting a dynamic central-helical-axial transfer of chirality. The potential for dynamic

control of axial chirality was demonstrated by its use as switchable catalyst to control the stereochemical

outcome of the enantioselective addition of diethylzinc to aromatic aldehydes, with successful reversal of

enantioselectivity for several substrates.

In Chapter 6 we demonstrate that photoresponsive phosphoramidite ligands based on the chiral light-driven

biaryl-substituted molecular described in Chapter 5 can be used to alter the activity and invert the

stereoselectivity of a copper-catalyzed asymmetric conjugate addition. The derivatives were obtained as a

mixture of diastereoisomers, each displaying a distinctive catalytic activity and opposite stereoselectivity.

The result is an elegant balance of two competing catalysts, of which the complementary catalytic

performance is tunable via internal dynamic transfer of chirality upon alkene photoisomerization.

Chapter 1

28

Chapter 7 describes the study towards the synthesis and application of a photoswitchable chiral phosphoric

acid based on a second generation molecular motor core. Direct derivatization of the 2,2‘-bisphenol-derived

chiral molecular switch described in Chapter 5 provided the target compound. The potential for application

of the chiral phosphoric acid as switchable organocatalyst in asymmetric transformations was investigated.

In order to increase catalytic activity and stereoselectivity, derivatization of the original biphenyl unit

design was attempted.

Chapter 8 describes the study towards the synthesis and application of a photoswitchable chiral

bis(diphenylphosphine)-ligand upon derivatization of the 2,2‘-bisphenol-functionalized chiral molecular

switch described in Chapter 5. We envisioned a large variation of axial chiral induction and steric hindrance

provided around the coordinated metal center upon photochemical isomerization of the responsive ligand.

Several metal-catalyzed aryl phosphination methodologies previously developed for conventional biaryl

scaffolds were attempted during the synthesis of the novel photoswitchable ligand. Experimental evidence

suggests that the highly hindered structure of the designed bidentate ligand may even preclude the proposed

synthetic route at all. An alternative proposal to develop a photoswitchable Brønsted acid catalyst based on

an analogous diphenylphosphine-hydroxyl derivative is presented.


29

1.6 References

(1) Kauffman, G. B.; Myers, R. D. J. Chem. Educ. 1975, 52, 777.

(2) Grossman, R. B. J. Chem. Educ. 1989, 1, 30–33.

(3) Eliel, E. L.; Wilen, S. H. Stereochemistry of organic compounds; Wiley: New York, 1994.

(4) Mislow, K. Introduction to Stereochemistry; Dover Publications: Dover, 2003.

(5) Yamamoto, H.; Carreira, E. M. Comprehensive chirality; Elsevier Science: Oxford, 2012.

(6) Bentley, R. In Encyclopedia of Molecular Cell Biology and Molecular Medicine; Wiley-VCH Verlag

GmbH & Co. KGaA: Weinheim, Germany, 2006.

(7) Gibney, E. Force of nature gave life its asymmetry,

http://www.nature.com/doifinder/10.1038/nature.2014.15995.

(8) Mason, S. Trends Pharmacol. Sci. 1986, 7, 20–23.

(9) Palczewski, K. J. Biol. Chem. 2012, 287, 1612–1619.

(10) Brown, G. H. Photochromism; Wiley-Interscience: New York, 1971.

(11) Durr, H.; Bouass-Laurent, H. Photochromism: Molecules and Systems; Elsevier: Amsterdam, 2003.

(12) Feringa, B. L.; Browne, W. R. Molecular Switches Vol. I, II; Wiley-VCH Verlag GmbH & Co. KGaA:

Weinheim, Germany, 2011.

(13) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789–1816.

(14) Szaciłowski, K. Chem. Rev. 2008, 108, 3481–3548.

(15) Matharu, A. S.; Jeeva, S.; Ramanujam, P. S. Chem. Soc. Rev. 2007, 36, 1868–1880.

(16) Kawata, S.; Kawata, Y. Chem. Rev. 2000, 100, 1777–1788.

(17) Berkovic, G.; Krongauz, V.; Weiss, V. Chem. Rev. 2000, 100, 1741–1754.

(18) Klajn, R. Chem. Soc. Rev. 2014, 43, 148–184.

(19) Wojtyk, J. T. C.; Buncel, E.; Kazmaier, P. M. Chem. Commun. 1998, 16, 1703–1704.

(20) Griffiths, J. Chem. Soc. Rev. 1972, 1, 481–493.

(21) Bandara, H. M. D.; Burdette, S. C. Chem. Soc. Rev. 2012, 41, 1809–1825.

(22) Irie, M. Chem. Rev. 2000, 100, 1685–1716.

(23) Tian, H.; Yang, S. Chem. Soc. Rev. 2004, 33, 85–97.

(24) Eggers, K.; Fyles, T. M.; Montoya-Pelaez, P. J. J. Org. Chem. 2001, 66, 2966–2977.

(25) Cordes, T.; Weinrich, D.; Kempa, S.; Riesselmann, K.; Herre, S.; Hoppmann, C.; Rück-Braun, K.; Zinth,

W. Chem. Phys. Lett. 2006, 428, 167–173.

(26) Steinle, W.; Rück-Braun, K. Org. Lett. 2003, 5, 141–144.

(27) Mallory, F. B.; Mallory, C. W. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA,

1984; pp 1–456.

(28) Cnossen, A.; Kistemaker, J. C. M.; Kojima, T.; Feringa, B. L. J. Org. Chem. 2014, 79, 927–935.

(29) Bauer, J.; Hou, L.; Kistemaker, J. C. M.; Feringa, B. L. J. Org. Chem. 2014, 79, 4446–4455.

(30) Fletcher, S. P.; Dumur, F.; Pollard, M. M.; Feringa, B. L. Science 2005, 310, 80–82.

(31) Koumura, N.; Geertsema, E. M.; van Gelder, M. B.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2002,

124, 5037–5051.

(32) Kistemaker, J. C. M.; Štacko, P.; Roke, D.; Wolters, A. T.; Heideman, G. H.; Chang, M.-C.; van der

Meulen, P.; Visser, J.; Otten, E.; Feringa, B. L. J. Am. Chem. Soc. 2017, 139, 9650–9661.

(33) Lehn, J.-M. Chem. - A Eur. J. 2006, 12, 5910–5915.

(34) Greb, L.; Lehn, J.-M. J. Am. Chem. Soc. 2014, 136, 13114–13117.

(35) Greb, L.; Eichhöfer, A.; Lehn, J.-M. Angew. Chemie Int. Ed. 2015, 54, 14345–14348.

(36) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; Royal Society of Chemistry: Cambridge, 2007.

(37) Erbas-Cakmak, S.; Leigh, D. A.; McTernan, C. T.; Nussbaumer, A. L. Chem. Rev. 2015, 115, 10081–

10206.

(38) Kinbara, K.; Aida, T. Chem. Rev. 2005, 105, 1377–1400.

(39) Browne, W. R.; Feringa, B. L. Nat. Nanotechnol. 2006, 1, 25–35.


10206.

(41) Cheng, C.; Stoddart, J. F. ChemPhysChem 2016, 17, 1780–1793.

(42) Koumura, N.; Zijlstra, R. W.; van Delden, R. A.; Harada, N.; Feringa, B. L. Nature 1999, 401, 152–155.

(43) Schliwa, M.; Woehlke, G. Nature 2003, 422, 759–765.

(44) Molecular Switches; Feringa, B. L., Browne, W. R., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:


(45) Kazaryan, A.; Kistemaker, J. C. M.; Schäfer, L. V; Browne, W. R.; Feringa, B. L.; Filatov, M. J. Phys.

Chem. A 2010, 114, 5058–5067.

(46) Lehn, J.-M. Proc. Natl. Acad. Sci. 2002, 99, 4763–4768.

(47) Göstl, R.; Senf, A.; Hecht, S. Chem. Soc. Rev. 2014, 43, 1982–1996.

(48) Szymański, W.; Beierle, J. M.; Kistemaker, H. A. V.; Velema, W. A.; Feringa, B. L. Chem. Rev. 2013,

Chapter 1

30

113, 6114–6178.

(49) Dai, Z.; Lee, J.; Zhang, W. Molecules 2012, 17, 1247–1277.

(50) Bloom, K.; Joglekar, A. Nature 2010, 463, 446–456.

(51) Berg, J.; Tymoczko, J.; Stryer, L. In Biochemistry. 5th edition, Section 34.3; W H Freeman: New York,

2002.

(52) Lodish, H.; Berk, A.; Zipursky, S. L.; Matsudaira, P.; Baltimore, D.; Darnell, J. In Molecular Cell

Biology. 4th edition, Section 18.3; W. H. Freeman: New York, 2000.

(53) Balzani, V.; Credi, A.; Venturi, M. Molecular Devices and Machines– A Journey into the Nano World;

Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, FRG, 2003.

(54) Kassem, S.; van Leeuwen, T.; Lubbe, A. S.; Wilson, M. R.; Feringa, B. L.; Leigh, D. A. Chem. Soc. Rev.

2017, 46, 2592–2621.

(55) Shirai, Y.; Morin, J.-F.; Sasaki, T.; Guerrero, J. M.; Tour, J. M. Chem. Soc. Rev. 2006, 35, 1043–1055.

(56) Shirai, Y.; Osgood, A. J.; Zhao, Y.; Kelly, K. F.; Tour, J. M. Nano Lett. 2005, 5, 2330–2334.

(57) Vives, G.; Kang, J.; Kelly, K. F.; Tour, J. M. Org. Lett. 2009, 11, 5602–5605.

(58) Villag mez, C. J.; Sasaki, T.; Tour, J. M.; Grill, L. J. Am. Chem. Soc. 2010, 132, 16848–16854.

(59) Morin, J.-F.; Shirai, Y.; Tour, J. M. Org. Lett. 2006, 8, 1713–1716.

(60) Saywell, A.; Bakker, A.; Mielke, J.; Kumagai, T.; Wolf, M.; García-López, V.; Chiang, P.-T.; Tour, J. M.;

Grill, L. ACS Nano 2016, 10, 10945–10952.

(61) Kudernac, T.; Ruangsupapichat, N.; Parschau, M.; Maciá, B.; Katsonis, N.; Harutyunyan, S. R.; Ernst, K.-

H.; Feringa, B. L. Nature 2011, 479, 208–211.

(62) Štacko, P. PhD thesis, Control of Translational and Rotational Movement at Nanoscale, Groningen, 2017.

(63) Heideman, H. unpublished results, University of Groningen.

(64) Chen, K.-Y.; Ivashenko, O.; Carroll, G. T.; Robertus, J.; Kistemaker, J. C. M.; London, G.; Browne, W.

R.; Rudolf, P.; Feringa, B. L. J. Am. Chem. Soc. 2014, 136, 3219–3224.

(65) Maeda, N.; Hirose, T.; Yokoyama, S.; Matsuda, K. J. Phys. Chem. C 2016, 120, 9317–9325.

(66) Ichimura, K. Science, 2000, 288, 1624–1626.

(67) Feringa, B. L.; van Delden, R. A. Angew. Chemie Int. Ed. 1999, 38, 3418–3438.

(68) Schulz, G. E.; Schirmer, R. H. Principles of Protein Structure; Springer: New York, 1979.

(69) Saenger, W. Principles of Nucleic Acid Structure; Springer: New York, 1984.

(70) Tu, Y.; Peng, F.; Adawy, A.; Men, Y.; Abdelmohsen, L. K. E. A.; Wilson, D. A. Chem. Rev. 2016, 116,

2023–2078.

(71) Yan, Q.; Luo, Z.; Cai, K.; Ma, Y.; Zhao, D. Chem. Soc. Rev. 2014, 43, 4199–4221.

(72) Green, M. M.; Reidy, M. P.; Johnson, R. D.; Darling, G.; O‘Leary, D. J.; Willson, G. J. Am. Chem. Soc.

1989, 111, 6452–6454.

(73) Prins, L. J.; Timmerman, P.; Reinhoudt, D. N. J. Am. Chem. Soc. 2001, 123, 10153–10163.

(74) Huck, N. P. M.; Jager, W. F.; de Lange, B.; Feringa, B. L. Science, 1996, 273, 1686–1688.

(75) Palmans, A. R. A.; Meijer, E. W. Angew. Chemie Int. Ed. 2007, 46, 8948–8968.

(76) Eelkema, R.; Pollard, M. M.; Vicario, J.; Katsonis, N.; Ramon, B. S.; Bastiaansen, C. W. M.; Broer, D. J.;

Feringa, B. L. Nature 2006, 440, 163.

(77) Bosco, A.; Jongejan, M. G. M.; Eelkema, R.; Katsonis, N.; Lacaze, E.; Ferrarini, A.; Feringa, B. L. J. Am.

Chem. Soc. 2008, 130, 14615–14624.

(78) Chen, C.-T.; Chen, C.-H.; Ong, T.-G. J. Am. Chem. Soc. 2013, 135, 5294–5297.

(79) Delden, R. A. van; Mecca, T.; Rosini, C.; Feringa, B. L. Chem. Eur. J. 2004, 10, 61–70.

(80) Pieraccini, S.; Gottarelli, G.; Labruto, R.; Masiero, S.; Pandoli, O.; Spada, G. P. Chem. Eur. J. 2004, 10,

5632–5639.

(81) Mathews, M.; Zola, R. S.; Hurley, S.; Yang, D.-K.; White, T. J.; Bunning, T. J.; Li, Q. J. Am. Chem. Soc.

2010, 132, 18361–18366.

(82) Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013–4038.

(83) Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. Chem. Rev. 2001, 101,

4039–4070.

(84) Green, M. M.; Jha, S. K. Chirality 1997, 9, 424–427.

(85) Teramoto, A. Prog. Polym. Sci. 2001, 26, 667–720.

(86) Takei, F.; Yanai, K.; Onitsuka, K.; Takahashi, S. Chem. Eur. J. 2000, 6, 983–993.

(87) Yashima, E.; Maeda, K.; Nishimura, T. Chem. Eur. J. 2004, 10, 42–51.

(88) Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3–12.

(89) Pijper, D.; Feringa, B. L. Soft Matter 2008, 4, 1349–1372.

(90) Bisoyi, H. K.; Li, Q. Angew. Chemie Int. Ed. 2016, 55, 2994–3010.

(91) Feringa, B. L.; Browne, W. R. In Molecular Switches; Wiley-VCH Verlag GmbH & Co. KGaA:

Weinheim, Germany, 2011; pp 101–106.

(92) Maxein, G.; Zentel, R. Macromolecules 1995, 28, 8438–8440.


31

(93) Maxein, G.; Mayer, S.; Müller, M.; Zentel, R. Am. Chem. Soc. Polym. Prepr. Div. Polym. Chem. 1996,

37, 460–461.

(94) Okamoto, Y.; Matsuda, M.; Nakano, T.; Yashima, E. Polym. J. 1993, 25, 391–396.

(95) Pijper, D.; Feringa, B. L. Angew. Chemie Int. Ed. 2007, 46, 3693–3696.

(96) Pijper, D.; Jongejan, M. G. M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2008, 130, 4541–4552.

(97) van Leeuwen, T.; Heideman, G. H.; Zhao, D.; Wezenberg, S. J.; Feringa, B. L. Chem. Commun. 2017, 53,

6393–6396.

(98) Iamsaard, S.; Aßhoff, S. J.; Matt, B.; Kudernac, T.; Cornelissen, J. J. L. M.; Fletcher, S. P.; Katsonis, N.

Nat. Chem. 2014, 6, 229–235.

(99) Li, Q.; Fuks, G.; Moulin, E.; Maaloum, M.; Rawiso, M.; Kulic, I.; Foy, J. T.; Giuseppone, N. Nat.

Nanotechnol. 2015, 10, 161–165.

(100) Foy, J. T.; Li, Q.; Goujon, A.; Colard-Itté, J.-R.; Fuks, G.; Moulin, E.; Schiffmann, O.; Dattler, D.;

Funeriu, D. P.; Giuseppone, N. Nat. Nanotechnol. 2017, 12, 540–545.

(101) Williams, G. J.; Domann, S.; Nelson, A.; Berry, A. Proc. Natl. Acad. Sci. 2003, 100, 3143–3148.

(102) Blanco, V.; Leigh, D. A.; Marcos, V. Chem. Soc. Rev. 2015, 44, 5341–5370.

(103) Vlatković, M.; Collins, B. S. L.; Feringa, B. L. Chem. Eur. J. 2016, 22, 17080–17111.

(104) Würthner, F.; Rebek, J. Angew. Chem. Int. Ed. 1995, 34, 446–448.

(105) Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. J. Am. Chem. Soc. 2003, 125, 2224–2227.

(106) Imahori, T.; Yamaguchi, R.; Kurihara, S. Chem. Eur. J. 2012, 18, 10802–10807.

(107) Berryman, O. B.; Sather, A. C.; Lledó, A.; Rebek, J. Angew. Chem. Int. Ed. 2011, 50, 9400–9403.

(108) Ueno, A.; Takahashi, K.; Osa, T. J. Chem. Soc. Chem. Commun. 1980, No. 17, 837–838.

(109) Peters, M. V; Stoll, R. S.; Kühn, A.; Hecht, S. Angew. Chem. Int. Ed. 2008, 47, 5968–5972.

(110) Osorio-Planes, L.; Rodríguez-Escrich, C.; Pericàs, M. A. Org. Lett. 2014, 16, 1704–1707.

(111) Balof, S. L.; P‘Pool, S. J.; Berger, N. J.; Valente, E. J.; Shiller, A. M.; Schanz, H.-J. Dalt. Trans. 2008,

No. 42, 5791.

(112) Blanco, V.; Carlone, A.; Hänni, K. D.; Leigh, D. A.; Lewandowski, B. Angew. Chem. Int. Ed. 2012, 51,

5166–5169.

(113) Beswick, J.; Blanco, V.; De Bo, G.; Leigh, D. A.; Lewandowska, U.; Lewandowski, B.; Mishiro, K.

Chem. Sci. 2015, 6, 140–143.

(114) Neilson, B. M.; Bielawski, C. W. J. Am. Chem. Soc. 2012, 134, 12693–126939.

(115) Neilson, B. M.; Bielawski, C. W. Organometallics 2013, 32, 3121–3128.

(116) Sud, D.; Norsten, T. B.; Branda, N. R. Angew. Chemie - Int. Ed. 2005, 44, 2019–2021.

(117) Wang, J.; Feringa, B. L. Science 2011, 331, 1429–1432.

(118) Vlatković, M.; Bernardi, L.; Otten, E.; Feringa, B. L. Chem. Commun. 2014, 50, 7773–7775.

(119) Zhao, D.; Neubauer, T. M.; Feringa, B. L. Nat. Commun. 2015, 6, 6652.

(120) Chen, C.-T.; Tsai, C.-C.; Tsou, P.-K.; Huang, G.-T.; Yu, C.-H. Chem. Sci. 2017, 8, 524–529.

(121) Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry; Freeman, W. H., Ed.; New York, 2002.

(122) Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1978, 11, 8–14.

(123) Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 3313–3362.

(124) Islam, M. R.; Mahdi, J. G.; Bowen, I. D. Drug Saf. 1997, 17, 149–165.

(125) Muraoka, T.; Kinbara, K.; Aida, T. Nature 2006, 440, 512–515.

(126) Muraoka, T.; Kinbara, K.; Kobayashi, Y.; Aida, T. J. Am. Chem. Soc. 2003, 125, 5612–5613.

(127) Vlatkovic, M.; Feringa, B. L.; Wezenberg, S. J. Angew. Chemie - Int. Ed. 2016, 55, 1001–1004.

(128) Lehn, J.-M.; Rigault, A. Angew. Chemie Int. Ed. English 1988, 27, 1095–1097.

(129) Stadler, A.-M.; Burg, C.; Ramírez, J.; Lehn, J.-M. Chem. Commun. 2013, 49, 5733.

(130) Zhao, D.; van Leeuwen, T.; Cheng, J.; Feringa, B. L. Nat. Chem. 2017, 9, 250-256.

(131) Willner, I.; Rubin, S. Angew. Chemie Int. Ed. English 1996, 35, 367–385.

(132) Beharry, A. A.; Woolley, G. A. Chem. Soc. Rev. 2011, 40, 4422–4437.

(133) Lubbe, A. S.; Szymanski, W.; Feringa, B. L. Chem. Soc. Rev. 2017, 46, 1052–1079.

(134) Gorostiza, P.; Isacoff, E. Y. Science, 2008, 322, 395–399.

(135) Fehrentz, T.; Schönberger, M.; Trauner, D. Angew. Chemie Int. Ed. 2011, 50, 12156–12182.

(136) Deiters, A. ChemBioChem 2009, 11, 47–53.

(137) Velema, W. A.; Szymanski, W.; Feringa, B. L. J. Am. Chem. Soc. 2014, 136, 2178–2191.

(138) Mayer, G.; Heckel, A. Angew. Chemie Int. Ed. 2006, 45, 4900–4921.

(139) Kamiya, Y.; Asanuma, H. Acc. Chem. Res. 2014, 47, 1663–1672.

(140) Dohno, C.; Uno, S.; Nakatani, K. J. Am. Chem. Soc. 2007, 129, 11898–11899.

(141) Feliciano, M.; Vytla, D.; Medeiros, K. A.; Chambers, J. J. Bioorg. Med. Chem. 2010, 18, 7731–7738.

(142) Blanco-Lomas, M.; Samanta, S.; Campos, P. J.; Woolley, G. A.; Sampedro, D. J. Am. Chem. Soc. 2012,

134, 6960–6963.

(143) De Poli, M.; Zawodny, W.; Quinonero, O.; Lorch, M.; Webb, S. J.; Clayden, J. Science, 2016, 352, 575–

Chapter 1

32

580.

(144) Gorostiza, P.; Volgraf, M.; Numano, R.; Szobota, S.; Trauner, D.; Isacoff, E. Y. Proc. Natl. Acad. Sci.

2007, 104, 10865–10870.

(145) Schierling, B.; Noel, A.-J.; Wende, W.; Hien, L. T.; Volkov, E.; Kubareva, E.; Oretskaya, T.; Kokkinidis,

M.; Rompp, A.; Spengler, B.; Pingoud, A. Proc. Natl. Acad. Sci. 2010, 107, 1361–1366.

(146) Ud-Dean, S. M. M. Interdiscip. Sci. Comput. Life Sci. 2011, 3, 79–90.

(147) Tian, T.; Song, Y.; Wang, J.; Fu, B.; He, Z.; Xu, X.; Li, A.; Zhou, X.; Wang, S.; Zhou, X. J. Am. Chem.

Soc. 2016, 138, 955–961.

(148) Chandramouli, B.; Di Maio, D.; Mancini, G.; Brancato, G. Biochim. Biophys. Acta - Biomembr. 2016,

1858, 689–697.

(149) Shimoboji, T.; Ding, Z. L.; Stayton, P. S.; Hoffman, A. S. Bioconjug. Chem. 2002, 13, 915–919.

(150) Mogaki, R.; Okuro, K.; Aida, T. J. Am. Chem. Soc. 2017, 139, 10072–10078.

(151) Lv, Z.; Chen, Z.; Shao, K.; Qing, G.; Sun, T. Polymers, 2016, 8, 310.

(152) Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, 5th ed.; Freeman, W. H., Ed.; New York, 2002.

(153) Kumita, J. R.; Smart, O. S.; Woolley, G. A. Proc. Natl. Acad. Sci. 2000, 97, 3803–3808.

(154) Flint, D. G.; Kumita, J. R.; Smart, O. S.; Woolley, G. A. Chem. Biol. 2002, 9, 391–397.

(155) Kusebauch, U.; Cadamuro, S. A.; Musiol, H.-J.; Lenz, M. O.; Wachtveitl, J.; Moroder, L.; Renner, C.

Angew. Chemie Int. Ed. 2006, 45, 7015–7018.

(156) Kusebauch, U.; Cadamuro, S. A.; Musiol, H.-J.; Moroder, L.; Renner, C. Chem. - A Eur. J. 2007, 13,

2966–2973.

(157) Poloni, C.; Stuart, M. C. A.; van der Meulen, P.; Szymanski, W.; Feringa, B. L. Chem. Sci. 2015, 6,

7311–7318.

(158) Doran, T. M.; Ryan, D. M.; Nilsson, B. L. Polym. Chem. 2014, 5, 241–248.

(159) Cochran, A. G.; Skelton, N. J.; Starovasnik, M. A. Proc. Natl. Acad. Sci. 2001, 98, 5578–5583.

(160) Coskun, A.; Banaszak, M.; Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A. Chem. Soc. Rev. 2012, 41,

19–30.

(161) Press Release: The Nobel Prize in Chemistry 2016,

https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2016/press.html.

(162) Abendroth, J. M.; Bushuyev, O. S.; Weiss, P. S.; Barrett, C. J. ACS Nano 2015, 9, 7746–7768.

(163) Kay, E. R.; Leigh, D. A. Angew. Chemie Int. Ed. 2015, 54, 10080–10088.

(164) Peplow, M. Nature 2015, 525, 18–21.

(165) Astumian, R. D. Science, 1997, 276, 917–922.

(166) Astumian, R. D. Phys. Chem. Chem. Phys. 2007, 9, 5067–5083.

(167) Cheng, C.; McGonigal, P. R.; Stoddart, J. F.; Astumian, R. D. ACS Nano 2015, 9, 8672–8688.

(168) Deng, H.; Olson, M. A.; Stoddart, J. F.; Yaghi, O. M. Nat. Chem. 2010, 2, 439–443.

(169) Mattia, E.; Otto, S. Nat. Nanotechnol. 2015, 10, 111–119.

(170) Watch Fire Ants Use Their Bodies To Form Living Architecture | Science | Smithsonian

http://www.smithsonianmag.com/science-nature/watch-fire-ants-use-their-bodies-to-form-living-

architecture-180947854/.

(171) Nanotechnology in fiction https://en.wikipedia.org/wiki/Nanotechnology_in_fiction.

Chapter 2

Spectroscopic and Theoretical Identification of Two

Thermal Isomerization Pathways for Bistable Chiral

Overcrowded Alkenes

This chapter presents the synthesis of four chiral overcrowded alkenes 1-4 and the experimental and

computational study of their photochemical and thermal behavior . By irradiation with UV light,

metastable diastereoisomers with opposite helicity were generated through high yielding E-Z

isomerizations. Kinetic studies on the metastable isomers using CD spectroscopy and HPLC analysis

revealed two pathways at higher temperatures for the thermal isomerization, namely a thermal E-Z

isomerization (TEZI) and a thermal helix inversion (THI). In order to demonstrate that these overcrowded

alkenes can be employed as bistable switches, photochromic cycling was performed, which showed that

these molecular switches display good selectivity and fatigue resistance over multiple irradiation cycles.

The alkenes studied hereto showed a remarkable and unprecedented combination of switching properties

including dynamic helicity, reversibility, selectivity, fatigue resistance and thermal stability.

This chapter has been published as part of: S. F. Pizzolato,‡ J. C. M. Kistemaker,

‡ T. van Leeuwen, Dr. T.

C. Pijper, Prof. Dr. B. L. Feringa,* Chem. Eur. J. 2016, 23, 13478–13487. ‡ Equally contributing authors.

The computational studies here reported were performed by J. C. M. K. and T. C. P. For more details, see

also: J. C. M. Kistemaker, PhD thesis, University of Groningen.

Chapter 2

34

2.1 Introduction

2.1.1 Photo- and thermally-responsive molecular switches

Responsive materials1–3

and dynamic molecular systems4–10

that change structure and functions as a result

of an external input signal are attracting major current attention with the prospect of smart materials11–17

and nanoscale devices.18–22

Photochemical switches allow for non-invasive control, reversibility and high

spatio-temporal precision.5 Overcrowded alkenes have been used in a wide variety of responsive nanoscale

systems, being it in a molecular car powered by four unidirectional molecular motors or as multi-state

switches featuring dynamic functions of which up to four distinct configurations can be addressed.23–25

The

large number of structural modifications that has been presented by our group and others has expanded the

field of molecular design with three generations of photoswitchable overcrowded alkenes, the majority of

which exhibits a strong directional preference and functions as rotary motors.7,26–32

Through

desymmetrization of our systems, the unidirectionality of the rotary motion has been extensively

demonstrated and various stereoisomers identified by spectroscopic and chromatographic techniques for

each variation in design.33–44

A key aspect of these systems is that the photochemical generation of

metastable species is followed by thermally induced isomerizations, for which the life-times have been

tuned through structural changes to range from nanoseconds to years.34,38,44,45

Hence, overcrowded alkenes

can be defined as either motors or switches depending on the activation energy and therefore speed of the

thermal isomerization step (i.e. when the rotation rate is the limiting step). Their propensity to undergo

continuous light- and thermal-induced directional rotary motion (motor behavior ), however, diminishes

their usefulness as switches in applications where thermal stability is desired, e.g. in the field of

photoswitchable catalysis.24,46,47

As such, there is a demand for thermally highly stable alkenes that can be

switched photochemically and reversibly between distinct geometrical chiral forms.

2.1.2 Second generation molecular motors

Molecular motors of the second generation consist of a symmetric ‗lower‘ half (for R=H) and an

asymmetric ‗upper‘ half that feature a single stereocenter (Scheme 2.1).30,48

Scheme 2.1. General scheme of photochemical E-Z isomerization and thermal helix inversion of second

generation molecular motors.

Upon irradiation with UV light they can undergo a photochemical E-Z isomerization, a process that results

in a metastable (MS) diastereoisomer which is of the opposite helicity. In this process, the methyl

substituent on the stereogenic center has changed from an unhindered outward facing axial orientation to an

equatorial orientation in which the methyl faces the lower half, thus creating steric hindrance. This steric

strain causes the MS diastereoisomer to be higher in energy with respect to the original configuration. The

strain can subsequently be reduced by a thermally activated isomerization in which (usually) the upper half

moves around the lower half, again resulting in an inversion of the helicity. In the resulting stable isomer,

the upper half has undergone a 180° rotation with respect to the lower half (see Scheme 2.1, in case R = H,

the symmetry in the lower half causes the initial and final states to be chemically identical). In theory, it is

possible that the thermal isomerization of the metastable state follows an alternative and competing

Spectroscopic and Theoretical Identification of Two Thermal Isomerization Pathways for Bistable Chiral

Overcrowded Alkenes

35

pathway other than thermal helix inversion (THI). Structurally similar stilbene switches are able to undergo

thermal E-Z isomerization (TEZI) from cis to trans, although the activation energy for this process usually

exceeds 150 kJ·mol−1

.49,50

For some overcrowded alkenes though, this barrier has been observed to be

significantly lower due to the steric strain in the minimum energy configurations, thus forcing the double

bond far from planarity. As an example, bis-fluorenylidenes exhibit activation energies for the TEZI of

~105 kJ·mol−1

.51,52

For second generation motors, in order to positively identify the outcome of the thermal

isomerization of the photochemically generated metastable state the lower half has to be desymmetrized.

The two-step process starting from the stable-(Z) state will then lead either to the opposite isomer stable-(E)

of the initial configuration, which is indicative of a THI, or back to the initial stable isomer stable-(Z), thus

indicating a reversible switching process by a TEZI (Scheme 2.2).

Scheme 2.2. General scheme for photochemical and thermal behavior (TEZI vs. THI) of desymmetrized

overcrowded alkenes stable-(Z) and metastable-(E).

Herein, we report on the switching behavior of four second-generation overcrowded alkenes, namely 1–4

(Scheme 2.3). Their photochemical and thermal isomerization processes have been studied by various

analytical methods, while the thermal isomerization processes are also studied by computational methods.

We will show that the MS isomers of 1–4 are able to undergo thermal isomerization through both the THI

and TEZI pathways. Finally, we will demonstrate that 1–4 exhibit properties that make them highly useful

bistable switches, such as high selectivity, low switching fatigue, and high thermal stability.

2.2 Results and discussion

2.2.1 Design

As mentioned above, the bridging units (X and Y, see Scheme 2.1) included in the rings connected by the

tetrasubstituted alkene play an important role in the structure‘s flexibility, thermal stability and switching

properties. Previous studies on overcrowded alkenes with symmetrical lower halves have shown the effect

of the size of the rings connected to the bridging alkene bond on the activation barrier of the thermal

relaxation step.48

In particular, the combination of a 5-membered ring in the lower half (fluorene) with a

sulfur or oxygen containing 6-membered ring in the upper half (Scheme 2.1, benzo[f]thiochromene (X=S,

Y=−) and benzo[f]chromene (X=O, Y=−), respectively) resulted in distinctive high energy activation

barriers for the thermal relaxation step and consequently long half-lives of the metastable species (Δ‡G° =

109 kJ·mol−1

, t½ at rt = 35 d (X=S) and Δ‡G° = 106 kJ·mol

−1, t½ at rt = 9.4 d (X=O), respectively). Due to

the lack of asymmetry in the lower half, the two aforementioned competing thermal pathways, i.e. THI and

Chapter 2

36

TEZI, could not be distinguished, as they would give access to the two undistinguishable products.

Therefore, we decided to extend our investigation by synthesizing four overcrowded alkenes of the second

generation with an asymmetric substitution pattern in the lower half (1–4, see Scheme 2.3), expecting these

systems to display thermal bi-stability.

2.2.2 Synthesis

Overcrowded alkenes 1-4 were synthesized according to the established methodology previously reported

for second generation molecular motors. The Barton-Kellogg coupling represents a critical synthetic step

(Scheme 2.3), in which a combination of highly reactive diazo species and thioketones are joined to create a

highly hindered tetrasubstituted alkene moiety through a cascade of exothermic reactions.

Hydrazone 8 was synthesized from commercially available 2,5-dimethylbenzenethiol in four steps with a

54% overall yield (Scheme 2.5). Compounds 9–11 with a naphthyl moiety were prepared following

modified literature procedures (Scheme 2.3).58,59

A distinct synthetic scheme for each overcrowded alkene

is reported (Schemes 2.5-2.8). A Barton-Kellogg coupling of thioketone 12 (Scheme 2.4) and the diazo

species, obtained by the in situ oxidation of the corresponding hydrazones 8–10 with

[bis(trifluoroacetoxy)iodo]-benzene (BTI), afforded mixtures of isomers of episulfides with varying E/Z

ratios. The mixtures were separated by flash column chromatography and subsequently desulfurized in

order to obtain the corresponding overcrowded alkenes. A Barton-Kellogg coupling of the diazo species 13

(Scheme 2.4) and the thioketone, obtained by thiation of the corresponding ketone 11, provided a mixture

of alkenes and episulfides which were directly desulfurized, yielding the desired overcrowded alkenes. The

E/Z isomers were separated by column chromatography and assigned by the difference in chemical shift of

the absorptions corresponding to the methoxy substituent and the protons in position 1 or 8 at the lower half

in the 1H NMR spectra (for example: stable-(Z)-1 3.42 ppm (CH3O-), stable-(E)-1 3.93 ppm (CH3O-); for

full details see Experimental section ―Characterization, irradiation experiments and Eyring analysis‖). The

enantiomers of 1–4 were separated by preparative chiral HPLC (Figure 2.2.1, Figure 2.2 and Experimental

section for full details).

Scheme 2.3. Condensed synthetic pathways towards overcrowded alkenes 1-4 via Barton-Kellogg coupling

as critical synthetic step.


Overcrowded Alkenes

37

Scheme 2.4. Synthesis of lower halves 12 and 13.

Scheme 2.5. Synthesis of molecular switch 1.

Chapter 2

38




Overcrowded Alkenes

39

Scheme 2.8. Synthesis of molecular switch 4, performed by T. van Leeuwen.

2.2.3 Photochemical and thermal isomerizations

Single enantiomers of each overcrowded alkene were subjected to circular dichroism (CD) spectroscopy in

order to assign absolute stereochemistry as well as to perform a qualitative analysis. The isolated

enantiomers of compounds 1–4 displayed strong Cotton effects in the area of ~250–320 nm and slightly

smaller Cotton effects of opposite sign at higher wavelengths (>320 nm) with the exception of compound 3

which lacked such a longer wavelength absorption band (Figure 2.1). The presence of such strong Cotton

effects around 400 nm is indicative of the helical shape of these overcrowded alkenes, while the lack of this

band for compound 3 could be due to the absence of a heteroatom in its core structure (which is present in

the other compounds).

In order to assign absolute stereochemistry, experimentally obtained CD spectra were compared to the

calculated CD spectra. Potential energy surfaces of 1–4 were investigated with the semi-empirical PM3

method and the geometries of the resulting minima and transition states were refined using DFT (B3LYP/6-

31G(d,p) (vide infra). Time-dependent (TD) DFT with the B3LYP functional and a 6-31+G(d,p) basis set

provided theoretical CD spectra of 1–4 and allowed for the assignment of the absolute stereochemistries of

1–4 (Figure 2.1). Due to the existence of multiple conformations (e.g. of the methoxy group) and the

uncertainty in the calculated Boltzmann distribution used to proportionate the spectra of the individual

conformations, the calculated spectra were not expected to display a complete match with the experimental

data. However, the match is sufficient to allow for the discrimination between the two possible enantiomers

and is therefore suitable for the assignment of the absolute stereochemistry of 1–4.31,40,55,60

Chapter 2

40

Figure 2.1. CD spectra of 1–4. Solid lines (──): experimental CD spectra of (Z,P,S)-1, (Z,P,S)-2, (Z,P,R)-

3, and (Z,M,R)-4 (heptane, 1.0·10−5

M). Dash and dotted lines (─ ▪ ─): theoretical ECD spectra calculated

with TD-DFT, normalized and shifted by 30 nm (B3LYP/6-31+G(d,p) applying Gaussian shapes (line

width = 0.3 eV) to 30 discrete transitions) used to assign enantiomers. Dashed lines (- - -): CD spectra of

PSS mixtures of 1 (312 nm), 2 (365 nm), 3 (312 nm), and 4 (365 nm). Irradiation conditions: the PSS

mixtures were obtained starting from the above mentioned solutions of stable Z-isomers (heptane, 1.0·10−5

M) after irradiation (indicated wavelength) at rt over 2 min.

The chiral descriptors for each species described in this work (e.g. (Z,P,S)-1, Figure 2.1) indicate

respectively: the configurational isomer of the tetrasubstituted alkene (E or Z), the configurational helicity

of the molecule (P or M), and the absolute stereochemistry of the stereogenic center (R or S).

The correlation between the Cotton effect and the helicity agrees with the results of Cnossen et al. in which

the same correlation was observed for four different overcrowded alkenes.55

Compounds with a positive

helicity display a negative Cotton effect for the longest wavelength absorption band and vice versa, with the

exception of 3 as this species lacks a strong CD absorption band in the 350–450 nm region (vide supra).

UV irradiation of solutions in heptane (312 or 365 nm, see Figure 2.1 for details) of each of the Z isomers

of 1–4 resulted in the inversion of the major bands in their CD spectra. This is indicative of an inversion in

helicity and shows that the photochemical Z-E isomerization of the stable-(Z)-1–4 to the metastable-(E)-1–4

has taken place. The presence of the metastable-(E) isomers was further confirmed by chiral HPLC analysis

(Figure 2.2) and 1H NMR spectroscopy (illustrated for 1 in Figure 2.3, see Experimental section for further

details).


Overcrowded Alkenes

41

Figure 2.2. Chiral HPLC traces of 1–4. Top: HPLC traces (heptane/2-propanol) of pure enantiomers

separated by preparative chiral HPLC (structures of stable-Z isomers depicted in Figure 2.1) as assigned by

CD absorption spectroscopy: (Z,P,S)-1 (Chiralcel OD-H, 98:2), (Z,P,S)-2 (Chiralpak AD-H, 97:3), (Z,P,R)-

3 (Chiralcel OD-H, 98:2), and (Z,M,R)-4 (Chiralcel OD, 99.3:0.7). Middle: HPLC traces of the PSS

mixtures of 1–4 (identical conditions). Bottom: HPLC traces after subsequent thermal isomerization of 1–4

(identical conditions). For irradiation and thermal isomerization conditions, see Figure 2.1 and Figure 2.4.

The ratio between the E and Z isomers at the photostationary state (PSS) in heptane solution was

determined by chiral HPLC analysis (E:Z ratio: (S)-1 95:5, (S)-2 96:4, (R)-3 97:3, and (R)-4 99:1), showing

an almost quantitative photoswitching process towards the metastable diastereoisomer for all four

compounds, with remarkably high ratios for this class of overcrowded alkene based switches.

Chapter 2

42

Figure 2.3. 1H NMR spectra of the switching process of 1. a):

1H NMR spectra of stable-(Z)-1 (~3 mg in

CDCl3, 0.8 mL); b): 1H NMR spectra after irradiation of stable-(Z)-1 (312 nm) to the metastable state

affording a PSS mixture in CDCl3 of stable-(Z)-1 : metastable-(E)-1 = 16 : 84 (note: PSS ratios are known

to be affected by nature of solvent, vide supra).

Heating the irradiated samples allowed them to undergo thermal isomerization (for conditions, see Figure

2.4), which resulted in major changes in their CD spectra. HPLC chromatograms of the resulting samples

showed a partial reversal of the metastable-(E) isomer to the initial, stable-(Z) isomer which is observed

together with the appearance of a new peak attributed to the stable-(E) isomer (Figure 2.2). These results

signify: i) that the photochemical Z to E isomerization results in the formation of a highly stable

diastereoisomer that is able to relax measurably only at high temperatures, and ii) that relaxation can take

place via two competing pathways, one leading to the initial isomer through TEZI and the other leading to

the corresponding E isomer through THI (Scheme 2.2).

In order to investigate the kinetic behavior of the two thermal isomerization pathways, samples of alkenes

1–4 were irradiated to PSS at room temperature after which their thermal relaxation was followed over

time. For alkenes 3 and 4, thermal relaxation was followed in real-time using CD spectroscopy at the

specific wavelength (381 nm and 395 nm, respectively) which showed the largest difference between the

initial stable-(Z) isomer and the PSS mixture (Figure 2.4). However, for alkenes 1 and 2 this setup was not

suitable as the thermal relaxation of these alkenes, in order to become observable, required temperatures

that are above the temperature range of the temperature controller of the CD spectrophotometer employed.

Instead, solutions of (Z,P,S)-1 and (Z,P,S)-2 in hexanol and dodecane, respectively, were irradiated to PSS

and placed in a temperature controlled oil bath. Aliquots were then taken regularly and analyzed by chiral

HPLC.


Overcrowded Alkenes

43

Figure 2.4. Decay curves (top/left axes) and Eyring plots (bottom/right axes) of metastable 1–4. Decay

curves of: (E,M,S)-1 recorded by HPLC taking aliquots from a hexanol solution (131–152 °C); (E,M,S)-2

recorded by HPLC taking aliquots from a dodecane solution (112–132 °C); (E,M,R)-3 recorded by CD in

dodecane (95–105 °C); (E,P,R)-4 recorded by CD in dodecane (84–105 °C). Least squares analysis on the

original Eyring equation for 1–4 with error bars of 3σ. (heptane, 1.0·10−5

M). Thermal decay conditions:

the PSS mixtures (hexanol or dodecane, 1.0·10−5

M) were heated at fixed temperatures starting from the

above mentioned solutions (black curves) after irradiation with UV light (indicated wavelength) at rt over 2

min under stirring.

A least squares analysis of the HPLC integrals of the major diastereoisomers of 1 and 2 versus time and the

change in CD absorption for 3 and 4 versus time provided the reaction rates (ktotal) for the thermal

isomerization process at various temperatures. The thermal isomerization process of these metastable

species corresponds to a unimolecular process with two decay paths and a kinetic analysis as a parallel 1st

order reactions system can be performed according to what previously described by Forst.61

The general

scheme for two parallel unimolecular reactions is as follows:

( 1 )

Starting from a common reagent species A, two distinct product species B and C are obtained with different

ratios and rates. The rate law for two parallel unimolecular reactions is described by the following equation:

Chapter 2

44

[ ]

[ ] [ ] [ ] ( 2 )

The integrated rate law for the decay of the starting species A is described by the following equation:

[ ] [ ] ( ) ( 3 )

The integrated rate law for the formation of each product species B and C are described by the

corresponding equations as follows:

[ ] [ ]

( ( ) ) ( 4 )

[ ] [ ]

( ( ) ) ( 5 )

The observed rate constant is the sum of the individual rate constants of formation of B and C (k1 and k2):

( 6 )

From the ratio [B]/[C], as it is usually referred to as branching ratio, the ratio of rate constants k1/k2 can be

calculated as follows:

[ ]

[ ]

( 7 )

Each formation rate constant can then be calculated as follows:

([ ]

[ ] )

( 8 )

([ ]

[ ] )

( 9 )

In this work, A denotes the metastable form, while B and C denotes the two corresponding stable forms:

( 10 )

The observed rate is the sum of the individual rates for TEZI and THI (kTEZI and kTHI) and these are related

as follows:

[ ( )]

[ ( )] ( 21 )

where the final ratio between the stable-(Z) and stable-(E) isomers is obtained from HPLC after correction

for the initial concentration of the stable-(Z) isomer at PSS. A least squares analysis of the rates versus the

temperature on the original Eyring equation:

(

) (

) ( 13 )

with appropriate weighing (1/k2) afforded the entropies and enthalpies of activation. The standard errors (σ)

were obtained from a Monte Carlo error analysis on the linearized Eyring equation:


Overcrowded Alkenes

45

( ) ( (

)

)

( 14 )

from forty thousand samples using calculated standard errors on rates and estimated standard errors on

temperatures. The kinetic analysis of compounds 1-4 was performed according to the general case as

described above. In particular for compounds 1 and 2, in order to calculate the most accurate values, the

value of ktot (overall kinetic constant) and σktot (standard deviation) at each temperature was obtained,

respectively, as average of decay constant of metastable-(Z) and formation constant of stable-(E) and

average of corresponding σst. The temperature of oil baths during the kinetics experiments was measured

with a Pt100 RTD Temperature Sensor and the error (3σst-T) associated, due to the oscillation in temperature

over time and between different spots inside the same oil bath, was assumed to be ±2 K. The fitting of

formation curves for TEZI and THI processes afforded both the total kinetic constant ktot (ktot = kTEZI + kTHI)

and each extrapolated final value of [st-(Z)] and [st-(E)] at infinite time. Hence, the branching ratio for each

experiment was calculated as the ratio of these two values, from which each kTEZI and kTHI could be

calculated as described above. For compounds 3 and 4, a single curve was obtained by monitoring the

change of CD signal over time for each fixed temperature. The fitting of the curve afforded the total kinetic

constant ktot (ktot = kTEZI + kTHI) and σktot (standard deviation), while the final ratio of [st-(Z)] and [st-(E)] for

each experiment was determined by HPLC analysis. The latter equalled to the branching ratio for each

experiment, from which each kTEZI and kTHI could be calculated as described above. The temperature of the

cuvette during the kinetics experiments was controlled and measured with a Peltier temperature control cell

and the error (3σst-T) associated was assumed to be ±1 K. The standard error associated to each kinetic

constant was determined through the quadratic variance of each variable. When a function used to calculate

a value (f) involves multiplications or divisions:

( 14 )

( 15 )

the associated standard error (σf) is calculated from the standard errors of the function parameters (σx, σy) as

follows:

(

) (

) (

) ( 16 )

√(

) (

) ( 17 )

As described in equations 8 or 9, in this work f denotes kTEZ or kTHI, while x denotes ktot and y denotes the

branching ratios of TEZ and THI products. The standard error associated to the branching ratios was also

determined accordingly. The determination of the error associated with the obtained thermodynamic

parameters (Δ‡G°, Δ

‡H°, Δ

‡S°, t½ at rt, T at t½=1 h) was performed through Monte Carlo analysis by

generation of a large number (40000 hits) of random cases limited in dispersion by the input kinetic

constants, temperature and associated standard errors. Eyring analysis for each compound was performed

by applying the direct Eyring equation with 1/k2 weighing.

(

)

(

) ( 18 )

The results of the Eyring analysis are summarized in Table 2.1. From the fitting curves in Figure 2.4 it is

evident that the increase in temperature is accompanied by a decrease in accuracy. This is expected for

these experiments and therefore an extensive error analysis has been performed to assure the validity of the

results from the Eyring analysis. While the error on the derived enthalpy (Δ‡H°) and entropy (Δ

‡S°) of

activation are appreciable, the error on the Gibbs free energy of activation (Δ‡G) remains small, particularly

Chapter 2

46

when it is calculated for a temperature in or near the range of temperatures in which the thermal relaxation

was observed.

Table 2.1. Kinetic parameters determined by the direct Eyring analysis (Figure 2.4), with standard errors

obtained from a Monte Carlo analysis for thermal isomerizations (TEZI and THI) of metastable 1–4.

(E,M,S)-1 (E,M,S)-2 (E,M,R)-3 (E,P,R)-4

t½ at rt (years) [a]

75 ±35 4.3±4.2·104 1.3 ±0.6 1.3 ±0.2

T at t½=1 h (°C) 138.2 ±0.4 121.3 ±0.3 116.0 ±0.7 99.1 ±0.2

Δ‡H°TEZI (kJ·mol

−1) 110 ±5.4 184 ±8.1 86.6 ±4.1 108 ±2.6

Δ‡S°TEZI (J·K

−1·mol

−1) −51.3 ±13 147 ±21 −98.5 ±11 −30.9 ±7.1

Δ‡G°TEZI (kJ·mol

−1) [b]

129 ±0.6 129 ±0.5 123 ±0.1 120 ±0.5

Δ‡H°THI (kJ·mol

−1) 118 ±5.7 208 ±9.2 99.4 ±4.6 96.5 ±2.4

Δ‡S°THI (J·K

−1·mol

−1) −53.2 ±14 182 ±23 −72.8 ±12 −68.0 ±6.6

Δ‡G°THI (kJ·mol

−1) [b]

138 ±0.6 140 ±0.6 127 ±0.1 122 ±0.5

[a] rt: 20 °C. [b] Standard condition: 100 °C and atmospheric pressure.

The reason for this is that extrapolation of these parameters to room temperature spans over hundred

degrees Celsius for some examples thus magnifying the uncertainty. This is notably observed for the half-

life at room temperature, an often reported feature. For example, the standard error determined for the half-

life of 2 is as large as the half-life itself. Therefore, we report a more appropriate characteristic of the first

order reaction, namely the ‗hour half-life temperature‘ which is the temperature at which the half-life

equals one hour. This property is not an extrapolation but usually falls within or close to the range of

measured temperatures and is derived from the Eyring equation by the use of the Lambert W function62

as

in the following equation:

( (

( )))

( 19 )

The error on the parameters discussed for different processes is reduced to less than a percent of the

parameter. Moreover, the temperature at which the half-life equals one hour is a much more chemically

intuitive feature, particularly when the half-lives at room temperature of the processes under investigation

are over a year or even exceeding forty thousand years (as for (E,M,S)-2).

Going from oxygen in 4 (X=O), carbon in 3 (X=C), to sulfur in 2 (X=S), the hour half-life temperature

increases from 99 to 116 and 121 °C, indicating an increase in stability of the metastable diastereoisomer.

Furthermore, substituting the xylene moiety in 1 for the naphthalene moiety in 2 increases the hour half-life

temperature even further to 138 °C. From the Gibbs free energy of activation for the two possible pathways

it is clear that under standard conditions the TEZI pathway is preferred over the THI pathway. Plotting the

Gibbs free energy versus temperature (Figure 2.5), hereby assuming that the enthalpy and entropy are

temperature independent, reveals that for the entire temperature range under investigation (experimental

temperature range: 85–152 °C) the barrier for the TEZI is lower than that for the THI for all alkenes 1–4.


Overcrowded Alkenes

47

Figure 2.5. Gibbs free energy of activation for the TEZI (solid lines) and the THI (dashed lines) processes

plotted vs. temperature for the metastable-(E)-diastereoisomers of alkenes 1–4. The experimental

temperature range is marked by grey vertical lines (85–152 °C), inversion points for the two processes are

marked for 3 and 4 by a dot. Inversion points for 1 and 2 fall outside measurable ranges of temperature and

free Gibbs energy.

A difference in the entropy of activation for the two processes logically leads to the existence of a point at

which the rates for the two processes are expected to be equal. Such a point would signify the inversion of

the two processes, because beyond this temperature the barrier of the THI will be lower than that of the

TEZI. For alkenes 3 and 4, these points are found at relevant temperatures (226 °C and 37.8 °C,

respectively) while for 1 and 2 the inversions would take place either far outside of the experimentally

significant temperature range or never at all (411 °C and <0 K, respectively).

2.2.4 Computational results

Previously, research on molecular motors has to a large extent been supported by computational

chemistry.31,48,53–55

For example, it has been shown that the energy barrier of the thermal helix inversion

can be predicted with reasonable accuracy (within several kJ·mol−1

) through the use of density functional

theory (DFT) at the B3LYP/6-31G(d,p) level.31,44,48,53,55

Indeed, this method has been utilized to design new

motors in silico by prediction of the helix inversion energy barriers of motors prior to their synthesis in

order to determine whether their rotation rates would be of the desired order of magnitude. The

experimental study of the thermal behavior of the metastable diastereoisomers (E)-1–4 was accompanied by

a computational study of the potential energy surface of overcrowded alkenes 1–4. As such computational

studies were entirely executed by J. C. M. Kistemaker and Dr. T. C. Pijper, the reader should refer to the

published version of the current work for a more more detailed discussion of the computational approach

used. The results obtained have been reported here for comparison with experimental data.

The calculated Gibbs free energies are summarized for alkenes 1–4 in Table 2.2 and the obtained

geometries for (S)-2 are depicted in Figure 2.7 as an example. The geometries of 1, 3 and 4 do not differ

significantly in general appearance from those of 2, although they naturally do differ in specific bond

angles and lengths. Going from alkene 4 to alkene 3 to alkene 2, the size of the bridging atom X in the

Chapter 2

48

upper half increases, which is accompanied by an increase in the size of that ring and thus forces the aryl

moiety towards the lower half (Figure 2.6b, Table 2.2). The increase in steric hindrance is alleviated by

additional folding of the six-membered ring, as can be seen from the dihedral angle made up by atoms 1, 2

and the central alkene (as indicated in Figure 2.6a for the metastable-(E) isomer). Both 1 and 2 are bridged

by a sulfur atom and therefore hardly differ in ring size, although the difference between the aryl and xylyl

moieties is to a small extent reflected by their dihedral angles (see ‗dihedral angle‘ in Table 2.2). The

barrier for the THI increases with an increase in the degree of folding of the upper half, as is seen from the

dihedral angle. A similar increase is observed for the calculated barrier for the TEZI, with the exception of

1 which exhibits a significantly higher barrier without an increase in folding with respect to 2.

Table 2.2. Relative Gibbs free energies of 1–4 calculated at the DFT-B3LYP/6-31G(d,p) level or

MRMP2/CASSCF(14,14)/6-31G(d) // CASSCF(10,10)/6-31G(d) level indicated by * (373.15 K, 1

atm, in kJ·mol−1

).

(S)-1 (S)-2 (R)-3 (R)-4

Stable-(Z) 0 0 0 0

TS TEZI* 165 150 146 138

Metastable-(E) 22.2 23.1 27.2 24.9

TS THI 163 165 151 146

Stable-(E) 0.94 1.74 1.89 1.46

MS-(E) X-ring size (pm)[a]

961 958 901 875

MS-(E) dihedral angle (°)[b]

46.7 47.6 42.6 41.4

[a] Summed lengths of the bonds making up the six-membered ring in the upper half (Figure 2.6b).

[b] Dihedral angle made up by atoms 1, 2 and the central alkene as indicated in Figure 2.6a.

Figure 2.6. a) Active space used in CASSCF(14,14) and MRMP2/CASSCF (14,14) calculations. π bonds

included are indicated with circles. b) Correlation between X-ring size and thermal relaxation energy

barrier.


Overcrowded Alkenes

49

Figure 2.7. Calculated geometries of (S)-2 (X = S). Left: top view with the upper half on top, the alkene on

the z-axis and the fluorene in the x-z plane, right: front view with the alkene on the y-axis and the fluorene

in the x-y plane. Calculations and rendering performed by J.C.M. Kistemaker.

Chapter 2

50

Table 2.3 provides an overview of the experimentally determined and calculated Gibbs free energies of

activation for the TEZI and THI pathways for alkenes 1–4. The calculated barriers for the THI agree

strongly with those found experimentally, differing no more than 3 kJ·mol−1

. The calculated barriers for the

TEZI deviate more from the experimentally determined barriers. The barriers of 2 and 3 correspond well

whereas the barrier of 1 is overestimated and the barrier of 4 is slightly underestimated. The slight

underestimation of the TEZI barrier for 4 still allows for a reasonable prediction of the behavior of the

overcrowded alkene, however, the overestimated barrier of 1 suggests almost equal rates for the THI and

TEZI processes while experimental results show the TEZI pathway to be significantly faster than the THI

pathway. This could imply that the computational approach used herein may not be as accurate for

overcrowded alkenes with xylene-derived upper halves as it is for those with naphthalene-derived upper

halves. Nonetheless, these computational methods provide valuable insight how the thermal isomerization

behavior relates to the geometric changes in these second generation overcrowded alkenes.

Table 2.3. Comparison of experimental and theoretical barriers for TEZI and THI of 1–4.[a]

Metastable: (E)-1 (E)-2 (E)-3 (E)-4

Δ‡G°TEZI (kJ·mol

−1) 129±0.6 129±0.5 123±0.1 120±0.5

Δ‡G

calcTEZI (kJ·mol

−1) 142 127 119 113

Δ‡G°THI (kJ·mol

−1) 138±0.6 140±0.6 127±0.1 122±0.5

Δ‡G

calcTHI (kJ·mol

−1) 141 142 124 121

[a] standard condition: 100 °C and atmospheric pressure.

2.2.5 Photoswitching process

It was found that the increased thermal stability of the metastable states of alkenes 1–4 makes them very

suitable candidates for use as bistable photoisomerisable switches. The switching properties of 1–4

(Scheme 2.9) were monitored by UV-vis absorption spectroscopy (Figure 2.8) and 1H NMR spectroscopy

(vide supra).

Scheme 2.9. General scheme for reversible highly selective photoswitching of stable (Z)-1–4 and

metastable (E)-1–4.

Solutions of stable 1–4 (heptane) in quartz cuvettes were irradiated at room temperature for a few minutes

towards either the metastable state using UV light (312 or 365 nm) or the stable state using visible light

(420 or 450 nm). Using UV-vis absorption spectroscopy, the reversible photochemical E-Z isomerizations

were found to be characterized by clear isosbestic points, indicating the absence of side reactions, as well as

bathochromic shifts of the major absorptions bands in the metastable state of about 30–80 nm. This is in

full agreement with the calculated structural change and concomitant change in the HOMO-LUMO gap.

Upon the formation of the metastable state the overcrowded alkene experiences an increase in twist as is

illustrated in the calculated structures in Figure 2.7. This twisting increases the energy of the HOMO by an

average 23 eV for 1–4 while at the same time lowering the LUMO by an average 246 eV, which together


Overcrowded Alkenes

51

significantly reduces the HOMO-LUMO gap. This is opposite to the observations of Cnossen et al. for

second generation molecular motors with six membered rings in both the upper as well as lower half in

which the twist over the double bond was lowered in the metastable state and a hypsochromic shift was

observed.55

The bathochromic shift upon formation of the metastable 1–4 allows for a highly selective

photochemical switching process in which both states can be addressed by the use of light of an appropriate

wavelength (Scheme 2.9, Figure 2.8). None of the overcrowded alkenes showed any noticeable degradation

over multiple switching cycles, thus exhibiting an excellent fatigue resistance of this family of molecular

switches.

Figure 2.8. UV-vis spectra of the switching process of 1–4. Experimental UV-vis absorption spectra in

black of (Z,P,S)-1, (Z,P,S)-2, (Z,P,R)-3, (Z,M,R)-4 (heptane, 1.0·10−5

M). Irradiation of 1 (312 nm), 2 (365

nm), 3 (312 nm), and 4 (365 nm) to the metastable state affords a PSS shown in red with two intermediate

moments in the process shown as well in red (E:Z ratio: (S)-1 95:5, (S)-2 96:4, (R)-3 97:3, and (R)-4 99:1).

Irradiation using a longer wavelength of 1 (420 nm), 2 (450 nm), 3 (420 nm), and 4 (450 nm) allowed for

the reversed E-Z isomerization towards the stable state affording a new PSS shown in blue with two

intermediate moments in the process shown as well in blue (Z:E ratio; (S)-1 64:36, (S)-2 82:18, (R)-3 97:3,

(R)-4 70:30). Inserts display irradiation cycles between the two PSS‘s for each compound.

The PSS ratios for the stable-(Z) to metastable-(E) isomerizations obtained upon irradiation with UV light

were determined by HPLC and were all found to yield ≥ 95% of the metastable-(E) state for the forward

isomerization (vide supra). The reverse reaction using visible light afforded varying PSS ratios (Z:E ratio;

(S)-1 64:36, (S)-2 82:18, (R)-3 97:3, (R)-4 70:30),63

as determined by HPLC and/or UV-vis (see

Experimental section). Alkene 3 hereby displayed the most efficient photoswitching, producing 97% of the

opposite diastereoisomer in both directions, and would therefore be the most suitable candidate for use as a

bistable photocontrolled switch. With respect to thermal stability, overcrowded alkene 1 exhibits the most

favorable behavior , possessing an hour half-life temperature of 138 °C. This is over 22 °C higher than that

Chapter 2

52

of 3 and the TEZI of 1 yields the starting isomer almost exclusively (>94%), making it remarkably bistable

as well as selective during the thermal isomerization.

2.2.6 Full experimental study of stable E-isomer isomers

The discussion held so far comprises the experimental and computational studies focused for simplicity

only on the stable Z-isomer isomers of 1-4 and the species directly involved via their photochemical and

thermal isomerization. A full experimental characterization of the analogous species obtained via

isomerization of stable E-isomer isomers of 1-3 and the thermal relaxation of their photo-generated

metastable Z-isomer isomers of 1-3 (Scheme 2.10) was also performed and is summarized in the current

section.

Scheme 2.10. General scheme for photochemical and thermal behavior (TEZI vs. THI) of desymmetrized

overcrowded alkenes stable-(E) and metastable-(Z).

As their properties are strictly related to their main scaffold and influenced to a lower extend by the

position of the methoxy-substituent located on the fluorenyl lower half, their photochemical and thermal

properties do not differ significantly from their diastereoisomeric counterparts described in the previous

sections. It is worth to mention that compound 4 had been synthesized and characterized by J. C. M.

Kistemaker and T. van Leeuwen prior to this work and no investigation of the E-isomer isomers of 4 was

performed at the time.

Similarly, to the Z-isomers (see section 1.2.3), metastable E-isomer isomers of 1-3 were subjected to photo-

chemical isomerization to the corresponding metastable Z-isomer upon monitoring via CD and UV-vis abs.

spectroscopy. The isolated enantiomers of compounds 1–3 displayed strong Cotton effects in the area of

~250–320 nm and slightly smaller Cotton effects of opposite sign at higher wavelengths (>320 nm) with

the exception of compound 3 which lacked such a longer wavelength absorption band (Figure 2.9). The

presence of such strong Cotton effects around 400 nm is indicative of the helical shape of these

overcrowded alkenes, while the lack of this band for compound 3 could be due to the absence of a

heteroatom in its core structure (which is present in the other compounds). The assignment of the absolute

configuration of each enantiomer was performed by comparison with the calculated and experimental CD

spectra of the corresponding stable Z isomers (see Figure 2.1).


Overcrowded Alkenes

53

Figure 2.9. CD spectra of (E)-1–3. Experimental CD spectra in solid lines of (E,M,R)-1, (E,P,S)-2,

(E,M,R)-3 (heptane, 1.0·10−5

M). CD spectra in dashed lines of PSS mixture of 1 (irrad. at 312 nm), 2

(irrad. at 365 nm), 3 (irrad. at 312 nm).

The switching properties of (E)-1–3 were monitored by UV-vis absorption spectroscopy. Solutions of

stable (E)-1–3 in a quartz cuvette were irradiated at rt over a few minutes, forming the metastable forms by

irradiation with shorter wavelength light (312 or 365 nm) or the stable forms by irradiation with longer

wavelength light (420 or 450 nm) (vide supra). For each compound, the reversible photo-induced

isomerization process of each compound is characterized by a clear isosbestic point and by a clear redshift

of the major absorption band by ~30–80 nm. As reported in the corresponding graphs, the compounds

showed no degradation over multiple switching cycles (Figure 2.10).

Figure 2.10. UV-vis spectra of the switching process of (E)-1–3. Experimental UV-vis absorption spectra

in black of (E,M,R)-1, (E,P,S)-2, (E,M,R)-3 (heptane, 1.0·10−5

M). UV-vis absorption spectra in red of PSS

towards metastable species of (E)-1 (312 nm), (E)-2 (365 nm), (E)-3 (312 nm) with two intermediate

moments during irradiation process. UV-vis absorption spectra in blue of PSS towards stable species of

(E)-1 (420 nm), (E)-2 (450 nm), (E)-3 (420 nm) with two intermediate moments during reverse irradiation

process. Inserts display irradiation cycles between the two PSS‘s for each compound as monitored by UV-

vis absorption at each specific local maximum of the corresponding metastable species.

Chapter 2

54

HPLC analysis of the various solutions afforded the composition of each PSS mixture (irradiation at 312 or

365 nm and 420 or 450 nm, respectively) in heptane, as well as the composition of each PSS mixture after

thermal decay (Figure 2.11).

Figure 2.11. HPLC traces of (E)-1–3. Top: HPLC traces (heptane:2-propanol) of pure enantiomers isolated

by HPLC as assigned by CD; (E,M,R)-1 (Chiralcel OD-H, 98:2), (E,P,S)-2 (Chiralcel AD-H, 97:3),

(E,M,R)-3 (Chiralcel OD-H, 98:2). Middle: HPLC traces of PSS mixtures of (E)-1–3 (identical conditions).

Bottom: HPLC traces after thermal isomerization of PSS mixtures of (E)-1–3 (identical conditions).

Eyring analysis for each compound was performed by applying the direct Eyring equation with 1/k2

weighing (Figure 2.12).

Figure 2.12. Decay curves and Eyring plots of metastable-(Z)-1–3. Decay curves of: (Z,P,R)-1 recorded by

HPLC taking aliquots from a hexanol solution (131–152 °C); (Z,M,S)-2 recorded by HPLC taking aliquots

from a dodecane solution (112–140 °C); (Z,M,R)-3 recorded by CD in dodecane (95–107 °C). Least squares

analysis on the original Eyring equation for (E)-1–3 with error bars of 3

The calculated Gibbs free energies are summarized for metastable-(Z)-isomers of alkenes 1–3 in Table 2.4.

Going from carbon in 3, to sulfur in 1 and 2, the hour half-life temperature increases expressing a higher

stability of the metastable state. Furthermore, exchanging the naphthalene moiety in 2 for the xylene moiety

in 1 markedly increases the hour half-life temperature. From the Gibbs free energy of activation for the two

possible pathways it is clear that under standard conditions TEZI is preferred over THI. Plotting the Gibbs

free energy versus temperature (Figure 2.13), hereby assuming that the enthalpy and entropy are

temperature independent, reveals also for isomers (E)-1–3 that for the entire temperature range under

investigation the barrier for the TEZI is lower than that for the THI. For alkenes (E)-2 and (E)-3, the

inversions points are found at experimentally relevant temperatures (-44.8 and 62.8 °C, respectively) while

for (E)-1 the inversion would take place below absolute zero (virtually at -399 K).


Overcrowded Alkenes

55

Table 2.4. Kinetic parameters determined by the direct Eyring analysis with errors obtained by a Monte

Carlo experiment for thermal isomerizations of metastable (Z)-1–3.

(Z,P,R)-1 (Z,M,S)-2 (Z,P,R)-3

t½ at rt (years) [a]

1.1±0.2·103 2.1±4.1·10

4 11±3.8

T at t½=1 h (°C) 144.6±0.3 126.7±0.5 122.3±0.8

‡H°TEZI (kJ mol

−1) 128±4.6 173±11 112±4.1

‡S°TEZI (J K

−1 mol

−1) −12.5±11 113±27 −36.3±11

‡G°TEZI (kJ mol

−1)

[b] 133±0.5 130±0.9 126±0.1

‡H°THI (kJ mol

−1) 130±4.8 156±11 87.3±3.3

‡S°THI (J K

−1 mol

−1) −31.9±12 40.9±26 −111±8.9

‡G°THI (kJ mol

−1) [b]

142±0.5 141±0.9 128.6±0.1

‡H°total (kJ mol

−1) 128±4.6 172±11 105±3.7

‡S°total (J K

−1 mol

−1) −11.6±11 113±27 −53.3±9.8

‡G°total (kJ mol

−1)

[b] 133±0.5 130±0.9 125±0.05

[a] room temperature: 20 °C. [b] standard condition: 100 °C and atmospheric pressure.

Figure 2.13. Gibbs free energy of activation for the TEZI (solid lines) and the THI (dashed lines) processes

plotted vs. temperature for the metastable-(Z)-diastereoisomers of alkenes 1–3. The experimental

temperature range is marked by grey vertical lines (95–152 °C), inversion points for the two processes are

marked for (E)-2 and (E)-3 by a dot. Inversion point for 1 falls outside measurable ranges of temperature

and free Gibbs energy.

Chapter 2

56

2.3 Conclusions

Four overcrowded alkenes have been synthesized and investigated experimentally and computationally.

The calculated CD spectra of 1–4 agree well with the experimental spectra which allowed for their absolute

stereochemical assignments. Irradiation with UV light allowed for high yielding E-Z isomerizations

providing metastable diastereoisomers. Kinetic studies on metastable 1–4 using CD and HPLC identified

two pathways at high temperatures for thermal isomerization. The thermal E-Z isomerizations and helix

inversions were studied computationally. Furthermore, the calculated THI and TEZI barriers were found to

be in close agreement with those observed experimentally. In order to show the value of these overcrowded

alkenes as bistable switches, photochemical switching cycles were performed which proved the alkenes to

be excellent switches. Switch 3 showed the best performance as a photo-switch while 1 excelled in thermal

stability, both exhibiting highly selective isomerizations. These favorable switching properties offer

attractive prospects towards the design of novel photoresponsive systems.

2.4 Acknowledgements

The author would like to thank J. C. M. Kistemaker, T. van Leeuwen and Dr. T. C. Pijper for their

fundamental contribution to this work. Synthesis and characterization of 4 was performed by T. van

Leeuwen and J. C. M. Kistemaker, Computational study was performed by J. C. M. Kistemaker and Dr. T.

C. Pijper.


Overcrowded Alkenes

57

2.5 Experimental section

2.5.1 General methods

Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe N.V. Solvents were reagent grade

and distilled and dried before use according to standard procedures. Dichloromethane and toluene were

used from the solvent purification system using an MBraun SPS-800 column. Tetrahydrofuran was distilled

over sodium under a nitrogen atmosphere prior to use. Column chromatography was performed on silica

gel (Silica Flash P60, 230–400 mesh). NMR spectra were recorded on a Varian Gemini-200, a Varian

AMX400 or a Varian Unity Plus 500 spectrometers, operating at 200 MHz, 400 MHz, and 500 MHz for 1H

NMR, respectively. Chemical shifts are denoted in δ values (ppm) relative to CDCl3 (1H: δ = 7.26;

13C: δ =

77.00). For 1H NMR, the splitting parameters are designated as follows: s (singlet), d (doublet), t (triplet), q

(quartet), p (pentet), sext (sextet), m (multiplet) and b (broad). MS (EI) and HRMS (EI) spectra were

obtained with a AEI MS-902 or with a LTQ Orbitrap XL. Melting point are measured on a Büchi Melting

Point B-545 apparatus. Preparative HPLC was performed on a Shimadzu semi-prep HPLC system

consisting of an LC-20T pump, a DGU-20A degasser, a CBM-20A control module, a SIL-20AC

autosampler, a SPD-M20A diode array detector and a FRC-10A fraction collector, using a Chiralpak

(Daicel) AD-H, Chiralcel OD or Chiralcel OD-H column. Elution speed was 0.5 mL/min for AD-H and

OD-H columns and 1.0 mL/min for the OD column, with mixtures of HPLC grade heptane and isopropanol

(BOOM) as eluent. HPLC analysis was performed using a Shimadzu LC-10ADVP HPLC pump equipped

with a Shimadzu SPDM10AVP diode array detector and chiral columns as indicated. Sample injections

were made using an HP 6890 Series Auto sample Injector. UV-vis absorption spectra were measured on a

Analityk Jena SPECORD S600 spectrophotometer. CD spectra were measured on a Jasco J-815 CD

spectrophotometer. All spectra were recorded at 20 °C using Uvasol grade heptane (Merck) as solvent.

Irradiation was performed using a Spectroline ENB-280C/FE lamp (312 nm, 365 nm) or a Thorlabs INC

OSL 1-EC fibre illuminator (420 nm, 450 nm). Thermal helix inversion/thermal E—Z isomerization were

monitored by CD spectroscopy using the apparatus described above and a JASCO PFD-350S/350L Peltier

type FDCD attachment with temperature control and cooling system or by HPLC analysis of aliquots

collected over time (See the Kinetic Experiments Section for further details). Temperature of oil baths

during the kinetics experiments were measured with a Pt1000 RTD Temperature Sensor. Room temperature

(rt) as mentioned in the experimental procedures, characterization and computational sections is to be

considered equal to 20 °C.

2.5.2 Synthetic procedures

Compounds 4, 15, 13, 26, 27, 11, and 13 were synthesized by J. C. M. Kistemaker and T. van Leeuwen.

Refer to published version of the manuscript for synthesis and full characterization.

2-methoxy-9H-fluoren-9-one (14)

To a stirred suspension of finely powdered KOH (2.1 g, 37 mmol) in DMSO

(20 mL) was added 2-hydroxy-9H-fluoren-9-one (2.0 g, 10 mmol) and

iodomethane (2 mL, 32 mmol). The reaction suspension was stirred for 30 min.

Water (50 mL) was added and the resulting mixture was extracted with Et2O (5 x

50 mL). The organic layer was washed with H2O (2 x 100 mL), dried over

MgSO4 and concentrated under reduced pressure. The obtained orange oil was purified by column

chromatography (SiO2, pentane:CH2Cl2 = 1:1) to yield 14 (1.97 g, 9.4 mmol, 92%) as an oil which

crystallized upon standing. m.p. 78 °C;

1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 1H), 7.44–7.35

(m, 3H), 7.23–7.14 (m, 2H), 6.96 (dd, J = 8.2, 2.5 Hz, 1H), 3.84 (s, 3H); 13

C APT NMR (100 MHz, CDCl3)

δ 193.8 (C), 160.8 (C), 144.8 (C), 136.9 (C), 135.9 (C), 134.8 (CH), 134.3 (C), 127.8 (CH), 124.3 (CH),

121.3 (CH), 120.2 (CH), 119.5 (CH), 109.3 (CH), 55.7 (CH3); HRMS (APCIpos): calcd for C14H11O2

Chapter 2

58

[M+H]+: 211.0759, found 211.0753; anal. calcd for C14H10O2: C 79.98%, H 4.79%, found: C 79.90%, H

4.79%.

(Z) & (E)-2-methoxy-9H-fluoren-9-ylidene)hydrazine (15)

A solution of 14 (1.5 g, 7.1 mmol) and hydrazine monohydrate (3 mL) in

MeOH (100 mL) was stirred and heated at reflux for 2 h. The solvent was

removed under reduced pressure and the crude product was re-dissolved in

CH2Cl2 (50 mL). The organic phase was extracted with H2O (2 x 50 mL) and

dried over Na2SO4. The crude product was purified by column chromatography

(SiO2, solvent gradient: pentane:EtOAc = 1:0 to 1:1) to yield 15 (1.3 g, 5.8

mmol, 82%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78–7.67 (m, 2H), 7.61–7.41 (m, 5H), 7.41–

7.13 (m, 7H), 6.86 (dt, J = 8.3, 2.4 Hz, 2H), 6.37 (d, J = 14.0 Hz, 2H), 3.84 (s, 3H), 3.79 (d, J = 2.4 Hz,

3H); 13

C APT NMR (100 MHz, CDCl3) δ 160.3 (C), 159.8 (C), 145.6 (C), 145.4 (C), 141.6 (C), 139.8

(C), 138.9 (C), 137.8 (C), 134.3 (C), 131.8 (C), 131.6 (C), 130.4 (C), 129.9 (CH), 128.7 (CH), 126.9 (CH),

126.7 (CH), 125.5 (CH), 121.2 (CH), 120.8 (CH), 120.7 (CH), 119.8 (CH), 119.0 (CH), 115.6 (CH), 114.1

(CH), 112.8 (CH), 105.4 (CH), 55.8 (CH3), 55.8 (CH3); HRMS (APCIpos): calcd for C14H13N2O [M+H]+:

225.10224, found 225.1026.

3,5,8-trimethylthiochroman-4-one (7)

A solution of 2-(2,5-dimethylphenyl)thiol (2.00 g, 14.5 mmol), NEt3 (4.00 mL,

28.9 mmol) and methacrylic acid (2.45 mL, 28.9 mmol) in THF (25 mL) was heated at

reflux under stirring for 16 h. Upon cooling, the reaction mixture was quenched with

aq. 1M HCl (30 mL) and the water layer was extracted with EtOAc (3 × 30 mL). The

combined organic layers were washed with brine and dried over Na2SO4. After

filtration, the volatiles were removed under reduced pressure and the crude 3-((2,5-

dimethylphenyl)thio)-2-methylpropanoic acid 5 was obtained as a light brown solid (3.20 g, 14.4 mmol).

Despite minor impurities, the crude product was used directly in the following step. A round-bottom flask

equipped with a septa-cap pierced with a needle was loaded with a solution of 5 (3.20 g, 14.4 mmol) and

two drops of DMF in CH2Cl2 (20 mL). Oxalyl chloride (2.50 mL, 28.50 mmol) was slowly added to the

solution dropwise, which turned from yellow to orange. The solution was stirred for 1 h at rt, then the

volatiles were removed under reduced pressure. Heptane (15 mL) was added and the solvent evaporated

under reduced pressure at 60 °C twice to remove completely the excess of oxalyl chloride, to yield the

crude 3-((2,5-dimethylphenyl)thio)-2-methylpropanoyl chloride 6 (3.44 g, 14.2 mmol) as a brownish oil.

The crude product was used directly in the following step without further purification. Under a nitrogen

atmosphere, 6 (4.10 g, 15.5 mmol) was re-dissolved in CH2Cl2 (70 mL) and cooled to 0 °C. AlCl3 (2.64 g,

19.8 mmol) was slowly added to the solution portionwise to avoid heating of the mixture. The mixture was

stirred for 2 h at low temperature. Subsequently, the mixture was warmed up and quenched with aq. 1M

HCl (50 mL) in an ice bath. The organic phase was separated and the aqueous phase was extracted with

CH2Cl2 (3 x 30 mL). The organic phases were combined and washed with brine and dried over Na2SO4.

After filtration, the volatiles were removed under reduced pressure and the crude product was purified by

column chromatography (SiO2, pentane:EtOAc = 20:1, Rf = 0.30) to yield 7 (2.40 g, 11.6 mmol, 80% from

the initial 2-(2,5-dimethylphenyl)thiol) as a light yellow oil. 1H NMR (200 MHz, CDCl3) δ 7.11 (d, J = 7.6

Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 3.26–2.81 (m, 4H), 2.54 (s, 3H), 2.27 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 199.8, 141.4, 139.7, 132.8, 132.6, 130.2, 128.0, 42.8, 32.2, 23.4, 19.9, 15.2;

HRMS (ESI, m/z): calcd for C12H15OS [M+H]+: 207.0838, found: 207.0838.


Overcrowded Alkenes

59

(3,5,8-trimethylthiochroman-4-ylidene)hydrazine (8)

Under a nitrogen atmosphere, a mixture of 7 (1.25 g, 6.06 mmol), hydrazine

monohydrate (4 mL) and Sc(OTf)3 (0.075 g, 0.151 mmol, 2.5 mol%) in EtOH (4 mL)

was heated at reflux for 16 h. The solution was allowed to cool to rt and water was

added under stirring until the product started precipitating. The mixture was cooled to

−25 °C for 16 h. The slurry was filtered on a P4 fritted glass filter, the solid residue was

washed with cold Et2O and cold pentane and dried under vacuo to yield 8 (0.90 g, 4.08

mmol, 67%) as white powder. m.p. 123–124 °C; 1H NMR (400 MHz, CDCl3) δ 7.04–6.90 (m, 2H), 5.40 (s,

2H), 3.46–3.31 (m, 1H), 3.06 (dd, J = 12.9, 6.4 Hz, 1H), 2.53 (dd, J = 12.9, 10.4 Hz, 1H), 2.39 (s, 3H), 2.28

(d, J = 7.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 150.8, 137.9, 135.3, 134.5,

133.3, 128.7, 128.3, 36.4, 34.5, 21.0, 19.9, 14.9; HRMS (APCI, m/z): calcd for C12H17N2S [M+H]+:

221.1107, found: 221.1107.

(Z) & (E)-4-(2-methoxy-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromane (1)

Under a nitrogen atmosphere, Lawesson‘s reagent (1.38

g, 3.4 mmol) was added to a stirred solution of 14 (480

mg, 2.27 mmol) in dry toluene (6 mL). The mixture was

heated at 90 ºC for approximately 1 h, until TLC

(pentane:CH2Cl2 = 2:1) started showing the formation of

degradation products. The mixture was concentrated and

the residue was purified by quick column

chromatography (SiO2, pentane:CH2Cl2 = 2:1). The wine red fraction was concentrated under reduced

pressure to yield the crude thioketone 12 as a dark wine red oil (to prevent hydrolysis, the product was kept

wet with CH2Cl2 and stored under nitrogen). Under a nitrogen atmosphere, a solution of 8 (500 mg,

2.27 mmol) in DMF (4 mL) was cooled to −40 °C and bis(trifluoroacethoxy)iodobenzene (920 mg, 2.27

mmol) was added to the stirred solution. The mixture was stirred for 2 min while the color turned from

yellow to dark pink, indicative of the formation in situ of the diazo compound 16. A solution of the crude

thioketone 12 in dry DMF (4 mL) and dry of CH2Cl2 (4 mL) was added to the mixture, which showed

evolution of nitrogen gas. The mixture was allowed to warm to rt and stirred for 16 h. The mixture was

diluted with EtOAc, washed with a sat. aq. NH4Cl solution, the organic layer was separated and the

aqueous layer was extracted with EtOAc (3 x 10 mL). The organic phases were collected, washed with

water, brine and dried over Na2SO4. After filtration, the volatiles were removed under reduced pressure and

the crude residue was re-dissolved in toluene (8 mL). Tris(dimethylamino)phosphine (0.32 mL, 1.74 mmol)

was added and the mixture was stirred for 16 h at 65 °C. The mixture was concentrated under reduced

pressure and the crude product was re-dissolved in CH2Cl2 (15 mL), washed with water, brine and dried

over Na2SO4. After filtration, the volatiles were removed under reduced pressure and the crude product was

purified by column chromatography (SiO2, solvent gradient: pentane:EtOAc = 50:1 to 20:1) to yield (Z)-1

(180 mg, 0.46 mmol, 21%) and (E)-1 (190 mg, 0.49 mmol, 22%) as yellow crystals (Z:E = 1:1.1).

(Z)-1: m.p. 168–169 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H),

7.51 (d, J = 8.3 Hz, 1H), 7.34 (td, J = 7.4, 0.9 Hz, 1H), 7.27 (td, J = 7.7, 1.3 Hz, 1H), 7.17 (d, J = 7.7 Hz,

1H), 7.05 (d, J = 7.7 Hz, 1H), 6.75 (dd, J = 8.3, 2.4 Hz, 1H), 5.88 (d, J = 2.3 Hz, 1H), 4.54 (app. sext, J =

7.4 Hz, 1H), 3.42 (s, 3H), 3.22 (dd, J = 12.6, 7.8 Hz, 1H), 2.42 (s, 3H), 2.35 (dd, J = 12.5, 8.8 Hz, 1H), 2.18

(s, 3H), 1.38 (d, J = 6.8 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 159.2, 144.6, 141.3, 139.8, 139.2, 137.6,

136.0, 135.1, 132.9, 132.8, 129.1, 128.0, 127.6, 125.8, 124.8, 119.6, 118.8, 114.8, 107.8, 55.0, 40.2, 37.1,

19.9, 19.7, 18.8, one signal (C) was not observed; HRMS (ESI, m/z): calcd for C26H25OS [M+H]+:

385.1621, found: 385.1617. Separation of the enantiomers was achieved by CSP-HPLC (Chiralcel OD-H,

heptane:2-propanol = 98:2, flow rate = 0.5 mL/min, Rt: 17.40 min for (Z,P,S)-1, 26.40 min for (Z,M,R)-1.

(E)-1: m.p. 159–161 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H),

7.52 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.95

Chapter 2

60

(dd, J = 8.3, 2.2 Hz, 1H), 6.80 (t, J = 7.7 Hz, 1H), 6.22 (d, J = 8.0, 1H), 4.51 (app. sext, J = 7.6 Hz, 1H),

3.93 (s, 3H), 3.22 (dd, J = 12.5, 7.8 Hz, 1H), 2.42 (s, 3H), 2.35 (dd, J = 12.5, 8.7 Hz, 1H), 2.13 (s, 3H), 1.37

(d, J = 6.8 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 159.2, 144.6, 139.6, 139.3, 138.9, 138.26, 137.6, 135.9,

134.9, 134.3, 132.9, 129.2, 128.1, 127.4, 126.1, 123.3, 120.1, 118.2, 112.2, 112.1, 55.7, 39.9, 37.1, 20.0,

19.7, 18.6; HRMS (ESI, m/z): calcd for C26H25OS [M+H]+: 385.1621, found: 385.1616. Separation of the

enantiomers was achieved by CSP-HPLC (Chiralcel OD-H, heptane:2-propanol = 98:2, flow rate = 0.5

mL/min, Rt: 16.60 min for (E,M,R)-1, 23.00 min for (E,P,S)-1.

3-((naphthalen-2-yl)thio)-2-methylpropanoic acid (18)

A solution of naphthalen-2-thiol (5.0 g, 31.2 mmol), NEt3 (8.70 mL, 62.4

mmol) and methacrylic acid (5.30 mL, 62.4 mmol) in THF (50 mL) was

heated at reflux under stirring for 16 h. Upon cooling, the reaction mixture was

quenched with aq. 1M HCl (40 mL) and the water layer was extracted with

EtOAc (3 x 30 mL). The combined organic layers were washed with brine and

dried over Na2SO4. After filtration, the volatiles were removed under reduced pressure and the crude

product was purified by recrystallization from heptane to yield 18 (5.65 g, 22.9 mmol, 73%) as a white

powder. m.p. 88–89 °C; 1

H NMR (200 MHz, CDCl3) δ 7.84–7.72 (m, 3H), 7.53–7.35 (m, 2H), 3.39 (dd, J =

13.4, 6.9 Hz, 1H), 3.02 (dd, J = 13.4, 7.0 Hz, 1H), 2.76 (ddd, J = 13.9, 7.0, 6.9 Hz, 1H), 1.33 (d, J = 7.0 Hz,

3H); 13

C NMR (75 MHz, CDCl3) δ 181.3, 133.7, 132.8, 132.0, 128.6, 128.3, 127.9, 127.7, 127.2, 126.6,

125.9, 39.4, 37.0, 16.5; HRMS (ESI, m/z): calcd for C14H15O2S [M+H]+: 247.0787, found: 247.0793.

2,3-dihydro-2-methyl-1H-naphtho[2,1-b]thiopyran-1-one (20)

A round-bottom flask equipped with a septa-cap pierced with a needle was loaded

with a solution of 18 (3.80 g, 15.5 mmol) and two drops of DMF in CH2Cl2 (60 mL).

Oxalyl chloride (6.32 mL, 31.0 mmol) was slowly added to the solution dropwise,

liberating gas and the solution turned from yellow to orange. The solution was stirred

for 1 h at rt, then the volatiles were removed under reduced pressure. Heptane (15

mL) was added and the solvent evaporated under reduced pressure at 60 °C twice to remove completely the

excess of oxalyl chloride, to yield the crude 2-methyl-3-(naphthalen-2-ylthio)propanoyl chloride 19 (4.10 g,

15.5 mmol) as a brownish oil. The product was used immediately in the following step without further

purification. Under a nitrogen atmosphere, 19 was re-dissolved in CH2Cl2 (60 mL) and the mixture cooled

to −50 °C. AlCl3 (3.10 g, 23.2 mmol) was slowly added to the solution portionwise to avoid heating of the

mixture. The mixture was stirred for 2 h, then it was let to warm to rt and quenched with aq. 1M HCl (40

mL)in an ice bath. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3 x

30 mL). The combined organic phases were combined and washed with brine and dried over Na2SO4. After

filtration, the volatiles were removed under reduced pressure and the crude product was purified by column

chromatography (SiO2, pentane:EtOAc 5:1, Rf = 0.40) to yield 20 (2.62 g, 11.5 mmol, 75%) as an orange

oil. 1H NMR (400 MHz, CDCl3) δ 9.07 (dq, J = 8.8, 0.9 Hz, 1H), 7.82–7.70 (m, 2H), 7.58 (ddd, J = 8.6, 6.8,

1.5 Hz, 1H), 7.44 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 3.30–3.06 (m, 3H), 1.40 (d, J =

6.6 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 199.2, 143.9, 133.2, 132.4, 131.6, 128.9, 128.4, 125.6, 125.5,

125.3, 125.0, 42.8, 32.8, 15.3. The data were identical in all respects to those previously reported.64

(2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)hydrazine (9)

Under a nitrogen atmosphere, a mixture of 20 (780 mg, 3.42 mmol) and hydrazine

monohydrate (2 mL) in EtOH (2 mL) was heated at reflux for 16 h. When full

conversion was reached — monitored by TLC (pentane:CH2Cl2 = 6:1) — the heating

was stopped and the solution was allowed to cool to rt without stirring over 3 h. Part

of the product precipitated as light-yellow crystals. After separation from the liquid

phase, the crystals were washed with cold Et2O, dissolved in CH2Cl2, dried over


Overcrowded Alkenes

61

Na2SO4 and, after filtration, the volatiles were removed under reduced pressure. The liquid phase was

diluted with CH2Cl2 (20 mL) and washed with water (3 x 20 mL), brine and dried over Na2SO4. After


chromatography (SiO2, solvent gradient: pentane:EtOAc:NEt3 = 80:15:5 to 30:65:5) to yield 9 (combined

collected fractions: 0.56 g, 2.31 mmol, 68%) as light yellow crystals. 1H NMR (400 MHz, CDCl3) δ 8.42

(d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.48 (ddd, J = 8.6, 6.9, 1.6 Hz, 1H),

7.40 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 3.61–3.49 (m, 1H), 3.20 (ddd, J = 12.8, 5.9,

2.2 Hz, 1H), 2.71 (ddd, J = 12.8, 9.7, 2.4 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ

149.3, 135.7, 133.0, 132.1, 130.8, 128.0, 127.7, 126.7, 126.1, 125.9, 125.1, 36.4, 34.0, 14.7. The data were

identical in all respects to those previously reported.65

(Z) & (E)-1-(2-Methoxy-9H-fluoren-9-ylidene)-2-methyl-1,2-dihydro-1H-benzo[f]thiocromene (2)

Under a nitrogen atmosphere, Lawesson‘s reagent (1.00

g, 2.55 mmol) was added to a stirred solution of 14 (360



(pentane:CH2Cl2 = 2:1) started showing the formation

of degradation products. The mixture was concentrated

and the residue was purified by quick column

chromatography (SiO2, pentane:CH2Cl2 = 2:1). The wine red fraction was concentrated under reduced

pressure to yield the crude thioketone 12 as a dark wine red oil (to prevent hydrolysis, the product was kept

wet with CH2Cl2 and stored under a nitrogen atmosphere). Under a nitrogen atmosphere, a solution of 9

(280 mg, 1.154 mmol) in DMF (6 mL) was cooled to −40 °C and bis(trifluoroacethoxy)iodobenzene (248

mg, 1.154 mmol) was added to the stirred solution. The mixture was stirred for 1 min while the color turned

from yellow to dark pink, indicative of the formation in situ of the diazo compound 21. A solution of the

crude thioketone 12 in dry DMF (1 mL) and dry CH2Cl2 (1 mL) was added to the mixture, which showed

the evolution of nitrogen gas. The mixture was allowed to warm to rt and stirred for 2 h. The mixture was

diluted with EtOAc, washed with a sat. aq. NH4Cl solution, the organic layer was separated and the

aqueous layer was extracted with EtOAc (3 x 10 mL). The organic phases were collected, washed with

water, brine and dried over Na2SO4. After filtration, the volatiles were removed under reduced pressure and

the crude product was purified by column chromatography (SiO2, pentane:EtOAc = 50:1, Rf ((Z)-22) =

0.40, Rf ((E)-22) = 0.30) to yield yield (Z)-22 (113 mg, 0.28 mmol, 24%) and (E)-22 (147 mg, 0.36 mmol,

31%) as yellow amorphous residues (Z:E = 1:1.3).

(Z)-22: 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 7.5

Hz, 1H), 7.63–7.57 (m, 3H), 7.51–7.44 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.12 (d, J

= 8.4 Hz, 1H), 6.63 (dd, J = 8.3, 2.4 Hz, 1H), 5.04 (d, J = 2.3 Hz, 1H), 3.73–3.61 (m, 1H), 2.83 (s, 3H),

2.74 (dd, J = 12.1, 10.1 Hz, 1H), 2.43 (dd, J = 12.1, 5.1 Hz, 1H), 1.24 (d, J = 6.9 Hz, 3H).

(E)-22: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.3

Hz, 1H), 7.62–7.57 (m, 2H), 7.50 (d, J = 7.4 Hz, 2H), 7.19 (d, J = 2.2 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H),

7.05 (t, J = 7.5 Hz, 1H), 6.95 (dd, J = 8.3, 2.3 Hz, 1H), 6.39 (t, J = 7.6 Hz, 1H), 5.37 (d, J = 7.8 Hz, 1H),

3.91 (s, 3H), 3.69–3.57 (m, 1H), 2.77 (dd, J = 12.1, 10.0 Hz, 1H), 2.40 (dd, J = 12.2, 5.3 Hz, 1H), 1.22 (d, J

= 6.9 Hz, 3H).

A solution of (Z)-22 (59 mg, 0.134 mmol) and tris(dimethylamino)phosphine (0.05 mL, 0.27 mmol) in

toluene (3 mL) was stirred for 16 h at 65 °C. The mixture was then concentrated under reduced pressure

and the crude product was re-dissolved in CH2Cl2, washed with water, brine and dried over Na2SO4. After


chromatography (SiO2, solvent gradient: pentane:EtOAc = 100:1 to 50:1) to yield (Z)-2 (52 mg, 0.13 mmol,

95% from (Z)-22, 22% from 9) as yellow needles. (Z)-2: m.p. 191–192 °C; 1H NMR (500 MHz, CDCl3) δ

8.02 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.82 (t, J = 8.5 Hz, 2H), 7.65 (d, J = 6.8 Hz, 1H), 7.60 (d,

Chapter 2

62

J = 8.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.40–7.35 (m, 2H), 7.34–7.29 (m, 1H), 7.28–7.22 (m, 1H), 6.60

(dd, J = 8.3, 2.3 Hz, 1H), 5.25 (d, J = 2.3 Hz, 1H), 4.77 (ddd, J = 7.8, 7.3, 6.8 Hz, 1H), 3.36 (dd, J = 12.3,

7.3 Hz, 1H), 2.88 (s, 3H), 2.59 (dd, J = 12.3, 7.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H); 13

C NMR (126 MHz,

CDCl3) δ 158.6, 142.1, 141.5, 138.9, 137.5, 137.3, 134.3, 134.1, 133.4, 133.0, 132.2, 128.0, 127.9, 127.6,

127.5, 125.8, 125.6, 125.1, 124.8, 119.5, 118.9, 115.4, 108.9, 54.4, 39.5, 37.4, 18.7, one signal (C) was not

observed; HRMS (ESI, m/z): calcd for C28H23OS [M+H]+: 407.1464, found: 407.1466. Separation of the

enantiomers was achieved by CSP-HPLC (Chiralpak AD-H, heptane:2-propanol = 97:3, flow rate = 0.5

mL/min, Rt: 14.5 min for (Z,P,S)-2, 21.8 min for (Z,M,R)-2.

Following the same methodology, (E)-22 (60 mg, 0.134 mmol) was treated with

tris(dimethylamino)phosphine (0.05 mL, 0.27 mmol) in toluene (3 mL), to yield (E)-2 (52 mg, 0.13 mmol,

95% from (E)-22, 22% from 9) as yellow needles.

(E)-2: m.p. 243–244 °C; 1H NMR (500 MHz, CDCl3) δ 7.85 (t, J = 7.4 Hz, 3H), 7.71–7.62 (m, 2H), 7.58

(d, J = 8.6 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.03–6.93

(m, 2H), 6.46 (t, J = 7.7 Hz, 1H), 5.65 (d, J = 8.0 Hz, 1H), 4.73 (ddd, J = 7.7, 7.3, 6.8, Hz 1H), 3.96 (s, 3H),

3.35 (dd, J = 12.2, 7. Hz 3, 1H), 2.59 (dd, J = 12.2, 7.7 Hz, 1H), 1.38 (d, J = 6.8 Hz, 3H); 13

C NMR (126

MHz, CDCl3) δ 159.3, 142.2, 139.7, 139.3, 137.4, 136.8, 134.6, 134.2, 134.1, 133.3, 132.1, 128.3, 128.1,

127.3, 127.2, 127.2, 125.6, 125.4, 124.9, 124.6, 120.2, 118.1, 112.6, 112.3, 55.8, 39.1, 37.3, 18.5; HRMS

(ESI, m/z): calcd for C28H23OS [M+H]+: 407.1464, found: 407.1465. Separation of the enantiomers was

achieved by CSP-HPLC (Chiralpak AD-H, heptane:2-propanol = 97:3, flow rate = 0.5 mL/min, 40 ºC. Rt:

19.4 min for (E,P,S)-2, 22.9 min for (E,P,R)-2.

3-methyl-2,3-dihydrophenanthren-4(1H)-one (23)

Compound 23 was prepared from 2,3-dihydrophenanthren-4(1H)-one by following the

procedure previously reported (320 mg, 1.52 mmol, 96%). Analytical data were in

accord with the literature.66

1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 8.7 Hz, 1H),

7.90 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.1, 1.4 Hz, 1H), 7.61 (ddd, J = 8.7, 7.0, 1.4 Hz,

1H), 7.48 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 3.21 (ddd, J = 17.4,

10.8, 5.0 Hz, 1H), 3.15 (ddd, J = 17.4, 4.8, 4.5 Hz, 1H), 2.77 (ddq, J = 11.9, 6.8, 4.7 Hz, 1H), 2.27 (dddd, J

= 12.9, 11.9, 10.4, 4.7 Hz, 1H), 1.99 (dddd, J = 12.9, 5.0, 4.7, 4.5 Hz, 1 H), 1.32 (d, J = 6.8 Hz, 3 H); 13

C

NMR (100 MHz, CDC13) δ 203.1, 145.6, 133.5, 132.5, 131.1, 128.3, 128.0, 126.9, 126.7, 126.3, 125.5,

43.6, 30.9, 30.1, 15.7.

(3-methyl-2,3-dihydrophenanthren-4(1H)-ylidene)hydrazine (10)

Compound 10 was prepared starting from 23 (320 mg, 1.52 mmol) by following the

procedure previously reported (226 mg, 1.01 mmol, 67%). Analytical data were in

accord with the literature.64

1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 8.4 Hz, 1H),

7.78 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.52–7.45 (m, 1H), 7.40 (app. t, J =

7.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 3.24–3.13 (m, 1H), 2.82 (dt, J = 15.3, 4.3 Hz,

1H), 2.68 (ddd, J = 15.3, 11.8, 3.9 Hz, 1H), 2.36–2.25 (m, 1H), 1.50–1.29 (m, 1H), 1.27 (d, J = 6.9 Hz,

3H); 13

C NMR (126 MHz, CDCl3) δ 151.7, 138.9, 133.4, 131.0, 129.9, 128.0, 128.0, 126.4, 126.4, 126.0,

124.8, 31.7, 29.7, 29.5, 16.1.

(Z) & (E)-4-(2-methoxy-9H-fluoren-9-ylidene)-3-methyl-1,2,3,4-tetrahydrophenanthrene (3)

Under a nitrogen atmosphere, Lawesson‘s reagent (810

mg, 2.00 mmol) was added to a stirred solution of 14 (280



(pentane:CH2Cl2 = 2:1) started showing the formation of

degradation products. The mixture was concentrated and


Overcrowded Alkenes

63

the residue was purified by quick column chromatography (SiO2, pentane:CH2Cl2 2:1). The wine red

fraction was concentrated under reduced pressure to yield the crude thioketone 12 as a dark wine red oil (to

prevent hydrolysis, the product was kept wet with CH2Cl2 and stored under a nitrogen atmosphere). Under a

nitrogen atmosphere, a solution of 10 (180 mg, 0.80 mmol) in DMF (4 mL) was cooled to –40 °C and

bis(trifluoroacethoxy)iodobenzene (384 mg, 0.90 mmol) was added to the stirred solution. The mixture was

stirred for 1 min while the color turned from yellow to dark pink, indicative of the formation in situ of the

diazo compound 24. A solution of the crude thioketone 12 in dry DMF (2 mL) and dry of CH2Cl2 (2 mL)

was added to the mixture, which showed the evolution of nitrogen gas. The mixture was allowed to warm

to rt and stirred for 16 h. The mixture was diluted with EtOAc, washed with a sat. aq. NH4Cl solution, the

organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic

phases were collected, washed with water, brine and dried over Na2SO4. After filtration, the volatiles were

removed under reduced pressure and the crude product was purified by column chromatography (SiO2,

pentane:EtOAc = 50:1) to yield a mixture of episulfides 25 (220 mg, 0.52 mmol, 65%, Z:E = 1:1) as a

yellow amorphous residue. (Z)-25: 1H NMR (200 MHz, CDCl3) δ 9.18 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.1

Hz, 1H), 7.74–7.51 (m, 4H), 7.51–7.33 (m, 3H), 7.26 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.61 (dd,

J = 8.3, 2.4 Hz, 1H), 5.46 (d, J = 2.4 Hz, 1H), 3.20–3.05 (m, 1H), 2.71 (s, 3H), 2.18 (dd, J = 14.6, 5.3 Hz,

1H), 1.95–1.80 (m, 1H), 1.75–1.53 (m, 1H), 1.11 (d, J = 6.9 Hz, 3H), 1.1–0.95 (m, 1H). (E)-25: 1H NMR

(400 MHz, CDCl3) δ 9.10 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 9.9 Hz, 1H), 7.67–7.55 (m, 3H), 7.48 (d, J = 8.5

Hz, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.97 (dd, J = 8.3, 2.3 Hz, 1H), 6.94 (d, J = 8.2

Hz, 1H), 6.41 (t, J = 7.1 Hz, 1H), 5.76 (d, J = 7.8 Hz, 1H), 3.92 (s, 3H), 3.14–3.04 (m, 1H), 2.16 (dd, J =

14.6, 5.1 Hz, 1H), 1.93–1.82 (m, 1H), 1.72–1.57 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H), 1.05–0.95 (m, 1H).

The mixture of (Z)- and (E)-25 was re-dissolved in toluene (15 mL), tris(dimethylamino)phosphine (0.29

mL, 1.60 mmol) was added and the mixture was stirred for 16 h at rt. The mixture was concentrated under

reduced pressure and the residue was re-dissolved in CH2Cl2 (15 mL), washed with water (2 x 15 mL),

brine and dried over Na2SO4. After filtration, the volatiles were removed under reduced pressure and the

crude product was purified by column chromatography (SiO2, pentane:EtOAc = 50:1) to yield (Z)-3 (98.1

mg, 0.25 mmol, 48% from mixture of (Z)- and (E)-25, 30% from 10) and (E)-3 (104.2 mg, 0.27 mmol, 51%

from mixture of (Z) & (E)-25, 32% from 10) as yellow needles. (Z)-3: m.p. 174–175 °C; 1H NMR (500

MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.1

Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.33 (dt, J = 7.5, 3.8 Hz, 1H), 7.25 (dt, J = 8.1,

2.0 Hz, 1H), 6.62 (dd, J = 8.3, 2.3 Hz, 1H), 5.49 (d, J = 2.2 Hz, 1H), 4.32 (app. sext, J = 7.5 Hz, 1H), 2.81

(s, 3H), 2.78–2.73 (m, 1H), 2.57 (td, J = 13.6, 5.0 Hz, 1H), 2.50–2.43 (m, 1H), 1.34 (d, J = 6.9 Hz, 3H),

1.26–1.11 (m, 1H); 13

C NMR (126 MHz, CDCl3) δ 158.5, 144.4, 141.0, 140.1, 139.1, 137.8, 133.4, 133.3,

132.7, 132.2, 132.1, 128.3, 128.0, 127.4, 126.9, 126.0, 125.8, 125.2, 125.2, 125.1, 119.4, 118.8, 115.0,

108.7, 54.3, 34.7, 31.0, 29.7, 20.9; HRMS (ESI, m/z): calcd for C29H25O [M+H]+: 389.1899, found:

389.1898. Separation of the enantiomers was achieved by CSP-HPLC (Chiralcel OD-H, heptane:2-

propanol = 98:2, flow rate = 0.5 mL/min, Rt: 17.35 min for (Z,P,R)-3, 21.50 min for (Z,M,S)-3.

(E)-3: m.p. 199–200 °C; 1H NMR (500 MHz, CDCl3) δ 7.95–7.84 (m, 3H), 7.71 (d, J = 8.3 Hz, 1H), 7.67

(d, J = 1.7 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.22 (t, J =

7.6 Hz, 2H), 7.02 (t, J = 7.4 Hz, 2H), 6.99 (dd, J = 8.3, 2.1 Hz, 1H), 6.48 (t, J = 7.7 Hz, 1H), 5.90 (d, J =

8.0 Hz, 1H), 4.29 (app. sext, J = 6.7 Hz, 1H), 3.96 (s, 3H), 2.80–2.70 (m, 1H), 2.58 (td, J = 13.3, 4.9 Hz,

1H), 2.51–2.35 (m, 1H), 1.28 (d, J = 6.9, 3H), 1.23–1.11 (m, 1H); 13

C NMR (126 MHz, CDCl3) δ 159.3,

144.5, 139.8, 139.5, 139.5, 137.7, 134.2, 133.5, 133.4, 132.2, 132.0, 128.6, 128.2, 126.8, 126.7, 125.7,

125.4, 125.0, 124.9, 124.5, 120.1, 118.0, 112.2, 112.2, 55.7, 34.6, 30.9, 29.6, 20.7. HRMS (ESI, m/z): calcd

for C29H25O [M+H]+: 389.1899, found: 389.1898. Separation of the enantiomers was achieved by CSP-

HPLC (Chiralcel OD-H, heptane:2-propanol = 99:1, flow rate = 0.5 mL/min, Rt: 13.70 min for (E,M,S)-3,

25.50 min for (E,P,R)-3.

Chapter 2

64

2.5.3 Irradiation experiments

Characterization and monitoring by UV-vis absorption and CD spectroscopy

Irradiation was performed using a Spectroline ENB-280C/FE lamp (for compounds (Z) & (E)-1 and (Z) &

(E)-3 312 nm was used, for compounds (Z) & (E)-2 and (Z) & (E)-4 365 nm was used) or a Thorlabs INC

OSL 1-EC fibre illuminator in combination with a cut-off filter (for compounds (Z) & (E)-1 and (Z) & (E)-

3 420 nm was used, for compounds (Z) & (E)-2 and (Z) & (E)-4 450 nm was used). Solutions of

enantiopure stable forms (heptane, 1.0·10-5

M) were transferred in a quartz cuvette with magnetic stirrer

and degassed with argon under stirring. The samples were irradiated under stirring over multiple cycles (2

min at 312/365 nm, 15–20 min at 420/450 nm) by placing the cuvette at a distance of 3 cm from the center

of the lamp. To ensure the PSS was reached, several spectra were recorded at set intervals until no further

changes were observed. Multiple UV-vis absorption spectra were recorded at set intervals during each cycle

to follow both irradiation processes stepwise. CD spectra were recorded of starting solutions and after

reaching the PSS mixtures at 312 or 365 nm as observed by UV-vis absorption.

Identification of (Z) and (E)-isomers of stable and metastable forms by 1H NMR spectroscopy

The configuration of the (Z) and (E)-isomers of both the stable and metastable forms could be easily

assigned by the difference in chemical shift of the absorption corresponding to the methoxy-substituent and

protons in position 1 and 8 on the fluorenyl half in the 1H NMR spectra. For example, in both stable-(Z)-1

and metastable-(Z)-1, the chemical shift of the absorption corresponding to the methoxy-substituent is

located in the range 3.50–3.40 ppm, while the proton in position 1 of the fluorenyl half (ortho to the

methoxy-substituent) is located in the range 5.90–5.80 ppm. Similarly, in both stable-(E)-1 and metastable-

(E)-1, the chemical shift of the absorption corresponding to the methoxy-substituent is located in the range

3.95–3.90 ppm, while the proton in position 8 of the fluorenyl half is located in the range 6.25–6.15 ppm.

These uncommon chemical shifts are caused by the atypical magnetic environment experienced by the

aforementioned protons in each isomer when placed close to the aromatic part of the upper half. The

chemical shifts differ of more than 0.5 ppm from their respective expected values, thus making the

assignment of the isomers feasible. Similar analysis was performed for the other compounds described in

this work (vide supra).

General procedure for irradiation experiments, characterization of metastable isomers and

determination of the composition of the photostationary state by 1H NMR spectroscopy

Stable isomers of 1-4 (~3 mg) were dissolved in CDCl3 (0.6 mL). This sample was placed in an NMR tube

and irradiated (312 or 365 nm) at a distance of 3 cm from the center of the lamp. 1H NMR spectra of the

sample were taken before, during and after irradiation at rt. No further changes were observed after 6 h of

irradiation. For 1H NMR spectra absorptions list of stable isomers, see characterization in the Synthetic

procedures section. The relative integration of the absorptions peaks from the two isomers revealed PSS

ratios of stable:metastable isomers at 312 or 365 nm) in CDCl3 reported as follows.

metastable-(E)-1: 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 1H), 7.54–7.48 (m, 2H), 7.13–7.06

(m, 2H), 6.91 (dd, J = 8.3, 2.2 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.17 (d, J = 7.9

Hz, 1H), 4.33–4.27 (m, 1H), 3.92 (s, 3H), 2.82–2.72 (m, 2H), 1.92 (s, 3H), 1.62 (d, J = 6.3 Hz, 3H).

PSS ratio (312 nm) of stable-(Z)-1 : metastable-(E)-1 = 16:84.

metastable-(Z)-1: 1H NMR (500 MHz, CDCl3) 7.88 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 7.5, 1.3 Hz, 1H), 7.47

(d, J = 8.3 Hz, 1H), 7.32–7.22 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.72 (dd, J = 8.3,

2.4 Hz, 1H), 5.81 (d, J = 2.4 Hz, 1H), 4.36–4.30 (m, 1H), 3.43 (s, 3H), 2.78 (qd, J = 12.5, 3.0 Hz, 2H), 2.42

(s, 3H), 1.98 (s, 3H), 1.60 (d, J = 6.3 Hz, 3H). The relative integration of the absorptions peaks from the

two isomers revealed a PSS ratio (312 nm) in CDCl3 of stable-(E)-1 : metastable-(Z)-1 = 3:97.

metastable-(E)-2: 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.71–7.66 (m, 3H), 7.63 (d, J =

8.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.41 (dt, J = 7.5, 1.0 Hz, 1H), 7.19 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H),

6.99 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 6.95 (dd, J = 8.4, 2.3 Hz, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.37 (ddd,


Overcrowded Alkenes

65

J = 8.3, 7.3, 1.2 Hz, 1H), 5.61 (d, J = 8.0 Hz, 1H), 4.63–4.55 (m, 1H), 3.95 (s, 3H), 2.96–2.82 (m, 2H), 1.69

(dd, J = 6.4, 0.9 Hz, 3H). PSS ratio (312 nm) of stable-(Z)-2 : metastable-(E)-2 = 14:86.

metastable-(Z)-2: 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.72–

7.67 (m, 2H), 7.63–7.59 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.35–7.28 (m, 2H),

7.23 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H), 5.24 (d, J = 2.3 Hz, 1H),

4.68–4.60 (m, 1H), 3.02 (s, 3H), 2.95–2.83 (m, 2H), 1.67 (d, J = 6.3 Hz, 3H). PSS ratio (312 nm) of stable-

(E)-2 : metastable-(Z)-2 = 5:95.

metastable-(E)-3: 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 8.7, 1.1 Hz, 1H),

7.73 (dd, J = 8.0, 1.4 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.50–7.46 (m, 1H), 7.42

(d, J = 8.2 Hz, 1H), 7.24–7.19 (m, 1H), 7.00 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 6.97–6.91 (m, 2H), 6.40 (ddd, J

= 8.2, 7.3, 1.2 Hz, 1H), 5.92 (d, J = 7.8 Hz, 1H), 4.10 (app. p, J = 6.7 Hz, 1H), 3.95 (s, 3H), 3.07–2.98 (m,

1H), 2.79–2.72 (m, 1H), 1.96–1.89 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H). PSS ratio (312 nm) of stable-(Z)-3 :

metastable-(E)-3 = 12:88.

metastable-(Z)-3: 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.78 (d,

J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.66–7.63 (m, 1H), 7.43 (dd, J = 8.3, 1.6 Hz, 2H), 7.31 (tt, J =

7.4, 5.9 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.08–7.01 (m, 1H), 6.55 (dd, J = 8.3, 2.4 Hz, 1H), 5.52 (d, J =

2.3 Hz, 1H), 4.15 (app. p, J = 6.5 Hz, 1H), 3.10–3.00 (m, 1H), 2.93 (s, 3H), 2.76 (dt, J = 15.1, 3.1 Hz, 1H),

1.97–1.90 (m, 1H), 1.55 (d, J = 6.7 Hz, 3H). PSS ratio (312 nm) of stable-(E)-3 : metastable-(Z)-3 = 5:95.

Collected 1H NMR spectra of stable isomers and PSS mixtures of compounds 1-3

Chapter 2

66


Overcrowded Alkenes

67

2.5.4 Kinetic experiments via thermal decay

(Z) & (E)-1. A flame-died Schlenk tube equipped with stirring bar and filled with argon was loaded with

hexanol (99% purity grade, 1.5 mL), then a solution of optically pure stable-(Z)-1 or stable-(E)-1 in hexanol

(0.5 mL, ~10−5

M) previously irradiated with UV light (312 nm) to reach the photostationary state was

injected in the tube. The solution obtained was freeze-thawed 3 times and the tube was filled with argon.

The tube was placed in a preheated oil bath at a fixed temperature (ranging from 131 ºC to 152 ºC) and

stirred for ~ 6 h (see corresponding Figure 2.3 or Figure 2.S6 for further details). At set time intervals

(ranging from 10 min to 300 min) an aliquot (~0.1 mL) was withdrawn and cooled in a HPLC vial

containing heptane (~0.2 mL). The temperature of the oil baths during the kinetics experiments were

measured with a Pt1000 RTD Temperature Sensor. Analysis by chiral HPLC (the same methods used for

the isolation of the pure enantiomers were applied to the analysis), setting the wavelength of the analysis at

the specific isosbestic point (λ = 344 nm), afforded the data for monitoring the decay of metastable-(E)-1 or

metastable-(Z)-1 and the formation of the stable-(Z)-1 and stable-(E)-1.

(Z) & (E)-2. A flame-died Schlenk tube equipped with stirring bar and filled with argon was charged with

dodecane (99% purity grade, 1.5 mL), then a solution of optically pure stable-(Z)-2 or stable-(E)-2 in

dodecane (0.5 mL, ~10−5

M) was injected in the tube. The solution obtained was bubbled with argon for 5

min and irradiated with UV light (365 nm) to reach photostationary state after 30 min. Then the tube was

placed in a preheated oil bath at a fixed temperature (ranging from 112 ºC to 140 ºC) and stirred for ~5 h

(see corresponding Figure 2.3 or Figure 2.S6 for further details). At a set of time intervals (ranging from 10

min to 300 min) an aliquot (~0.1 mL) was withdrawn and quenched in a HPLC-vial containing heptane

(~0.2 mL). The temperature of oil baths during the kinetics experiments were measured with a Pt1000 RTD

Temperature Sensor. Analysis by chiral HPLC (the same programs used for the isolation of the pure

enantiomers were applied to the analysis), setting the wavelength of the analysis at the specific isosbestic

point (λ = 366 nm), afforded the data for monitoring the decay of metastable-(E)-1 or metastable-(Z)-2 and

the formation of the stable-(Z)-1 and stable-(E)-1.

(Z) & (E)-3. A UV-vis quartz cuvette with screw cap was filled with a solution of optically pure stable-(Z)-

3 or stable-(E)-3 in dodecane (~10−5

M) previously bubbled with argon and irradiated with UV light (312

nm) to reach photostationary state. The cuvette was transferred into a CD spectrometer equipped with a

Peltier temperature control cell preheated at a fixed temperature (ranging from 95 ºC to 107 ºC) and heated

over 24 h (see corresponding Figure 2.3 or Figure 2.S6 for further details). The decay process was followed

Chapter 2

68

via time course experiment by monitoring the change in CD signal at λ = 381 nm (wavelength of maximal

CD signal difference) over time. Analysis by chiral HPLC (the same programs used for the isolation of the

pure enantiomers were applied to the analysis) of the final solutions after completion of decay process of

metastable-(E)-3 afforded the final ratio of stable-(Z)-3 and stable-(E)-3.

(Z)-4. A UV-vis quartz cuvette with screw cap was filled with a solution of optically pure stable-(Z)-4 in

dodecane (~10−5

M) bubbled with argon and irradiated with UV light (312 nm) to reach photostationary

state. The cuvette was transferred into a CD spectrometer equipped with a Peltier temperature control cell

preheated at a fixed temperature (ranging from 84 ºC to 105 ºC) and heated over 24 h (see corresponding

Figure 2.3 for further details). The decay process was followed by a time course experiment, monitoring the

change in CD signal at λ = 395 nm over time. Analysis by chiral HPLC (the same program used for the

isolation of the pure enantiomer was applied to the analysis) of the final solutions after completion of decay

process of metastable-(E)-4 afforded the final ratio of stable-(Z)-4 and stable-(E)-4.

2.5.5 Collected PSS ratios and TEZI/THI ratios of compounds 1-4

The TEZI/THI ratios of stable products after thermal decay of each metastable form were calculated at the

corresponding temperature at which the half-life is 1 h (T at t1/2 = 1 h) from the determined thermodynamic

parameters (see main text, Table 1 for (Z)-1–4 and Experimental section, Table 2.4 for (E)-1–3):

Compound (Z)-1

PSS (312 nm): stable-(Z)-1 : metastable-(E)-1 = 5:95


TEZI/THI-ratio at T at t1/2 = 1 h (138.2 °C): stable-(Z)-1 : stable-(E)-1 = 93:7

Compound (E)-1

PSS (312 nm): stable-(E)-1 : metastable-(Z)-1 = 3:97



Compound (Z)-2




Compound (E)-2




Compound (Z)-3




Compound (E)-3




Overcrowded Alkenes

69


Compound (Z)-4




2.6 References

(1) H.-J. Schneider, Ed., Chemoresponsive Materials, Royal Society of Chemistry, Cambridge, 2015.

(2) J. Zhang, Q. Zou, H. Tian, Adv. Mater. 2013, 25, 378–399.

(3) H. Dong, H. Zhu, Q. Meng, X. Gong, W. Hu, Chem. Soc. Rev. 2012, 41, 1754–1808.

(4) A. Coskun, M. Banaszak, R. D. Astumian, J. F. Stoddart, B. A. Grzybowski, Chem. Soc. Rev. 2012, 41,

19–30.

(5) B. L. Feringa, W. R. Browne, Molecular Switches Vol. I, II, Wiley-VCH Verlag GmbH & Co. KGaA,


(6) W. R. Browne, B. L. Feringa, Nat. Nanotechnol. 2006, 1, 25–35.

(7) M. Schliwa, Molecular Motors, Wiley-VCH Verlag GmbH, 2006.

(8) M. Schliwa, G. Woehlke, Nature 2003, 422, 759–765.

(9) E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem. Int. Ed. 2007, 46, 72–191.

(10) M. von Delius, D. A. Leigh, Chem. Soc. Rev. 2011, 40, 3656–3676.

(11) F. D. Jochum, P. Theato, Chem. Soc. Rev. 2013, 42, 7468–7483.

(12) Q. Yan, Z. Luo, K. Cai, Y. Ma, D. Zhao, Chem. Soc. Rev. 2014, 43, 4199–4221.

(13) M. Schwartz, Smart Materials, CRC Press, 2008.

(14) M. W. Urban, Ed., Handbook of Stimuli-Responsive Materials, Wiley-VCH Verlag GmbH & Co. KGaA,


(15) M. Shahinpoor, H.-J. Schneider, Eds., Intelligent Materials, Royal Society of Chemistry, Cambridge,

2007.

(16) M. A. C. Stuart, W. T. S. Huck, J. Genzer, M. Müller, C. Ober, M. Stamm, G. B. Sukhorukov, I. Szleifer,

V. V Tsukruk, M. Urban, et al., Nat. Mater. 2010, 9, 101–113.

(17) J. Thévenot, H. Oliveira, O. Sandre, S. Lecommandoux, Chem. Soc. Rev. 2013, 42, 7099–7116.

(18) Y. Shirota, H. Kageyama, Chem. Rev. 2007, 107, 953–1010.

(19) N. Koch, Ed. , Supramolecular Materials for Opto-Electronics, Royal Society Of Chemistry, Cambridge,

2014.

(20) C. J. Bruns, J. F. Stoddart, Acc. Chem. Res. 2014, 47, 2186–2199.

(21) G. Du, E. Moulin, N. Jouault, E. Buhler, N. Giuseppone, Angew. Chem. Int. Ed. 2012, 51, 12504–12508.

(22) A. Coskun, J. M. Spruell, G. Barin, W. R. Dichtel, A. H. Flood, Y. Y. Botros, J. F. Stoddart, Chem. Soc.

Rev. 2012, 41, 4827–4859.

(23) T. Kudernac, N. Ruangsupapichat, M. Parschau, B. Maciá, N. Katsonis, S. R. Harutyunyan, K.-H. Ernst,

B. L. Feringa, Nature 2011, 479, 208–211.

(24) J. Wang, B. L. Feringa, Science 2011, 331, 1429–1432.

(25) S. J. Wezenberg, M. Vlatković, J. C. M. Kistemaker, B. L. Feringa, J. Am. Chem. Soc. 2014, 136, 16784–

16787.

(26) W. M. Horspool, F. Lenci, CRC Handbook of Organic Photochemistry and Photobiology, Vol. 1 & 2,

CRC Press, Boca Raton, USA, 2003.

(27) G. S. Kottas, L. I. Clarke, D. Horinek, J. Michl, Chem. Rev. 2005, 105, 1281–1376.

(28) B. L. Feringa, J. Org. Chem. 2007, 72, 6635–6652.

(29) N. Koumura, R. W. Zijlstra, R. A. van Delden, N. Harada, B. L. Feringa, Nature 1999, 401, 152–155.

(30) N. Koumura, E. M7. Geertsema, M. B. van Gelder, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2002,

124, 5037–5051.

(31) J. C. M. Kistemaker, P. Štacko, J. Visser, B. L. Feringa, Nat. Chem. 2015, 7, 890–896.

Chapter 2

70

(32) E. M. Geertsema, S. J. van der Molen, M. Martens, B. L. Feringa, Proc. Natl. Acad. Sci. U. S. A. 2009,

106, 16919–16924.

(33) R. A. van Delden, M. K. J. ter Wiel, H. de Jong, A. Meetsma, B. L. Feringa, Org. Biomol. Chem. 2004, 2,

1531–1541.

(34) J. Vicario, A. Meetsma, B. L. Feringa, Chem. Commun. 2005, 5910–5912.

(35) D. Pijper, R. A. van Delden, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 17612–17613.

(36) J. Vicario, M. Walko, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2006, 128, 5127–5135.

(37) M. M. Pollard, M. Lubomska, P. Rudolf, B. L. Feringa, Angew. Chem. Int. Ed. 2007, 46, 1278–1280.

(38) M. Klok, N. Boyle, M. T. Pryce, A. Meetsma, W. R. Browne, B. L. Feringa, J. Am. Chem. Soc. 2008, 130,

10484–10485.

(39) A. Cnossen, D. Pijper, T. Kudernac, M. M. Pollard, N. Katsonis, B. L. Feringa, Chem. Eur. J. 2009, 15,

2768–2772.

(40) T. C. Pijper, D. Pijper, M. M. Pollard, F. Dumur, S. G. Davey, A. Meetsma, B. L. Feringa, J. Org. Chem.

2010, 75, 825–838.

(41) A. A. Kulago, E. M. Mes, M. Klok, A. Meetsma, A. M. Brouwer, B. L. Feringa, J. Org. Chem. 2010, 75,

666–679.

(42) L. F. Tietze, M. A. Düfert, T. Hungerland, K. Oum, T. Lenzer, Chemistry 2011, 17, 8452–8461.

(43) L. Greb, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 13114–13117.

(44) J. Bauer, L. Hou, J. C. M. Kistemaker, B. L. Feringa, J. Org. Chem. 2014, 79, 4446–4455.

(45) M. K. J. ter Wiel, R. A. van Delden, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 14208–

14222.

(46) R. Göstl, A. Senf, S. Hecht, Chem. Soc. Rev. 2014, 43, 1982–1996.

(47) V. Blanco, D. A. Leigh, V. Marcos, Chem. Soc. Rev. 2015, 44, 5341–70.

(48) M. Klok, M. Walko, E. M. Geertsema, N. Ruangsupapichat, J. C. M. Kistemaker, A. Meetsma, B. L.

Feringa, Chemistry 2008, 14, 11183–11193.

(49) G. B. Kistiakowsky, W. R. Smith, J. Am. Chem. Soc. 1934, 56, 638–642.

(50) A. V. Santoro, E. J. Barrett, H. W. Hoyer, J. Am. Chem. Soc. 1967, 89, 4545–4546.

(51) I. Agranat, M. Rabinovitz, A. Weitzen-Dagan, I. Gosnay, J. Chem. Soc. Chem. Commun. 1972, 732–733.

(52) P. U. Biedermann, J. J. Stezowski, I. Agranat, European J. Org. Chem. 2001, 2001, 15–34.

(53) A. Kazaryan, J. C. M. Kistemaker, L. V Schäfer, W. R. Browne, B. L. Feringa, M. Filatov, J. Phys. Chem.

A 2010, 114, 5058–5067.

(54) G. Pérez-Hernández, L. González, Phys. Chem. Chem. Phys. 2010, 12, 12279–12289.

(55) A. Cnossen, J. C. M. Kistemaker, T. Kojima, B. L. Feringa, J. Org. Chem. 2014, 79, 927–935.

(56) B. O. Roos, P. R. Taylor, P. E. M. Siegbahn, Chem. Phys. 1980, 48, 157–173.

(57) It is noted that multi-reference methods based on the density matrix renormalization group (DMRG)

approach are capable of handling much larger active spaces. Unfortunately, however, this approach is

unavailable in almost all QC software package.

(58) N. Ruangsupapichat, M. M. Pollard, S. R. Harutyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 53–60.

(59) D. J. van Dijken, J. Chen, M. C. A. Stuart, L. Hou, B. L. Feringa, J. Am. Chem. Soc. 2016, 138, 660–669.

(60) N. Berova, P. L. Polavarapu, K. Nakanishi, R. W. Woody, Eds. , Comprehensive Chiroptical

Spectroscopy, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2012.

(61) Forst, W. Theory of Unimolecular Reactions; Academic Press: New York, 2012.

(62) The Lambert W function solves y=x.e^x for x as x=W(y), see ref. 32 for further details.

(63) Despite considerable overlap in the UV, the PSS towards MS is nearly quantatative while the reverse PSS

towards stable is not, indicating that stable to MS quantum yields are much higher than MS to stable

quantum yields. This has also been observed by Cnossen et al. (see ref. 55) for a series of second

generation molecular motors.


124, 5037–5051.

(65) Pijper, T. C.; Pijper, D.; Pollard, M. M.; Dumur, F.; Davey, S. G.; Meetsma, A.; Feringa, B. L. J. Org.

Chem. 2010, 75, 825–838.

(66) Harada, N.; Koumura, N.; Feringa, B. L. J. Am. Chem. Soc. 1997, 119, 7256–7264.

Chapter 3 Chapter 3

Bifunctional Molecular Photoswitches based on

Overcrowded Alkenes for Dynamic Control of

Catalytic Activity in Michael Addition Reactions

The emerging field of artificial photoswitchable catalysis has recently shown striking examples of

functional light-responsive systems allowing for dynamic control of activity and selectivity in

organocatalysis and metal-catalyzed transformations. While our group has already disclosed systems

featuring first generation molecular motors as the switchable central core, a design based on second

generation molecular motors is lacking. Herein, the syntheses of two bifunctionalized molecular switches

based on a photoresponsive tetrasubstituted alkene core are reported. They feature a thiourea substituent

as hydrogen-donor moiety in the upper half and a basic dimethyl amine group in the lower half. This

combination of functional groups offers the possibility for application of these molecules in

photoswitchable catalytic processes. The light-responsive central cores were synthesized via a Barton-

Kellogg coupling of the prefunctionalized upper and lower halves. Derivatization via Buchwald-Hartwig

amination and subsequent introduction of the thiourea substituent afforded the target compounds. Control

of catalytic activity in the Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-

pentanedione is achieved upon irradiation of stable-(E) and stable-(Z) isomers of the bifunctional catalyst

1. Both isomers display a decrease in catalytic activity upon irradiation to the metastable state, providing

systems with the potential to be applied as ON/OFF catalytic photoswitches.

This chapter has been published as: S. F. Pizzolato, B. S. L. Collins, T. van Leeuwen, B. L. Feringa, Chem.

Eur. J. 2017, 23, 6174–6184.

Chapter 3

72

3.1 Introduction

3.1.1 Photocontrol of catalytic functions

External control of catalytic systems by light is a highly challenging and still underdeveloped field of

modern organic chemistry. In the quest for responsive catalytic systems, many advantages arise from the

use of light as a clean, non-invasive stimulus, where judicious choice of irradiation wavelength may allow

precise control over catalyst function, activity and selectivity. A number of photoresponsive catalysts have

been developed over the last decade, exploiting the established switching properties of azobenzenes,

diarylethenes and overcrowded alkenes.1–5

Promising results in photochemical control of catalyst activity or

selectivity have been achieved via different approaches by harnessing cooperative,6–12

steric13–20

and

electronic effects21–25

of the photo-accessible isomers.

For instance, Hecht and co-workers developed a series of photoswitchable catalysts, based on a 3,5-

disubstituted azobenzene core featuring a piperidine base, in which the modulation of steric shielding was

used to control catalytic activity (Scheme 3.1a).16

Upon photoswitching, the basic piperidine nitrogen atom

is exposed in the (Z)-isomer, allowing enhancement of rate of the aza-Henry reaction of nitroethane to p-

nitroanisaldehyde compared to the (E)-isomer (kZ/kE = 35.5). Rebek and co-workers introduced a light-

responsive cavitand/piperidinium complex that displayed switchable catalytic activity for the Knoevenagel

condensation of aromatic aldehydes with malonitrile.17

The cavitand features an azobenzene arm capable of

competing with the piperidinium ion for the cavity when irradiated with UV light, allowing reversible

control of the guest binding and reactivity. Imahori and co-workers reported a bis(trityl alcohol)-substituted

azobenzene as a cooperative bifunctional switchable catalyst capable of reversible activity control when

applied to a Morita–Baylis–Hillman reaction of 3-phenylpropanal and 2-cyclopenten-1-one.10

The

switchable catalyst was able to increase the yield of the reaction after 2 h (background, 27%) from 37%

using the less active state (E)-isomer to 78% yield using the more active (Z)-isomer. Pericás and co-workers

developed a switchable azobenzene-thiourea organocatalyst, which was used to achieve control of Michael

addition reactions through reversible hydrogen-bond shielding of the catalytic unit, enabled by a nitro group

as the blocking moiety.20

The (E)-isomer effectively catalyzes the Michael addition of 2,4-pentanedione to

(E)-3-bromo-β-nitrostyrene (full conversion was achieved after 19 h), while the photogenerated (Z)-isomer,

in which the nitro group engages in hydrogen bonding interactions with the thiourea moiety, leads to a

significantly lower reaction rate (only 23% conversion after 20 h). Chen and co-workers developed a

pseudo-enantiomeric pair of optically switchable helicenes containing a catalytic 4-N-methylaminopyridine

(MAP).26

Successful application was found in the enantiodivergent Steglich rearrangement of O- to C-

carboxylazalactones, with formation of either enantiomer with up to 91% ee (R) and 94% ee (S),

respectively. Branda and co-workers developed various systems for exploiting the characteristic switching

of structural and electronic properties of diarylethenes to allow for instance for control of Lewis

acidity/basicity,27,28

stereoselectivity8 and substrate reactivity,

29–33 Other approaches, including the

application of photoresponsive systems for controlling the rate of ring-opening polymerizations,24,34–36

are

summarized in comprehensive recent reviews.1–5

Our group demonstrated stimuli-responsive control of the activity and enantioselectivity of a catalyst via

dynamic conformational changes of a first generation molecular motor equipped with two functional groups

able to cooperatively accelerate a reaction (Scheme 3.1b; for the switching process of the main core, see

Scheme 3.2a).9 The two pseudo-enantiomeric (Z)-isomers of the molecular motor during its rotary cycle

were shown to control the stereochemical outcome of an organocatalytic thiol 1,4-addition, allowing access

to both enantiomers of the product depending on the state of the catalyst. This organocatalyst bears a 2-

aminopyridine base and a weakly acidic thiourea functionality, which were proposed to engage in bidentate

coordination of the substrates, leading to both accelerated reaction rates and high levels of stereocontrol.

Subsequently we extended the application of this concept to an organocatalyzed Henry reaction upon

structural modification of the chiral catalyst, improving its versatility and efficiency through a more

constrained catalytic pocket.12

Bifunctional Molecular Photoswitches based on Overcrowded Alkenes for Dynamic Control of Catalytic

Activity in Michael Addition Reactions

73

Scheme 3.1. a) Photoswitchable azobenzene-based piperidine as light- and heat-triggered catalyst to

achieve rate control of Henry reaction via reversible steric shielding of basic/nucleophilic site. b)

Photoswitchable overcrowded alkene-based light- and heat-triggered thiourea-DMAP bifunctional catalyst

to achieve control of rate and enantioselectivity in a Michael addition reaction via reversible E-Z

photoisomerization and thermal helix inversion.

Furthermore application of dynamic control of chirality with responsive phosphine ligands for palladium-

catalyzed enantioselective allylic substitution was demonstrated.37

A similar chiral first generation

molecular motor scaffold was recently exploited in a light- and heat-responsive bis-urea receptor capable of

multi-state regulation of dihydrogen phosphate ion binding affinity.38

A major difference in binding affinity

of the interchangeable isomers was observed, enabling external control of substrate binding by the dynamic

host.

3.1.2 Unique features of molecular motors

Having established the potential of molecular motors39–42

as multiple switching elements in dynamic

chemical systems for stereoselective catalysis and anion recognition, we engaged in the challenge of

developing a prototype for a responsive bifunctional organocatalyst43–47

based on the second generation

molecular motor core. Unlike the first generation molecular motor (Scheme 3.2a),48

the second generation

motor structure features non-identical upper and lower halves, in which the upper half contains the sole

stereogenic center of the molecule (Scheme 3.2b).49–54

Upon irradiation with UV-light the central stilbene-

type alkene can undergo a photochemical E-Z isomerization that yields a metastable (MS) diastereoisomer

(top/right structures), which holds the opposite helical chirality to the original stable (St) diastereoisomer

(top/left structures). The metastable species can subsequently undergo a thermally activated isomerization

in which the upper half moves along the lower half, again resulting in an inversion of helicity, namely

thermal helix inversion (THI).50

In the resulting stable isomer (bottom/right structures), the upper half has

undergone a 180° rotation with respect to the lower half.

Chapter 3

74

Scheme 3.2. Isomerization processes leading to unidirectional rotation in: (a) first generation molecular

motor (four-stage cycle with four distinctive stereoisomers); (b) second generation molecular motor (four-

stage cycle with only two distinctive stereoisomers in case of symmetrically substituted lower half). St =

stable isomer, MS = metastable isomer.

In our previous study we showed that the combination of a 5-membered ring in the lower half (fluorene)

with a sulfur containing 6-membered ring in the upper half (5,8-dimethylthiochromene and

benzo[f]thiochromene) resulted in distinctive high energy activation barriers for the thermal relaxation step

in the rotary cycle of the second generation molecular motors and consequently long half-lives of the

metastable species.50,55

More precisely, the THI energy barrier dramatically increases due to the high

conformational constraints, resulting in an alternative and predominant thermal relaxation process, known

as thermal E-Z isomerization (TEZI) (for 5,8-dimethylthiochromene: Δ‡G°THI (100 °C, 1 atm) = 138 kJ・

mol−1, Δ

‡G°TEZI (100 °C, 1 atm) = 129 kJ・mol

−1, t½ (20 °C, 1 atm) = 75 years; for benzo[f]thiochromene:

Δ‡G°THI (100 °C, 1 atm) = 140 kJ・mol

−1, Δ

‡G°TEZI (100 °C, 1 atm) = 129 kJ・mol

−1, t½ (20 °C, 1 atm) =

4300 years). We demonstrated that these overcrowded alkene systems could be used as thermally highly

stable and selective photoswitchable bistable systems, both important requirements for reliable

photoresponsive catalysts, where each state should be selectively addressable with a high photostationary

state (PSS) ratio while remaining stable over time.

An interesting aspect of the second generation molecular motor scaffold is the possibility of functionalizing

the otherwise symmetrical lower half with two different catalytically active moieties (depicted as A and B

in Scheme 3.3), which could dynamically cooperate with the single functionality (C) on the upper half.

Through this design two distinct bifunctional catalytic pairs could be accessed. Notably these two pairs of

catalytic functional groups would also be addressed with two opposite helical chirality, P or M, upon

irradiation and thermal relaxation. We envision such a design as a feasible future route for stimuli-

responsive switchable catalysts in multi-tasking systems and one-pot multi-step diastereo- and

enantioselective reactions.2–4,9,37,56–60



75

Scheme 3.3. Proposed design of a trifunctional light- and heat-responsive organocatalyst for diastereo- and

enantioselective one-pot multi-step systems. The catalyst is envisioned to be switchable between four

different states, each displaying a different combination of active cooperative catalytic pair (AC or BC) and

helicity (P or M). In the scheme are displayed only two of the four possible products accessible by

combining three starting components (depicted as geoometrical shapes) in a chemo- and enantioselective

fashion (suggested handedness of the newly generated stereogenic centers indicated on the connecting

bond). By triggering the proper catalyst states, both enantiomers of each diastereoisomer could be accessed.

While the ultimate goal remains the syntheses of tri-functionalized bistable switches and their use as

catalysts in one-pot multistep reactions, initial studies have focused on the feasibility of introducing well-

established catalytic functional groups onto the overcrowded alkene scaffold found in second generation

molecular motors. Herein we report the first syntheses of two bifunctional molecular switches 1 and 2

based on the second generation molecular motor scaffold (Figure 3.1a). Featuring catalytic functions, each

switch was obtained both as (E)- and (Z)-stereoisomers (only (E)-isomer shown). Related to analogous

examples,9,16

these switches may allow for dynamic control of activity as ON/OFF or OFF/ON catalysts

(Figure 3.1b). Moreover, the present preliminary study is a stepping stone for future synthesis of more

complex trifunctionalized photoswitchable catalysts for multi-step synthesis (see Scheme 3.3).


3.2.1 Design

In order to address high switching performance and thermal stability, the aforementioned bistable switch

core was chosen (thiopyran upper half – fluorene lower half, Figure 3.1a).

Chapter 3

76

Figure 3.1. (a) Bifunctional molecular switches 1 and 2 ((Z)-isomers omitted). (b) General scheme for

photoswitching of bifunctional catalyst and potential application as an OFF/ON catalyst. c) Retrosynthetic

analysis of 1 and 2.

Our prototypes feature a thiourea substituent in the upper half, a well-established hydrogen-donor moiety in

organocatalysis,47,61,62

and a basic dimethyl amine group in the lower half. These functionalities were

chosen to reflect commonly encountered functional groups within the field of organocatalysis47,62–68

and to

avoid synthetic compatibility issues associated with the Barton-Kellogg coupling,69,70

the signature

synthetic step for this family of overcrowded alkenes. The reaction conditions required to synthesize the

thioketone and diazo coupling partners (Figure 3.1c) impose challenges to the synthetic design. For

instance, the established methodology commonly adopted to generate the thioketone includes the use of

Lawesson‘s reagent or P4S10 at high temperatures for prolonged reaction times, which may cause problems

with other functionalities present in the molecule. In line with these considerations, we chose to install a

dimethylamine substituent in the lower half, which is expected to tolerate the conditions for thioketone

formation. On the other hand, the more sensitive thiourea motif in the upper half is to be installed after the

construction of the tetrasubstituted alkene and amination of the upper half via a Buchwald-Hartwig

coupling (Figure 3.1c).71

3.2.2 Synthesis

The synthesis of (E)-1 and (Z)-1 is outlined in Schemes 3.4 and 3.5. The lower half coupling partner was

synthesized from commercially available 2-aminofluorene (Scheme 3.4). Methylation of the aniline moiety

via reductive amination with formaldehyde and sodium cyanoborohydride provided 3 (89%). Oxidation of



77

the fluorene was then achieved under an atmosphere of air using the trialkyl ammonium salt Triton B as a

catalyst in pyridine (89%). Fluorenone 4 was converted into the reactive thioketone 5 via thionation with

P4S10 in moderate yield (33%), where experimental observations indicate a subtle balance between

conversion of starting material and decomposition of product in this step, both highly dependent on

temperature and reaction time.

Scheme 3.4. Synthesis of lower half of switches 1 and 2.

The synthesis of the upper half started from commercially available 2-bromo-1,4-dimethylbenzene

(Scheme 3.5). By reacting with chlorosulfuric acid, the aryl halide was first converted to the corresponding

arylsulfonyl chloride 6 (90%). Subsequent reduction with zinc powder and sulfuric acid provided a 1.0:0.6

mixture of 4-bromo-2,5-dimethylbenzenethiol 7 and the corresponding disulfide, respectively (82%

overall), which was converted quantitatively to pure 7 by reduction with sodium borohydride. A 1,4-

addition reaction with methacrylic acid afforded the sulfide 8 (38%). The thiopyranone ring was finally

constructed via a two-step procedure from acid 8 via conversion to the more reactive acyl chloride with

oxalyl chloride followed by intramolecular Friedel-Crafts acylation to afford 9 (93%). All steps could be

performed on gram-scale with an overall yield of 26% over five steps from commercial starting material.

Scheme 3.5. Synthesis of the upper half of molecular switch 1.

Chapter 3

78

Scheme 3.6. Synthesis of molecular switches (E)-1 and (Z)-1. Note: (E)-13 and (Z)-13 were assigned via

the 1H NMR chemical shifts of the absorption peaks corresponding to the dimethylamine substituent and

the protons in position 1 or 8 on the fluorenyl lower half in line with previously reported analogous second

generation molecular motor scaffolds (see Experimental section for further details).

Ketone 9 was converted to the corresponding hydrazone 10 (42%) via condensation with hydrazine

monohydrate (Scheme 3.6). The hydrazone 10 could be transformed into the required diazo coupling

partner 11 for the Barton-Kellogg coupling reaction via rapid in situ oxidation at low temperature with

[bis(trifluoroacetoxy)iodo]-benzene. Reaction with thioketone 5 yielded a mixture of episulfides, (E)-12

and (Z)-12, which were readily converted via desulfurization with triphenylphosphine to the overcrowded

alkenes (E)-13 and (Z)-13. The two isomers could be separated by flash column chromatography to provide

(E)-13 and (Z)-13 in 35% and 21% yield, respectively, starting with hydrazone 10. The geometry of

isomers (E)-13 and (Z)-13, obtained in their stable states only, was assigned on the basis of the 1H NMR

chemical shifts of the absorptions corresponding to the dimethylamine substituent and the protons in

position 1 or 8 on the fluorenyl lower half (highlighted in Scheme 3.6) in line with previously reported

analogous second generation molecular motor scaffolds (for example: St-(E)-13, δ (-NMe2) = 3.07 ppm, St-

(Z)-13, δ (-NMe2) = 2.69 ppm; St = stable form; see Experimental section for further details). Initial

attempts to install the benzophenone imine moiety on bromides 13 via Buchwald-Hartwig amination failed,

with no detectable conversion even after prolonged reaction times. A halide exchange to the iodide species

before the Buchwald-Hartwig reaction, however, allowed us to successfully continue the synthesis.

Bromides (E)-13 and (Z)-13 were converted separately via aromatic Finkelstein reaction to the

corresponding iodides (E)-14 and (Z)-14 using a combination of copper iodide and potassium iodide. High



79

temperatures and long reaction times were required, providing (E)-14 in good yield (90%) and (Z)-14 as a

mixture of product and unconverted bromide starting material ((Z)-14:(Z)-13 = 8:1, 48%). The more

reactive iodide species were then submitted to the Buchwald-Hartwig amination reaction using a

palladium(II) acetate – 1,1‘-bis(diphenylphosphino)ferrocene catalytic system to install the benzophenone

imine moiety ((E)-15: 36%, (Z)-15: 63%). After hydrolysis to the free amine 16 ((E)-16: 80%, (Z)-16:

91%), nucleophilic addition to 3,5-bis(trifluoromethyl)phenyl isothiocyanate afforded the target thiourea-

functionalized switches ((E)-1: 85%, (Z)-1: 90%).

The related switches (E)-2 and (Z)-2 were synthesized via an analogous route starting from 6-bromo-2-

naphthol as shown in Schemes 3.7 and 3.8.

Scheme 3.7. Synthesis of the upper half of molecular switch 2 from commercial starting material in 70%

yield over five steps.

Chapter 3

80

Scheme 3.8. Synthesis of molecular switches (E)-2 and (Z)-2.

3.2.3 Photoswitching process

The switching properties of (E)-1, (Z)-1, (E)-2 and (Z)-2 were monitored by UV-vis absorption

spectroscopy (Figure 3.2) and 1H NMR spectroscopy (illustrated for (E)-1 in Figure 3.3 and (Z)-1 in Figure

3.4, vide infra). Solutions of stable (E)-1, (Z)-1, (E)-2 and (Z)-2 in tetrahydrofuran (1.0-2.0·10−5

M) in 1 cm

quartz cuvettes were irradiated at room temperature under stirring for a few minutes towards the metastable

state using UV light ((E)-1 and (Z)-1, 312 nm; (E)-2 and (Z)-2, 365 nm). The photochemical E-Z

isomerizations were found to be characterized by clear isosbestic points, indicating the absence of side-

reactions. All four switches exhibited a decrease in intensity of the absorption bands at 300–350 nm upon

irradiation at 312 nm or 365 nm and the appearance of a new absorption band in the region 350–480 nm,

characteristic of the generated metastable isomers. The metastable isomers were shown to be highly

thermally stable, exhibiting no degradation or back-isomerization upon standing at room temperature for

extended periods of time.

The PSS ratios for all four switches were determined using 1H and

19F NMR spectroscopy. In a general

procedure, the compound (approximately 0.5 mg) was dissolved in CD2Cl2 (0.7 mL) and the sample was

irradiated in an NMR tube at 312 nm at room temperature. The isomerization process was monitored over

time by means of 1H NMR spectroscopy (see Figure 3.3 for St-(E)-1). No further changes were observed

after 15 min of irradiation. Both isomers, St-(E)-1 and MS-(Z)-1 were assigned using two dimensional

COSY and NOESY NMR experiments (see Experimental section for further details). The relative



81

integration of the absorptions of the two isomers revealed a PSS ratio (312 nm) in CD2Cl2 of St-(E)-1:MS-

(Z)-1 = 18:82.

Figure 3.15 UV-vis spectra of the switching process of 1 and 2. Experimental UV-vis absorption spectra in

black of stable forms of (E)-1, (Z)-1, (E)-2, and (Z)-2 (THF, 1.0–2.5·10−5

M). Irradiation of (E)-1 (312 nm),

(Z)-1 (312 nm), (E)-2 (365 nm), and (Z)-2 (365 nm) to the metastable isomers affords a PSS shown in darl

gray with five intermediate moments in the process (total irradiation time: 5-10 min) shown in light gray

(St:MS ratio: (E)-1, 18:82; (Z)-1, 10:90; (E)-2, 20:80; (Z)-2, 16:84, ratios as determined by 1H and

19F

NMR spectroscopy in CD2Cl2, vide infra). Similar results were also obtained when CH2Cl2, toluene or

acetonitrile were used as solvent.

Chapter 3

82

Figure 3.3. (a) 1H NMR spectra of St-(E)-1 (approximately 0.5 mg in CD2Cl2, 0.7 mL), with magnification

of corresponding 19

F NMR spectra as inserts. (b) 1H NMR spectra after irradiation with 312 nm light of St-

(E)-1 to the metastable state MS-(Z)-1 affords a PSS mixture of St-(E)-1:MS-(Z)-1 = 18:82, with

magnification of corresponding 19

F NMR spectra. Spectral region of solvent residual peak (5.30–5.10 ppm)

cut for clarity.



83

An analogous experiment with St-(Z)-1 was performed (Figure 3.4). A PSS ratio of St-(Z)-1:MS-(E)-1 =

10:90 was achieved after irradiation at 312 nm in CD2Cl2 for 15 min.

Figure 3.4. (a) 1H NMR spectra of St-(Z)-1 (approximately 0.5 mg in CD2Cl2, 0.7 mL), with magnification

of corresponding 19

F NMR spectra as inserts. (b) 1H NMR spectra after irradiation with 312 nm light of (Z)-

1 to the metastable state MS-(E)-1 affords a PSS mixture of St-(Z)-1:MS-(E)-1 = 10:90, with magnification

of corresponding 19

F NMR spectra. Arrows indicate absorption peaks of corresponding hydrogen atoms in

St-(Z)-1 and MS-(E)-1.

Comparable results were obtained for St-(E)-2 and St-(Z)-2, affording, upon irradiation with 365 nm light, a

PSS ratio of St-(E)-2:MS-(Z)-2 = 20:80 and St-(Z)-2:MS-(E)-2 = 16:84, respectively (see Experimental

section for further details). Interestingly, irradiation at longer wavelength (395 nm for 1 and 420 nm for 2)

gave PSS mixtures consisting mostly of the metastable isomer,72

even though this isomer absorbs more

strongly at these wavelengths, and led to no, or minimal, change in the UV-vis spectra.73

Similar results

were also obtained when dichloromethane, toluene or acetonitrile were used as solvent. Notably, the

corresponding unfunctionalized molecular switches constituting the light-responsive core of 1 and 2 have

been shown to undergo efficient reversible switching with 312/365 nm and 420/450 nm light over multiple

cycles with no evidence of fatigue.55

Moreover, the thiourea moiety was present in our previous successful

examples of functionalized molecular motors employed in photoresponsive catalytic and anion binding

systems.9,12,38

From a parallel series of irradiation tests performed on compounds 13, 16 and 28 (an

analogous compound of 13 lacking the amine moiety in the lower half) (Figure 3.5), the reduced

photoswitching behavior appears to arise due to the detrimental influence of the dimethylamine substituent.

Compound 28 was in fact the only compound in this study which displayed efficient reversible photo-

isomerization (see Experimental section for further details).

Chapter 3

84

Figure 3.5. The different intermediates or substructures of target compound 1 studied to investigate the role

of the amine substituents in the reversibility of the photoswitching process.

This lack of reversible switching considerably reduces the possibility of using these switches as efficient

reversible ON/OFF catalysts and future studies will aim to discern what functional groups, specifically

what functional groups with potentially catalytic capabilities, are compatible with efficient reversible

photoisomerization.

It was hypothesized that the lone pair of the dimethylamine substituent might be responsible for the

deactivation of the switching process, originating from a detrimental difference between the absorbances

and quantum yields of the stable and metastable isomers. Hence, the addition of a Brønsted acid may result

in a recovery of the reversible switching properties, providing the possibility for a pH-gated photo-

responsive system. Solutions of St-(E)-1 and St-(Z)-1 (THF, 1.0–2.5·10−5

M) were irradiated with UV-light

(365 nm and 395 nm) before and after the addition of excess of acid or base (respectively, aliquots of 2M

aq. HCl and 2M aq. NaOH) (see Experimental section for further details). Large changes in the UV-vis

spectra profiles and shift of the isosbestic points during irradiation cycles were observed upon addition of

aliquots of both base and acid (365 nm in presence of base, 395 nm in presence of acid). This observation

could be explained by activation of the backward switching path upon protonation of the dimethylamine

substituent. However, degradation could not be excluded as alternative reasoning for the observed change

in the UV-vis spectra during the backward irradiation, as the original spectra could not be recovered upon

multiple irradiation cycles. Nevertheless, such observation opens new insights for future development of

pH-gated photo-responsive systems based on molecular motors/switches.

3.2.4 Catalytic activity

Having investigated the photoresponsive dynamic motion of bifunctionalized switches 1-2, we next studied

their ability as photoswitchable cooperative catalysts. Wang and co-workers reported a BINAM-based

catalyst bearing a combination of an aromatic dimethylamine substituent as the active nucleophilic group

and a thiourea as the H-bond donor moiety displaying promising activity as a catalyst for the Morita-

Baylis-Hillman (MBH) reaction.67

Despite the literature claims, our attempts to catalyze the reaction

between 2-cyclohexen-1-one and 3-phenylpropionaldehyde by either (E)-1, (Z)-1, (E)-2, (Z)-2 or the

original literature catalyst did not lead to any conversion to the desired Michael adduct as determined by 1H NMR spectroscopy (Scheme 3.9). We postulate that these disappointing results are due to the limited

catalytic activity of the dimethylaniline moiety, both in terms of the low nucleophilicity of the aryl amine

and the structurally constrained nature of the tertiary amine within the catalyst. Future studies will focus on

the introduction of alternative, more nucleophilic, aliphatic amine functionalities (e.g. aliphatic amine) into

the lower half, in line with the majority of successful catalysts reported for the asymmetric organocatalyzed

MBH reaction.74–78



85

Scheme 3.9. Attempted catalysis of the Morita-Baylis-Hillman reaction between 2-cyclohexen-1-one and

3-phenylpropionaldehyde using either (E)-1, (Z)-1, (E)-2 or (Z)-2; no conversion to the desired Michael

adduct was observed by 1H NMR spectroscopy.

While our initial model of cooperative catalysis induced by photocontrolled geometrical changes appears to

be completely unsuccessful, other recent reports led us to reassess the molecular photoswitches (E)-1, (Z)-1,

(E)-2 and (Z)-2. Studies by both Hecht and Pericás have addressed the possibility of shielding a catalytic

moiety, in one photoaccessible isomer, either by simple steric interactions (Hecht) or through hydrogen

bonding interactions (Pericás).16,20

Analysis of the photoswitches (E)-1, (Z)-1, (E)-2 and (Z)-2 suggests that

the catalytically active hydrogen bonding thiourea moiety could be analogously deactivated in both the St-

(Z) or MS-(Z) isomers either through steric shielding of the thiourea moiety by the dimethylamine group or

through hydrogen bonding interactions. In order to investigate these ideas further, we tested our system in

the Michael addition reaction (as described by Pericás) between (E)-3-bromo-β-nitrostyrene and 2,4-

pentanedione, in which we postulated that the thiourea moiety in the upper half could engage in hydrogen

bonding with the nitro-substituent of the substrate, activating it towards nucleophilic attack. The

dimethylaniline moiety in the lower half was anticipated to allow control on the activity of the thiourea

moiety by steric hindrance or hydrogen bonding interactions, thus causing a difference in catalytic activity

between the more accessible (E)-isomers (either St-(E) or MS-(E)) and the corresponding blocked (Z)-

isomers (either MS-(Z) or St-(Z)). Each distinct case could then, respectively, represent a successful

example of ON/OFF (St-(E) to MS-(Z)) or OFF/ON (St-(Z) to MS-(E)) catalytic switches. Figure 3.6

illustrates the progress of the conversion, monitored by 1H NMR spectroscopy, of the Michael reaction

between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione, mediated by different forms of the thiourea

catalysts in combination with trimethylamine. When the reaction was conducted in the absence of catalyst,

only 10% conversion was observed after 18 h (v0 = 5.56·10-4

M h-1

), in line with the results reported by

Pericás and co-workers. In the presence of 3 mol% of St-(E)-1, a clear acceleration of the reaction was

observed, with 60% conversion reached after 18 h (v0 = 5.33·10-3

M h-1

). Interestingly, when the reaction

was performed under the same conditions with a PSS mixture (312 nm) of St-(E)-1:MS-(Z)-1 = 20:80 as

catalyst, the rate of the reaction was substantially decreased, reaching only 19% conversion after 18 h (v0 =

1.08·10-3

M h-1

). These results are highly supportive of a model similar to the one described by Hecht and

Pericás, in which shielding in one geometric isomer inhibits the activating abilities of a key catalytic

functionality in the molecule. Additionally, the catalyst St-(E)-1 could be switched to the less active state

MS-(Z)-1 during the course of the reaction by irradiation of the sample after 4 h. In the presence of 3 mol%

of St-(Z)-1, an increase of the reaction rate compared to the blank reaction was observed, with 40%

conversion reached after 18 h (v0 = 2.94x10-3

M h-1

). Remarkably, when the reaction was performed under

the same conditions with a PSS mixture (312 nm) of St-(Z)-1:MS-(E)-1 = 12:88 as catalyst, the rate of the

reaction decreased, reaching less than 16% conversion after 18 h (v0 = 1.02·10-3

M h-1

). Contrary to

expectations, the deactivated isomer St-(Z)-1 showed moderate catalytic activity, while the expected active

isomer MS-(E)-1 provided only minimal increase in reaction rate beyond the observed background

reaction. Similar to St-(E)-1, St-(Z)-1 could also be switched to the less active state during the course of the

reaction by irradiation of the sample after 4 h. It should be noted that no degradation of the catalyst

occurred during the irradiation process, as well as no thermal decay of the metastable species was detected,

as determined by 1H NMR spectroscopy throughout the kinetic experiments.

Due to the limited activity displayed by the catalysts, the background blank reaction may still play an

important role in the conversion of the substrate. Assuming that the background blank reaction still affords

Chapter 3

86

10% conversion during 18 h (v0 = 5.56·10-4

M h-1

) even in the presence of the catalyst, the sole contribution

of the catalysts can then be calculated as follows in terms of conversion ( ., equation 1), initial reaction

rate ( , equation 2), and turnover frequency (TOF, equation 3):

(1)

(2)

⁄ (3)

Figure 3.6. (a) Photoswitching of catalytic activity of (E)-1 in Michael addition: background blank reaction

- no cat. (black); catalyzed by St-(E)-1 (red); catalyzed by PSS mixture of St-(E)-1:MS-(Z)-1 = 18:82 upon

UV irradiation (312 nm) of St-(E)-1 (green); catalyzed by St-(E)-1 upon intermediate irradiation (indicated

with orange bar) after 4 h (blue). (b) Photoswitching of catalytic activity of (Z)-1 in Michael addition:

background blank reaction - no cat. (black); catalyzed by St-(Z)-1 (red); catalyzed by PSS mixture of St-

(Z)-1:MS-(E)-1 = 10:90 upon UV irradiation (312 nm) of St-(Z)-1 (green); catalyzed by St-(Z)-1 upon

intermediate irradiation (indicated with orange bar) after 4 h (blue). (c) Reaction Scheme 3.of Michael

addition. (d) Comparison between the net activity (yield (%) indicated above corresponding bar,

contribution of background reaction subtracted) of (E)-1 and (Z)-1 as not irradiated (blue) and pre-

irradiated mixture (red). For reaction conditions, irradiation and monitoring procedures, see Experimental

section.

In the case of St-(E)-1, by subtracting the contribution of the background reaction, a 50% conversion (v0 =

5.33·10-3

M h-1

- 0.56·10-3

M h-1

= 4.77·10-3

M h-1

, TOF = 1.59 h

-1) can be attributed to the sole catalyst



87

action. In the case of the corresponding PSS mixture of St-(E)-1:MS-(Z)-1 = 20:80, a mere 9% conversion

(v0 = 1.08·10-3

M h-1

- 0.56·10-3

M h-1

= 0.52·10-3

M h-1

, TOF = 0.173 h-1

) can be attributed to the catalyst

mixture. Notably, this value appears to be proportional to the fraction of St-(E)-1 present in the catalyst

mixture (stable-(E)-1 = 20%), if compared to the former not-irradiated sample (i.e. St-(E)-1 = 100%).

Similar behavior is encountered in the second set of experiments involving St-(Z)-1 and MS-(E)-1. By

subtracting the background reaction contribution, pure St-(Z)-1 appears to give 30% conversion after 18 h

(v0 = 2.94·10-3

M h-1

- 0.56·10-3

M h-1

= 2.38·10-3

M h-1

, TOF = 0.793 h

-1), while the PSS mixture of St-(Z)-

1:MS-(E)-1 = 12:88, afforded only 6% conversion (v0 = 1.02·10-3

M h-1

- 0.56·10-3

M h-1

= 0.46·10-3

M h-1

,

TOF = 0.153 h

-1).

As shown by the experimental results, both stable isomers displayed significant loss of catalytic activity

upon irradiation to the metastable state. As opposed to our assumption, this behavior does not seem

predominantly regulated by shielding of the thiourea moiety by the amine substituent, either through steric

or hydrogen bonding interactions (vide infra, Computational study), but apparently other parameters play a

key role.

3.2.5 Computational study

Although the exact reason for the observed decrease in catalytic activity upon irradiation remains elusive,

DFT calculations on various conformations of all four isomers, St-(E)-1, MS-(Z)-1, St-(Z)-1 and MS-(E)-1,

have allowed us to gather further information to help interpret the results. Conformational analysis on all

four isomers allowed us to identify the most stable cis and trans conformations of all the possible ground

state isomers of 1 (Figure 3.7), where cis and trans describes the conformation of the thiourea motif.

It was found in accordance with a previous study that the presumably less catalytically active anti

conformation of the thiourea unit for each stable and metastable isomers of 1 lies lower in energy. 79

However the Gibbs free energy difference (ΔG ≈ 4 kcal mol-1

) is the same for all isomers of 1. The

calculations also allow us to rule out the possibility of intramolecular hydrogen bonding interactions

between the thiourea and dimethylaniline moieties, where the distances are too large in all four isomers for

hydrogen bonding. Future research will focus on the investigation of a possible substantial alteration of the

electronic properties upon switching to the metastable states, which could provide a plausible explanation

for the detrimental impact on the catalytic activity.

Figure 3.7. DFT optimized structures of the cis (top) and trans (bottom) conformations adopted by the

thiourea substituent for each stable and metastable isomer of 1 (from left to right, the order follows the

switching cycle for second generation molecular motor as depicted in Scheme 3.2b: St-(E)-1, MS-(Z)-1, St-

(Z)-1, and MS-(E)-1. Calculations and rendering performed by T. van Leeuwen.

Chapter 3

88

3.3 Conclusions

We have described the design and synthesis of two photoresponsive bifunctionalized catalysts based on an

overcrowded alkene core. Each motor half is equipped with a catalytically active "arm", with the aim of

obtaining bifunctional switches whose catalytic activity could be turned ON and OFF by light-induced

configurational isomerization. The compounds show switching upon irradiation with 312 nm light, forming

the corresponding metastable states with good photostationary states. Interestingly, they do not exhibit

reversible switching and further investigations are required to determine the influence of the dimethylamine

group on the reversibility of the switching processes of bistable switches based on overcrowded alkenes.

Switches St-(E)-1 and St-(Z)-1 display properties of photoswitchable catalytic activity control in the

Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione. From the

experimental results, both isomers displayed a decrease in catalytic activity upon irradiation to the

metastable state, which could not be accredited to any detectable decomposition of the catalysts. As

opposed to our initial assumption of controlling the activity of the thiourea moiety by steric hindrance or

hydrogen bonding interactions, both E- and Z-isomers behave comparably as ON/OFF catalytic switches

upon photoisomerization with clear changes in reaction rate and turnover frequency, regardless of the

catalyst geometry. Therefore such behavior does not seem predominantly regulated by the steric hindrance

exerted by the amine substituent around the thiourea moiety. As demonstrated in this work, an aromatic

amine substituent was shown to be detrimental for the photochemical reversibility of the switching process

and to be a poorly active catalytic moiety. These studies provide valuable insight into the requirements for

the design of more effective and complex trifunctionalized molecular switches, which may allow the

photocontrol of catalyst activity and selectivity in multicomponent reactions. Key to the successful

development of these future catalysts will be a deeper understanding of the effect of ancillary functional

groups on reversible photoswitching and the introduction of more active catalytic groups to ensure higher

catalyst performance.


The author would like to thank Dr. B. S. L. Collins and T. van Leeuwen for their fundamental contribution

to this work. Synthesis and characterization of catalysts (E)/(Z)-1 was performed by Dr. B. S. L. Collins.

Computational study was performed by T. van Leeuwen. The authors would like to thank Ing. P. van der

Meulen for the technical support during the kinetic NMR spectroscopy experiments.



89



Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe N.V. Solvents were reagent grade

and distilled and dried before use according to standard procedures. Dichloromethane and toluene were

used from the solvent purification system using a MBraun SPS-800 column. THF was distilled over sodium

under nitrogen atmosphere prior to use. Column chromatography was performed on silica gel (Silica Flash

P60, 230–400 mesh). NMR spectra were recorded on a Varian Gemini-200 (50 MHz), a Varian Oxford

NMR 300 (75 MHz), an Agilent Technologies 400-MR (100 MHz) or on a Varian Unity Plus 500 (125

MHz) spectrometer in the reported solvent. Chemical shifts are denoted in δ values (ppm) relative to CDCl3

(1H: δ = 7.26 and

13C: δ = 77.00), to CD2Cl2 (

1H: δ = 5.32 and

13C: δ = 54.0), d6-acetone (

1H: δ = 2.05 and

13C: δ = 29.84 and 206.26) or d8-toluene (

1H: δ = 2.09). For

1H and

19F NMR, the splitting parameters are

designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sext (sextet), m (multiplet),

b (broad) and app. (apparent). MS (EI) and HRMS (EI) spectra were obtained with a AEI MS-902 or with a

LTQ Orbitrap XL. Melting points were measured on a Büchi Melting Point B-545 apparatus. Irradiation

was performed using a Spectroline ENB-280C/FE lamp (312 nm), a Thorlabs M365F1 (365 nm), M395F1

(395 nm) and M420F2 (420 nm) fiber-coupled coupled high power LEDs. UV-vis absorption spectra were

measured on a Analityk Jena SPECORD S600 spectrophotometer. All spectra were recorded at 20 °C using

Uvasol-grade THF (Merck) as solvent. Room temperature (rt) as mentioned in the experimental procedures,

characterization and photoisomerization experiments is to be considered equal to 20 °C.

3.5.2 Computational Details

Density functional theory (DFT) calculations were carried out with the Gaussian 09 program (rev. D.01)

program package.80

All of the calculations were performed on systems in the gas phase using the Becke‘s

three parameter hybrid functional81

with the LYP correlation functionals82,83

(DFT B3LYP/6-31G(d,p)).

Each geometry optimization was followed by a vibrational analysis to determine that a minimum or saddle

point on the potential energy surface was found. For compounds with more than one minimum energy or

saddle point conformation, the conformation with the lowest energy was chosen.


N,N-dimethyl-9H-fluoren-2-amine (3)

To a solution of commercially available 2-aminofluorene (6.0 g, 33.11 mmol) in

an acetonitrile : THF solvent mixture (2:1, 150 mL) was added formaldehyde

(37% aq., 25 mL, 331 mmol) followed by sodium cyanoborohydride (6.44 g,

102 mmol). After stirring at rt for 10 min acetic acid (6.63 mL, 116 mmol) was

added via syringe. The reaction mixture was then allowed to stir for a further 3 h at rt. The reaction mixture

was then cooled with the aid of an ice bath, followed by neutralization via the cautious addition of NaOH

(1N aq., 100 mL). The aqueous phase was then extracted into EtOAc (2 x 50 mL) and the combined

organic phases were washed with sat. aq. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered

and concentrated. The crude reaction mixture was then purified by recrystallization from EtOH to provide

the title compound N,N-dimethyl-9H-fluoren-2-amine 3 (6.15 g, 29.39 mmol, 89%) as a white solid.

Characterization data was according to the literature.84

m.p. 179.7-181.3 °C. 1H NMR (400 MHz, CDCl3) δ

7.63 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.17 (td, J = 7.4, 1.1 Hz, 1H),

6.95 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 3.85 (s, 2H), 3.02 (s, 6H). 13

C NMR (75 MHz,

CDCl3) δ 150.2, 144.9, 142.3, 142.2, 131.0, 126.5, 124.7, 124.6, 120.3, 118.4, 111.6, 109.2, 41.0, 37.0;

HRMS (ESI, m/z): calcd for C15H16N [M+H]+: 210.1277, found: 210.1277.

Chapter 3

90

2-(dimethylamino)-9H-fluoren-9-one (4)

A 250 mL two-necked round bottom flask fitted with a reflux condenser was

charged successively with N,N-dimethyl-9H-fluoren-2-amine 3 (1.96 g,

9.35 mmol), pyridine (50 mL) and benzyltrimethylammonium hydroxide (40 wt%

solution in EtOH, 0.3 mL, 0.1 equiv). An air inlet was then introduced through the

septum and a stream of air was allowed to pass through the reaction mixture. The

reaction mixture was then allowed to stir at rt for 18 h under this set-up. After this time the pyridine was

removed under reduced pressure. The residue was then dissolved in CH2Cl2 (30 mL) and washed with

water (3 x 30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure.

Successive recrystallizations from hot toluene, followed by washing with pentane provided the title

compound 2-(dimethylamino)-9H-fluoren-9-one 4 (1.86 g, 8.34 mmol, 89%) as dark purple crystals. m.p.

165.1-166.9 °C; 1H NMR (200 MHz, CDCl3) δ 7.56 (d, J = 7.3, 1H), 7.44–7.27 (m, 3H), 7.11 (td, J = 7.2,

1.7 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 8.3, 2.6 Hz, 1H), 3.03 (s, 6H); 13

C NMR (100 MHz,

CDCl3) δ 195.0, 151.2, 145.9, 135.7, 134.8, 134.2, 126.8, 124.1, 121.2, 118.9, 116.6, 108.4, 40.7; HRMS

(ESI, m/z): calcd for C15H14NO [M+H]+: 224.1070, found: 224.1069.

2-(Dimethylamino)-9H-fluorene-9-thione (5)

A 50 mL two-necked round bottom flask fitted with a reflux condenser and

nitrogen inlet was charged with 2-(dimethylamino)-9H-fluoren-9-one 4 (0.630 g,

2.82 mmol), dry toluene (8 mL) and phosphorus pentasulfide (0.94 g, 4.20 mmol,

1.5 equiv) under nitrogen. The reaction mixture was then stirred at 100 °C for

approximately 2 h, while the conversion was monitored by TLC (CH2Cl2 in

pentane, 30%). The mixture was concentrated under reduced pressure and the residue was purified by quick

column chromatography (SiO2, CH2Cl2 in pentane, 30%). The blue fraction was concentrated under

reduced pressure to yield the title compound 2-(dimethylamino)-9H-fluorene-9-thione 5 (0.85 g,

2.77 mmol, 33%) as dark blue crystals. Rf (CH2Cl2 in pentane, 30%): 0.65; m.p. 75.7–76.5 °C; 1H NMR

(200 MHz, CDCl3) δ 7.63 (dt, J = 7.3, 1.0 Hz, 1H), 7.36 (td, J = 7.4, 1.2 Hz, 1H), 7.31–7.14 (m, 2H), 7.14

(d, J = 2.6 Hz, 1H), 7.01 (td, J = 7.5, 1.2 Hz, 1H), 6.70 (dd, J = 8.3, 2.6 Hz, 1H), 3.03 (s, 6H); 13

C NMR

(100 MHz, CDCl3) δ 229.4, 151.2, 145.4, 142.3, 141.4, 134.4, 131.8, 126.7, 123.9, 120.6, 118.4, 116.3,

108.1, 40.7; HRMS (ESI, m/z): calcd for C15H14NS [M+H]+: 240.0842, found: 240.0841.

4-bromo-2,5-dimethylbenzenesulfonyl chloride (6)

A 500 mL round bottom flask was charged with a solution of 2-bromo-1,4-

dimethylbenzene (13.8 mL, 100 mmol) in CHCl3 (150 mL). The flask was fitted with a

dropping funnel and cooled in an ice bath. Chlorosulfuric acid (26.6 mL, 400 mmol, 4

equiv) was then added dropwise with stirring. The reaction mixture was stirred for 30

min at this temperature and then warmed to rt and allowed to stir for a further 4 h. After

this time the reaction mixture was carefully poured onto a crushed ice/water mixture (500 mL). The CHCl3

layer was separated and the aqueous layer was extracted into CHCl3 (2 x 200 mL). The combined organic

extracts were washed with brine (300 mL), dried over MgSO4, filtered and concentrated to provide the title

compound 4-bromo-2,5-dimethylbenzenesulfonyl chloride 6 (25.6 g, 90.4 mmol, 90%) as a white solid

which was used in the next step without further purification. Rf (CH2Cl2 in pentane, 5%): 0.47; m.p. 53.4–

55.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.61 (s, 1H), 2.71 (s, 3H), 2.46 (s, 3H);

13C NMR (100

MHz, CDCl3) δ 141.8, 137.4, 137.0, 136.7, 133.0, 130.3, 22.6, 19.7; LRMS (EI) m/z (abundance%, ion

label): 50(50), 51(100), 64(51), 65(58), 77(88), 78(56), 61 (33), 103(90), 104(87), 105(50), 122(12),

137(16), 182(16), 183(51), 184(35), 185(61), 186(16), 216(22), 218(22), 229(12), 231(12), 247(50),

219(50), 282(35, M+), 284(52), 286(13); elem. anal. calcd for C8H8BrClO2S: C 33.88%, H 2.84%, S

11.31%, found: C 33.89%, H 2.84%, S 11.45%.



91

4-bromo-2,5-dimethylbenzenethiol (7)

A 500 mL round bottom flask was charged with a suspension of 4-bromo-2,5-

dimethylbenzenesulfonyl chloride 6 (14.18 g, 50 mmol) in water (150 mL) and cooled to

0 °C. Concentrated H2SO4 (18.7 mL, 350 mmol, 7 equiv) was then added dropwise via a

dropping funnel followed by the addition of zinc powder (16.35 g, 250 mmol, 5 equiv) in

small portions and the reaction mixture was stirred at low temperature for a further 30

min. The dropping funnel was then exchanged for a reflux condenser and the reaction mixture was heated

to reflux for 4 h. After this time the reaction mixture was cooled to rt and extracted into CHCl3 (2 x 50 mL)

and CH2Cl2 (50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4,

filtered and concentrated under reduced pressure to provide a mixture of the title compound 4-bromo-2,5-

dimethylbenzenethiol 7 and the corresponding disulfide 1,2-bis(4-bromo-2,5-dimethylphenyl)disulfane (as

deduced by 1H NMR spectroscopy) (8.90 g, 1.00 : 1.18 ratio, approximately 82%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1.18 H), 7.32 (s, 1H), 7.29 (s, 1.18 H), 7.14 (s, 1H), 3.23 (s, 1H),

2.35 (s, 4H), 2.30 (s, 7.4 H), 2.27 (s, 3H). A solution of the above mixture (1.0 g, approximately 4.6 mmol)

in THF (20 mL) was treated with NaBH4 (0.87 g, 23.0 mmol) in small portions. The resultant suspension

was allowed to stir at rt for 3 h, after which time the reaction was quenched via the cautious addition of ice

cold water (10 mL) followed by aq. 1M HCl (10 mL) until cessation of gas formation. The aqueous layer

was then extracted into EtOAc (50 mL) and the organic extracts were washed with brine (50 mL), dried

over MgSO4, filtered and concentrated under reduced pressure to provide the title compound 4-bromo-2,5-

dimethylbenzenethiol 7 as a white solid (1.0 g, 4.6 mmol, quantitative). The product contained some minor

impurities as determined by 1H NMR spectroscopy but was used in the subsequent reaction without further

purification. Rf (pentane, 100%): 0.70; m.p. 91.6–94.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.14

(s, 1H), 3.23 (s, 1H), 2.30 (s, 3H), 2.27 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 136.0, 135.4, 133.7, 131.9,

130.1, 121.9, 22.3, 20.4; HRMS (ESI): calcd. for C8H8BrS [M-H]+: 214.9525, found 214.9538.

3-((4-bromo-2,5-dimethylphenyl)thio)-2-methylpropanoic acid (8)

A solution of 4-bromo-2,5-dimethylbenzenethiol 7 (8.81 g, 40.6 mmol) in THF

(150 mL) cooled in an ice bath was treated with triethylamine (8.48 mL,

60.8 mmol, 1.5 equiv) followed by methacrylic acid (5.16 mL, 60.8 mmol, 1.5

equiv). The reaction mixture was then warmed to rt and further heated to reflux and

stirred at this temperature for 6 h. After this time the reaction mixture was cooled

to rt and treated with aq. 1M HCl (70 mL). The aqueous layer was extracted into EtOAc (2 x 50 mL) and

the combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and

concentrated under reduced pressure. The resultant white solid was subjected to flash column

chromatography (SiO2, MeOH in CH2Cl2, gradient 0–2%) to provide the title compound 3-((4-bromo-2,5-

dimethylphenyl)thio)-2-methylpropanoic acid 8 (4.63 g, 15.3 mmol, 38%) as a white solid. Rf (EtOAc in

CH2Cl2, 10%): 0.44; m.p. 99.9–101.2 °C; 1H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 7.25 (s, 1H), 4.85

(br s, 1H), 3.18 (dd, J = 7.4, 13.0 Hz, 1H), 2.92 (dd, J = 6.4, 13.0 Hz, 1H), 2.60 (h, J = 6.9 Hz, 1H), 2.32 (s,

3H), 2.29 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CD3OD) δ 178.5, 138.8, 136.9, 135.9,

134.5, 132.4, 123.3, 40.9, 37.7, 22.4, 19.8, 17.3; HRMS (ESI): calcd. for C12H14BrO2S [M-H]+: 300.9982,

found 300.9904.

6-bromo-3,5,8-trimethylthiochroman-4-one (9)

A solution of 3-((4-bromo-2,5-dimethylphenyl)thio)-2-methylpropanoic acid 8

(4.54 g, 15.0 mmol) in CH2Cl2 (100 mL) was cooled in an ice bath and treated with

a few drops of N,N-dimethylformamide followed by the dropwise addition of oxalyl

chloride (1.90 mL, 22.48 mmol, 1.5 equiv). The reaction mixture was then allowed

to warm to rt and was stirred at this temperature for 1 h. After this time the reaction

mixture was concentrated under reduced pressure to provide 3-((4-bromo-2,5-

Chapter 3

92

dimethylphenyl)thio)-2-methylpropanoyl chloride as confirmed by 1H NMR spectroscopy. The acyl

chloride was used directly in the following step without further purification. 1H NMR (400 MHz, CDCl3) δ

7.38 (s, 1H), 7.20 (s, 1H), 3.35–3.23 (m, 1H), 3.15–2.95 (m, 1H), 2.90–2.80 (m, 2H), 1.40 (d, J = 6.9 Hz,

2H). The residue was re-dissolved in CH2Cl2 (100 mL) and the solution was cooled in an ice bath. Under

a stream of nitrogen AlCl3 (3.0 g, 22.48 mmol, 1.5 equiv) was added in small portions. The reaction

mixture was then allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was

then cooled in an ice bath and quenched via the cautious addition of water. The aqueous layer was

separated and extracted into CH2Cl2 (2 x 50 mL) and the combined organic extracts were washed with sat.

aq. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced

pressure. The 1H NMR spectrum of the crude reaction mixture indicated the presence of the title compound

6-bromo-3,5,8-trimethylthiochroman-4-one 9 and some minor quantities of the corresponding de-

brominated ketone (20 : 1.0). The crude reaction mixture was purified by flash column chromatography

(SiO2, EtOAc in pentane, gradient 0–2%) to provide the title compound 6-bromo-3,5,8-

trimethylthiochroman-4-one 9 (3.98 g, 14.02 mmol, 93%, contaminated with small quantities of the de-

brominated ketone which was carried through into the subsequent reaction) as a pale pink solid. Rf (EtOAc

in pentane, 2%): 0.56; m.p. 43.1–45.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 3.19–3.11 (m, 1H),

3.03–2.97 (m, 2H), 2.54 (s, 3H), 2.24 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H); 13


200.4, 140.8, 137.8, 136.5, 134.2, 133.1, 123.2, 43.3, 32.9, 21.7, 19.7, 15.4; HRMS (ESI): calcd. for

C12H14BrOS [M+H]+: 284.9943, found 284.9947.

(E)-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)hydrazone (10)

A 100 mL round bottom flask was charged with 6-bromo-3,5,8-

trimethylthiochroman-4-one 9 (2.73 g, 9.59 mmol), EtOH (22 mL) and hydrazine

monohydrate (9.3 mL, 190 mmol, 20 equiv). The reaction mixture was heated to

reflux and allowed to stir at this temperature for 20 h. After this time the reaction

mixture was cooled to rt and concentrated under reduced pressure to remove the

majority of the EtOH. The residue was then diluted with CH2Cl2 (10 mL) and

washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced

pressure. The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in

pentane, gradient 5–30%) followed by recrystallization from hot EtOH to provide the title compound (E)-

(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)hydrazone 10 (1.20 g, 3.99 mmol, 42%) as an off-white

solid. Rf (EtOAc in pentane, 10%): 0.64 (with considerable tailing); m.p. 107–109 °C; 1H NMR (400 MHz,

CD2Cl2) δ 7.30 (s, 1H), 5.49 (br s, 2H), 3.38 (app. dp, J = 10.7, 6.8 Hz, 1H), 3.07 (dd, J = 12.9, 6.6 Hz,

1H), 2.48 (dd, J = 12.9, 10.8 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H); minor AB quartet

observed at 6.95 ppm identified as small quantity of de-brominated hydrazone by comparison with an

authentic sample (vide infra); 13

C NMR (100 MHz, CD2Cl2) δ 150.1, 138.4, 137.3, 135.3, 135.2, 132.3,

124.1, 37.0, 35.4, 21.6, 19.7, 15.0; two minor signals at 128.9 ppm and 128.5 ppm identified as small

quantity of de-brominated hydrazone by comparison with an authentic sample (vide infra); HRMS (ESI):

calcd. for C12H16BrN2S: 299.0212, found 299.0215.

(E)-(3,5,8-trimethylthiochroman-4-ylidene)hydrazone

See reference for full experimental details and further characterization.55

1H NMR (400 MHz, CD2Cl2) δ 7.04–6.90 (m, 2H), 5.42 (br s, 2H), 3.37 (app. dp, J =

10.4, 6.7 Hz, 1H), 3.07 (dd, J = 12.9, 6.5 Hz, 1H), 2.50 (dd, J = 12.9, 10.4 Hz, 1H), 2.35

(s, 3H), 2.28 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CD2Cl2) δ 150.6,

138.4, 135.8, 135.2, 133.6, 128.9, 128.5, 36.9, 34.8, 21.2, 20.0, 15.1.



93

(E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((E)-13)

and (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((Z)-

13)

A 100 mL round bottom flask was charged with a solution of

(E)-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)hydrazone 10 (915 mg, 3.05 mmol) in N,N-

dimethylformamide (25 mL) under nitrogen and cooled to –

30 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene

(1.33 g, 3.05 mmol, 1.0 equiv) in N,N-dimethylformamide

(10 mL) was then added at this temperature via syringe. The resulting solution was stirred for

approximately 1 min followed by the addition of a solution of 2-(dimethylamino)-9H-fluorene-9-thione 5

(1.09 g, 4.57 mmol, 1.5 equiv) in N,N-dimethylformamide (30 mL) via syringe. The resulting solution was

stirred at this temperature for 1 h and then allowed to warm slowly to rt and stirred at this temperature for a

further 16 h. After this time the reaction mixture was diluted with EtOAc and washed sequentially with sat.

aq. NH4Cl (30 mL), water (2 x 30 mL) and brine (20 mL). The organic phase was dried over MgSO4,

filtered and concentrated under reduced pressure. The residue was dissolved in p-xylene (100 mL) and

treated with triphenyl phosphine (1.60 g, 6.09 mmol, 2.0 equiv). The resulting solution was heated to reflux

and allowed to stir at this temperature for 22 h. After this time the reaction mixture was cooled to rt and the

solvent was removed under reduced pressure. The crude residue was then analyzed by 1H NMR

spectroscopy, indicating the presence of the title compounds (E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-13 and (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 in a 1.0 : 0.79 ratio. The crude reaction mixture was then

purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 1–3%). The early fractions

were concentrated and dissolved in EtOAc leaving a white precipitate that was discarded. The mother

liquor was concentrated to give a red solid that was washed with hot EtOH to provide the title compound

(Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (144 mg).

The EtOH washings were then concentrated and submitted to further flash column chromatography (SiO2,

aluminium oxide, CH2Cl2 in pentane, gradient 10–20%) to provide a red solid which was further washed

with hot EtOH to provide additional (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-

9H-fluoren-2-amine (Z)-13 (163 mg). Combining these solid provided (Z)-9-(6-bromo-3,5,8-

trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (307 mg, 0.64 mmol, 21%).

The later fractions were combined and re-submitted to flash column chromatography twice: (toluene,

isocratic 100%) followed by (EtOAc in pentane, gradient 1–10%). The resultant yellow solid was then

washed with EtOH to provide the title compound (E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-

N,N-dimethyl-9H-fluoren-2-amine (E)-13 (508 mg, 1.07 mmol, 35%) as a bright yellow solid.

(E)-13: Rf (EtOAc in pentane, 5%): 0.47; m.p. 149–151 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.1

Hz, 1H), 7.50 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz,

1H), 6.77 (t, J = 8.1 Hz, 1H), 6.08 (d, J = 8.1 Hz, 1H), 4.55 (m, 1H), 3.23 (dd, J = 12.6, 7.8 Hz, 1H), 3.07

(s, 6H), 2.40 (s, 3H), 2.32 (dd, J = 12.5, 9.0 Hz, 1H), 2.23 (s, 3H), 1.38 (d, J = 6.7 Hz, 3H); 1H NMR (400

MHz, CD2Cl2) δ 7.59 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H),

7.13 (t, J = 7.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.06 (d, J = 7.9 Hz, 1H),

4.55 (m, 1H), 3.26 (dd, J = 12.5, 7.9 Hz, 1H), 3.07 (s, 6H), 2.40 (s, 3H), 2.32 (dd, J = 12.5, 9.0 Hz, 1H),

2.22 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CD2Cl2) δ 151.1, 143.6, 141.1, 140.1, 139.3,

139.2, 137.8, 137.3, 136.1, 134.7, 133.0, 130.6, 128.1, 125.6, 123.7, 123.5, 120.5, 118.2, 113.0, 110.3, 41.3,

41.0, 37.9, 20.3, 19.9, 18.4; note: minor signal observed at 105.4 ppm that cannot be accounted for; HRMS

(ESI): calcd. for C27H27BrNS [M+H]+: 476.1042, found 476.1042.

(Z)-13: Rf (EtOAc in pentane, 5%): 0.57; m.p. 212.3–214.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J =

7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.21

(t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.81 (s, 1H), 4.56 (h, J = 7.2 Hz, 1H), 3.22 (dd, J = 12.4, 7.9

Chapter 3

94

Hz, 1H), 2.71 (s, 6H), 2.40 (s, 3H), 2.35–2.30 (m, 1H), 2.33 (s, 3H), 1.37 (d, J = 7.8 Hz, 3H); some

broadened signals observed in 13

C NMR spectrum, which were postulated to be due to trace of acid in the

sample – the sample was washed sequentially with sat. aq. NaHCO3 and brine, followed by drying over

MgSO4 – the subsequent 13

C spectrum recorded in CD2Cl2 shows sharp signals: 1H NMR (400 MHz,

CD2Cl2) δ 7.86 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.31 (t,

J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.61 (dd, J = 8.3, 2.2 Hz, 1H), 5.76 (d, J = 2.3 Hz, 1H), 4.59–4.50

(m, 1H), 3.23 (dd, J = 12.2, 7.9 Hz, 1H), 2.69 (s, 6H), 2.39 (s, 3H), 2.31 (stack of s and dd, 4H), 1.35 (d, J =

6.7 Hz, 3H); (100 MHz, CD2Cl2) δ 150.9,143.9, 142.4, 140.0, 139.52, 139.46, 137.6, 137.4, 136.2, 134.2,

132.8, 129.4, 128.4, 125.5, 125.4, 123.7, 120.0, 118.6, 112.7, 108.0, 40.9*, 37.8, 20.3, 19.8, 18.9 – one 13

C

signal missing in aliphatic region, but an HSQC NMR experiment confirmed the overlay of the carbon

atoms marked ― * ‖ at 40.9 ppm (see attached spectra in Experimental section, NMR Spectra section);

HRMS (ESI): calcd. for C27H27BrNS [M+H]+: 476.1042, found 476.1044.

(E)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((E)-14)

A 50 mL pressure flask with stirring bar was charged successively with

potassium iodide (5.57 g, 33.56 mmol, 40 equiv), copper iodide (2.40 g,

12.59 mmol, 15 equiv), (E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-13 (0.40 g, 0.84 mmol) and

N,N-dimethylformamide (10 mL). The septum was then exchanged for a

Teflon screw cap and the reaction mixture was heated to 140 °C and allowed to

stir at this temperature for 48 h. After this time the reaction mixture was cooled

to rt, diluted with EtOAc (20 mL) and washed sequentially with sat. aq. NH4Cl (20 mL), water (2 x 20 mL)

and brine (20 mL). The organic phases were dried over MgSO4, filtered and concentrated under reduced

pressure. The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in

pentane, gradient 2.5–5%) to provide the title compound (E)-9-(6-iodo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-14 (394 mg, 0.75 mmol, 90%) as a yellow solid. Rf (EtOAc

in pentane, 5%): 0.30; m.p. 173–175 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.60 (d, J = 8.1 Hz,

1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.13 (t, J = 7.1 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.78 (t, J = 7.6

Hz, 1H), 6.04 (d, J = 7.9 Hz, 1H), 4.54 (app. sext, J = 7.7 Hz, 1H), 3.23 (dd, J = 7.0, 12.3 Hz, 1H), 3.07 (s,

6H), 2.38 (s, 3H), 2.34 (dd, J = 9.1, 12.5 Hz, 1H), 2.28 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H); 1H NMR (400

MHz, CD2Cl2) δ 7.82 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 7.14 (t, J =

7.2 Hz, 1H), 6.82 (dd, J = 8.0, 2.3 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 4.60–4.51 (m,

1H), 3.26 (dd, J = 12.3, 8.2 Hz, 1H), 3.08 (s, 6H), 2.38 (s, 3H), 2.34 (dd, J = 12.0, 8.9 Hz, 1H), 2.28 (s,

3H), 1.39 (d, J = 6.8 Hz, 3H); 13

C NMR spectra in CDCl3, CD2Cl2 and d6-acetone all miss at least one 13

C

signal – extensive analysis using 2D NMR experiments COSY, HSQC and gHMBC (see attached spectra in

Experimental section, NMR Spectra section) suggest that two of the carbon atoms marked as ― * ‖ overlay

at the signal at 139.22 ppm (and the third is at 139.20 ppm): 13

C NMR (100 MHz, CD2Cl2) δ 151.1, 144.0,

141.1, 140.5, 139.6, 139.22*, 139.20*, 137.8, 137.4, 134.6, 130.6, 128.1, 125.6, 123.5, 120.5, 118.2, 112.9,

110.3, 99.8, 41.3, 41.1, 37.8, 25.9, 19.6, 18.4; HRMS (ESI): calcd. for C27H27INS: 524.0903, found

524.0893.

(Z)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((Z)-14)

A 50 mL pressure flask with stirring bar was charged successively with potassium

iodide (3.57 g, 21.49 mmol, 40 equiv), copper iodide (1.55 g, 8.06 mmol, 15

equiv), (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-

fluoren-2-amine (Z)-13 (256 mg, 0.54 mmol) and N,N-dimethylformamide (7 mL).

The septum was then exchanged for a Teflon screw cap and the reaction mixture

was heated to 140 °C and allowed to stir at this temperature for 48 h. After this

time the reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed



95

sequentially with sat. aq. NH4Cl (20 mL), water (2 x 20 mL) and brine (20 mL). The organic phases were

dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was

analyzed by 1H NMR spectroscopy and the conversion to the desired iodide was determined to be

approximately 76% via integration of the signals corresponding to the proton marked ― * ‖. This crude

residue was then re-submitted to the previous reaction conditions exactly and allowed to stir at 140 °C for a

further 24 h. After this time the reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed

sequentially with sat. aq. NH4Cl (20 mL), water (2 x 20 mL) and brine (20 mL). The organic phases were

dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was then

purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 1–2%) to provide an 8 : 1

mixture of the title compound (Z)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-

fluoren-2-amine (Z)-14 and the starting material (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-

N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (136 mg, approximately 0.26 mmol, 48% – also contains small

quantity of EtOAc as determined by 1H NMR) as a yellow solid which was used in the subsequent

palladium-catalyzed amination reaction without further purification. Rf (EtOAc in pentane, 2%): 0.49; m.p.

213–221 °C large range observed presumably due to mixture of bromide and iodide; signals reported in

square brackets correspond to bromo-derivative (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-

N,N-dimethyl-9H-fluoren-2-amine (Z)-13: 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.1 Hz, 1H), 7.75 (s,

1H), 7.59 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.32 (td, J = 0.9, 7.4 Hz, 1H), 7.21 (td, J = 1.2, 7.7

Hz, 1H), 6.61 (dd, J = 1.8, 8.4 Hz, 1H), [5.81 (d, J = 2.4 Hz, 0.16 H)], 5.79 (d, J = 2.4 Hz, 1H), 4.57 (app.

sext, J = 7.8 Hz, 1H), 3.21 (dd, J = 7.8, 11.8 Hz, 1H), 2.72 (s, 6H), 2.40–2.36 (m, 1H), 2.39 (s, 3H), 2.38 (s,

3H), 1.36 (d, J = 6.8 Hz, 3H); as for (Z)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-

9H-fluoren-2-amine (Z)-14, the sample was washed sequentially with sat. aq. NaHCO3 and brine, followed

by drying over MgSO4 prior to the 13

C spectrum being recorded in CD2Cl2: 1H NMR (400 MHz, CD2Cl2) δ

7.86 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 7.0 Hz,

1H), 7.20 (t, J = 7.5 Hz, 1H), [5.75 (d, J = 2.2 Hz, 0.17H)], 5.72 (d, J = 2.3 Hz, 1H), 4.59–4.49 (m, 1H),

3.22 (dd, J = 12.1, 8.1 Hz, 1H), 2.70 (s, 6H), [2.69 (s, 1.15H)], 2.36–2.39 (m, 7H), 1.35 (d, J = 6.6 Hz, 3H); 13

C NMR (100 MHz, CD2Cl2) δ 150.9, 144.0, 142.4, 140.6, 139.5, 139.4, 139.3, 139.1, 137.8, 137.4, 134.2,

129.4, 128.4, 125.5, 125.4, 120.0, 118.6, 112.7, 107.9, 100.1, 41.0, 40.9, 37.7, 25.8 (a number of other

signals of lower intensity are observed – for example at 132.8 ppm – which overlay exactly with 13

C signals

for (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13;

HRMS (ESI): calcd. for C27H27INS [M+H]+: 524.0903, found 524.0890.

(E)-9-(6-((diphenylmethylene)amino)-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-

fluoren-2-amine ((E)-15)


palladium acetate (13 mg, 0.06 mmol, 0.10 equiv), DPPF (48 mg,

0.09 mmol, 0.15 equiv), (E)-9-(6-iodo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-14 (302 mg,

0.57 mmol) and sodium tert-butoxide (110 mg, 1.15 mmol, 2.0 equiv),

followed by toluene (8 mL). The mixture was then purged with argon

for 5 min. After this time a solution of benzophenone imine (266 mg,

1.43 mmol, 2.5 equiv) in toluene (2 mL) was added via syringe and the septum was exchanged for a Teflon

screw cap. The reaction mixture was then heated to 100 °C and allowed to stir at this temperature for 24 h.

After this time the reaction mixture was cooled to rt, diluted with EtOAc (15 mL), washed with water (2 x

15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude

reaction mixture was then purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 1–

10%) to provide the title compound (E)-9-(6-((diphenylmethylene)amino)-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-15 (119 mg, 0.21 mmol, 36%) as a yellow solid. Rf (EtOAc

in pentane, 5%): 0.51; m.p. 197.0–204.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.9 Hz, 2H), 7.62

Chapter 3

96

(d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.48–7.38 (m, 7H), 7.22–7.20 (m, 2H), 7.16 (t, J = 7.5 Hz,

1H), 6.82 (app. t, J = 7.5 Hz, 2H), 6.40 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.53 (app. sext, J = 7.3 Hz, 1H),

3.18 (dd, J = 7.3, 12.2 Hz, 1H), 3.07 (s, 6H), 2.26–2.21 (m, 1H), 2.24 (s, 3H), 2.07 (s, 3H), 1.32 (d, J = 7.0

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 167.1, 150.5, 148.7, 143.8, 140.5, 139.7, 139.4, 138.9, 138.2,

136.6, 135.2, 134.0, 132.9, 131.0, 130.7, 129.3, 129.2, 128.8, 128.3, 128.2, 127.33, 127.31, 125.5, 123.6,

120.9, 120.2, 117.9, 112.7, 110.3, 41.4, 40.1, 37.8, 20.3, 18.6, 15.1; HRMS (ESI): calcd. for C40H37N2S

[M+H]+: 577.2672, found 577.2671.

(Z)-9-(6-((diphenylmethylene)amino)-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-

fluoren-2-amine ((Z)-15)


palladium acetate (8 mg, 0.03 mmol, 0.1 equiv), DPPF (29 mg,

0.05 mmol, 0.15 equiv), (Z)-9-(6-iodo-3,5,8-trimethylthiochroman-4-

ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-14 (122 mg, 0.23 mmol)

and sodium tert-butoxide (44 mg, 0.46 mmol, 2.0 equiv), followed by

toluene (4 mL). The mixture was then purged with argon for 5 min. After

this time a solution of benzophenone imine (104 mg, 0.57 mmol, 2.5

equiv) in toluene (1 mL) was added via syringe and the septum was

exchanged for a Teflon screw cap. The reaction mixture was then heated to 100 °C and allowed to stir at

this temperature for 48 h. After this time the reaction mixture was cooled to rt, diluted with EtOAc

(10 mL), washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated

under reduced pressure. The crude reaction mixture was then purified by flash column chromatography

(SiO2, EtOAc in pentane, gradient 1–5%) to provide the title compound (Z)-9-(6-

((diphenylmethylene)amino)-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine

(Z)-15 (83 mg, 0.14 mmol, 63%) as an orange solid. Rf (EtOAc in pentane, 5%): 0.68; m.p. 86.6–94.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H),

7.46 (t, J = 8.4 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.31–7.23 (m, 4H), 7.18 (d, J = 7.4 Hz, 1H), 7.09 (d, J =

7.4 Hz,2H), 6.63 (d, J = 6.0 Hz, 1H), 6.44 (s, 1H), 6.16 (s, 1H), 4.48 (app. sext, J = 7.8 Hz, 1H), 3.13 (dd, J

= 7.0, 12.2 Hz, 1H), 2.78 (s, 6H), 2.23 (s, 3H), 2.13 (dd, J = 8.5, 12.4 Hz, 1H), 1.98 (s, 3H), 1.16 (d, J = 6.8

Hz, 3H); 1H NMR (400 MHz, (CD3)2CO) δ 7.95 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.68 (d, J =

7.8 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.40–7.38 (m, 3H), 6.69 (dd, J = 2.4, 8.5 Hz,

1H), 6.53 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 4.61–4.52 (m, 1H), 3.30 (dd, J = 8.0, 12.4 Hz, 1H), 2.80 (s, 6H),

2.24 (s, 3H), 2.13 (dd, J = 8.6, 12.4 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H), note: some residual CH2Cl2 observed

in this sample and one of the methyl groups (s, 3H) is postulated to lie under the residual solvent signal for

d6-acetone at approximately 2.10 ppm; 13

C NMR (100 MHz, (CD3)2CO) δ 168.7, 151.6, 150.8, 145.0,

143.0, 140.6, 140.3, 139.4, 138.4, 137.7, 135.7, 133.9, 133.7, 131.8, 130.1, 130.0, 129.7, 129.6, 129.3,

128.9, 128.7, 126.9, 126.2, 125.9, 121.3, 120.5, 119.2, 113.1, 109.4, 41.1, 41.0, 38.3, 19.9, 19.3, 15.5;

HRMS (ESI): calcd. for C40H37N2S [M+H]+: 577.2672, found 577.2665.

(E)-4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochroman-6-amine ((E)-16)

To a solution of (E)-9-(6-((diphenylmethylene)amino)-3,5,8-

trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-15

(112 mg, 0.19 mmol) in THF (1 mL) was added aq. 2M HCl (0.15 mL,

0.30 mmol, 1.5 equiv) dropwise via syringe. After stirring for 1 h at rt the

reaction mixture was diluted by the addition of aq. 0.5M HCl (3 mL). The

aqueous phase was then extracted into diethyl ether. The remaining aqueous

phase was basified by the addition of solid Na2CO3 (pH > 10) and extracted

into EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The crude

reaction mixture was purified by flash column chromatography (SiO2, CH2Cl2 in pentane, gradient 50–



97

100%, then EtOAc in CH2Cl2, isocratic 2%) to provide the title compound (E)-4-(2-(dimethylamino)-9H-

fluoren-9-ylidene)-3,5,8-trimethylthiochroman-6-amine (E)-16 (64 mg, 0.16 mmol, 80%) as a yellow solid.

Rf (CH2Cl2, 100%): 0.83; m.p. decomposition above 260 °C; 1H NMR (400 MHz, CD2Cl2) δ 7.60 (d, J =

8.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.11 (td, J = 1.0, 7.5 Hz, 1H), 6.81 (dd, J =

2.2, 8.5 Hz, 1H), 6.74 (td, J = 1.2, 7.7 Hz, 1H), 6.68 (s, 1H), 6.26 (d, J = 8.1 Hz, 1H), 4.48 (app. sext, J =

7.6 Hz, 1H), 3.63 (br s, 2H), 3.19 (dd, J = 7.9, 12.6 Hz, 1H), 3.07 (s, 6H), 2.35 (s, 3H), 2.24 (dd, J = 9.2,

12.6 Hz, 1H), 1.93 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CD2Cl2) δ 151.0, 145.1, 144.1,

140.8, 139.42, 139.35, 138.2, 136.1, 133.9, 130.5, 127.60, 127.58, 125.5, 123.8, 121.1, 120.4, 118.0, 116.4,

112.7, 110.3, 41.3, 41.1, 38.3, 20.2, 18.5, 13.7; HRMS (ESI): calcd. for C27H29N2S [M+H]+: 413.2046,

found 413.2047.

(Z)-4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochroman-6-amine ((Z)-16)

To a solution of (Z)-9-(6-((diphenylmethylene)amino)-3,5,8-

trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-15

(75 mg, 0.13 mmol) in THF (1 mL) was added aq. 2M HCl (0.10 mL, 0.20 mmol,

1.5 equiv) dropwise via syringe. After stirring for 1 h at rt the reaction mixture

was diluted by the addition of aq. 0.5M HCl (2 mL). The reaction mixture was

then basified by the addition of solid Na2CO3 (pH > 10) and extracted into EtOAc.

The combined organic extracts were dried over MgSO4, filtered and concentrated.

The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in hexane, gradient

10–20%) to provide the title compound (Z)-4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochroman-6-amine (Z)-16 (49 mg, 0.12 mmol, 91%) as a yellow solid. Rf (EtOAc in pentane,

20%): 0.45; m.p. decomposition above 230 °C; 1H NMR (400 MHz, CD2Cl2) δ 7.88 (d, J = 7.9 Hz, 1H),

7.59 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.30 (td, J = 1.0, 7.5 Hz, 1H), 7.21 (td, J = 1.3, 7.7 Hz,

1H), 6.62 (s, 1H), 6.60 (dd, J = 2.4, 8.4 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 3.65 (br s, 2H), 3.17 (dd, J = 8.0,

12.5 Hz, 1H), 2.68 (s, 6H), 2.37 (s, 3H), 2.24 (dd, J = 9.3, 12.5 Hz, 1H), 2.01 (s, 3H), 1.35 (d, J = 6.8 Hz,

1H); 13

C NMR (100 MHz, CD2Cl2) δ 150.9, 145.1, 144.1, 142.2, 139.9, 139.2, 137.7, 136.4, 133.5, 129.4,

128.0, 127.7, 125.4, 125.3, 121.1, 119.7, 118.5, 116.2, 112.4, 108.6, 41.1, 40.8, 38.2, 20.1, 19.0, 13.8;

HRMS (ESI): calcd. for C27H29N2S [M+H]+: 413.2046, found 413.2046.

(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochroman-6-yl)thiourea ((E)-1)

To a solution of (E)-4-(2-(dimethylamino)-9H-fluoren-9-

ylidene)-3,5,8-trimethylthiochroman-6-amine (E)-16 (50 mg,

0.12 mmol) in CH2Cl2 (6 mL) cooled to 0 °C was added a

solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate

(39 mg, 0.15 mmol, 1.2 equiv) in CH2Cl2 (1 mL) via syringe.

The reaction mixture was allowed to warm to rt and was

stirred at this temperature for 18 h. After this time incomplete

conversion was observed by TLC and the reaction mixture was re-cooled to 0 °C and a second batch of 3,5-

bis(trifluoromethyl)phenyl isothiocyanate (39 mg, 0.15 mmol, 1.2 equiv) in CH2Cl2 (1 mL) was added via

syringe. Again the reaction mixture was allowed to warm to rt and allowed to stir at this temperature for 16

h. The reaction mixture was then concentrated under reduced pressure and purified by flash column

chromatography (SiO2, CH2Cl2 in pentane, gradient 50–100%, then EtOAc in CH2Cl2, isocratic 2%) to

provide the title compound (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-

ylidene)-3,5,8-trimethylthiochroman-6-yl)thiourea (E)-1 (70 mg, 0.10 mmol, 85%) as a yellow solid. Rf

(EtOAc in pentane, 20%): 0.36; m.p. 174.7–177.3 °C; 1H NMR (400 MHz, CD2Cl2) δ 8.80 (s, 1H), 7.82 (s,

2H), 7.73 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.37 (s, 1H), 7.36 (d, J = 2.2 Hz, 1H),

7.28 (s, 1H), 6.95 (td, J = 0.8, 7.4 Hz, 1H), 6.81 (dd, J = 2.3, 8.4 Hz, 1H), 6.50 (td, J = 1.2, 7.4 Hz, 1H),

Chapter 3

98

5.94 (d, J = 8.2 Hz, 1H), 4.57 (app. sext, J = 7.1 Hz, 1H), 3.33 (dd, J = 7.8, 12.7 Hz, 1H), 3.08 (s, 6H), 2.47

(s, 3H), 2.43 (dd, J = 8.9, 12.7 Hz, 1H), 2.11 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H); 13

C NMR (100 MHz,

CD2Cl2) δ 181.0, 151.2, 142.7, 141.8, 141.5, 141.0, 140.2, 139.2, 138.1, 137.7, 134.9, 134.3, 132.8, 131.9

(q, JC-F = 33.0 Hz), 130.4, 128.5, 128.3, 126.2 (m), 125.3, 123.5 (q, JC-F = 272.8 Hz), 122.5, 120.7, 120.0

(m), 118.8, 113.0, 110.0, 41.3, 40.6, 37.7, 20.1, 18.2, 15.5; 19

F NMR (376 MHz, CD2Cl2) δ –63.22; HRMS

(ESI): calcd. for C36H32F6N3S2: 684.1936, found 684.1935.

(Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochroman-6-yl)thiourea ((Z)-1)

To a solution of (Z)-4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-

3,5,8-trimethylthiochroman-6-amine (Z)-16 (40 mg, 0.10 mmol) in

CH2Cl2 (2 mL) cooled to 0 °C was added a solution of 3,5-

bis(trifluoromethyl)phenyl isothiocyanate (66 mg, 0.24 mmol) in

CH2Cl2 (1 mL) via syringe. The reaction mixture was then allowed

to warm to rt and was stirred at this temperature for 18 h. After this

time the reaction mixture was concentrated under reduced pressure

and purified by flash column chromatography (SiO2, Et2O in a CH2Cl2: pentane mixture, 1 : 1, 1%) to

provide the title compound (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-

ylidene)-3,5,8-trimethylthiochroman-6-yl)thiourea (Z)-1 (60 mg, 0.09 mmol, 90%) as a yellow solid.

Rf (EtOAc in pentane, 20%): 0.75; m.p. decomposition above 130 °; 1H NMR (400 MHz, CD2Cl2) δ 8.26 (s,

1H), 7.89 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.61 (s, 2H), 7.60 (d, J = 7.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H),

7.33 (t, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.24 (td, J = 1.3, 7.8 Hz, 1H), 7.20 (s, 1H), 6.29 (dd, J = 2.2, 8.5 Hz,

1H), 5.34 (d, J = 2.3 Hz, 1H), 4.54 (app. sext, J = 7.3 Hz, 1H), 3.33 (dd, J = 7.6, 12.5 Hz, 1H), 2.45 (dd, J =

9.0, 4.5 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 6H), 2.13 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz,

CD2Cl2) δ 108.9, 150.1, 142.9, 142.2, 142.0, 141.3, 140.3, 140.1, 137.6, 137.4, 134.6, 133.6, 133.2, 131.7

(q, JC-F = 33.0 Hz), 130.1, 128.5, 127.9, 126.7, (m), 125.8, 125.0, 123.5 (q, JC-F = 272.8 Hz), 120.9, 120.1

(m), 118.9, 113.0, 106.7, 40.6, 40.2, 37.7, 19.8, 18.6, 15.8; 19

F NMR (376 MHz, CD2Cl2) δ –63.11; HRMS

(ESI): calcd. for C36H32F6N3S2 [M+H]+: 684.1936, found 684.1934.

O-(6-Bromonaphthalen-2-yl) dimethylcarbamothioate (17)

O-(6-Bromonaphthalen-2-yl) dimethylcarbamothioate 17 was synthesized

from 6-bromo-2-naphthol (12.5 g, 56 mmol) by following the procedure

previously reported (17.0 g, 54.9 mmol, 98%). Characterization data was

according to the literature.85

m.p. 127.5–130.2 °C; 1H NMR (400 MHz,

CDCl3) δ 8.01 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 8.8, 2.0

Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 9.0, 2.3 Hz, 1H), 3.49 (s, 3H), 3.40 (s, 3H); 13

C NMR (100

MHz, CDCl3) 188.0, 152.3, 133.0, 132.5, 130.3, 129.8, 128.5, 124.1, 120.0, 43.8, 39.2; HRMS (ESI): calcd.

for C13H13BrNOS [M+H]

+: 309.9896, found 309.9896; Anal. calcd. for C13H12BrNOS: C, 50.33; H, 3.90;

N, 4.52, found: C, 50.23; H, 3.87; N 4.48.

S-(6-Bromonaphthalen-2-yl) dimethylcarbamothioate (18)

S-(6-Bromonaphthalen-2-yl) dimethylcarbamothioate 18 was synthesized

from O-(6-bromonaphthalen-2-yl) dimethylcarbamothioate 17 (6.1 g,

19.7 mmol) by following the procedure previously reported (5.4 g,

17.3 mmol, 88%). Characterization data was according to the literature.85

m.p. 106.8–108.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.03–7.96 (m, 2H), 7.75

(d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.59–7.53 (m, 2H), 3.12 (s, 3H), 3.05 (s, 3H); 13

C NMR (75

MHz, CDCl3) 166.6, 135.1, 134.2, 133.3, 131.8, 129.8, 129.7, 129.5, 127.4, 126.8, 121.0, 36.9; HRMS



99

(EI): calcd. for C13H13BrNOS [M+H]+: 309.9896, found 309.9893; Anal. calcd. for C13H12BrNOS: C,

50.33; H, 3.90; N, 4.52, found: C, 50.22; H, 3.83; N 4.48.

6-Bromonaphthalene-2-thiol (19)

6-Bromonaphthalene-2-thiol 19 was synthesized from S-(6-bromonaphthalen-2-yl)

dimethylcarbamothioate 18 (2.3 g, 7.4 mmol) by following the procedure

previously reported (1.7 g, 7.2 mmol, 98%). Characterization data was according to

the literature.85

m.p. 175.6–178.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H),

7.70 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.5 Hz,

1H), 3.60 (s, 1H); 13

C NMR (50 MHz, CDCl3) 132.8, 132.6, 130.5, 130.2, 129.5, 129.2, 128.8, 128.1,

127.3, 119.8; HRMS (EI): calcd. for C10H7BrS [M+]: 238.9525, found 238.9348.

3-((6-Bromonaphthalen-2-yl)thio)-2-methylpropanoic acid (20)

A solution of 6-bromonaphthalene-2-thiol 19 (1.0 g, 4.18 mmol),

triethylamine (1.16 mL, 8.36 mmol, 2 equiv) and methacrylic acid

(0.70 mL, 8.36 mmol, 2 equiv) in THF (40 mL) was heated at reflux

under stirring for 16 h. Upon cooling, the reaction mixture was

quenched with aq. 1M HCl (40 mL) and the aqueous layer was extracted with EtOAc (3 x 30 mL). The

combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The volatiles

were removed under reduced pressure and the crude product was purified by multiple trituration from

pentane to provide the title compound 3-((6-bromonaphthalen-2-yl)thio)-2-methylpropanoic acid 20

(1.21 g, 3.72 mmol, 88%) as a white solid. m.p. 112.8-114.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J =

1.9 Hz, 1H), 7.78–7.73 (m, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.8, 2.0

Hz, 1H), 7.47 (dd, J = 8.6, 1.9 Hz, 1H), 3.38 (dd, J = 13.4, 6.9 Hz, 1H), 3.03 (dd, J = 13.4, 7.0 Hz, 1H),

2.76 (sext, J = 7.0 Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 180.7, 133.7, 132.9,

132.1, 130.0, 129.7, 128.8, 128.7, 127.7, 127.6, 119.7, 39.5, 36.7, 16.6; HRMS (ESI, m/z): calcd for

C14H12BrO2S [M+]: 322.9743, found: 322.9736.

8-Bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-one (21)

A 50 mL round-bottom flask equipped with a septa-cap pierced with a needle was

loaded with a solution of 3-((6-bromonaphthalen-2-yl)thio)-2-methylpropanoic

acid 20 (1.0 g, 3.07 mmol) and two drops of N,N-dimethylformamide in CH2Cl2

(20 mL). Oxalyl chloride (0.54 mL, 6.15 mmol, 2 equiv) was slowly added to the

solution dropwise, liberating gas and turning from yellow to orange. The solution

was stirred for 1 h at rt, then the volatiles were removed under reduced pressure. Heptane (15 mL) was

added to the residue and evaporated under reduced pressure at 60 °C twice to remove completely the excess

of oxalyl chloride, to provide the crude 3-((6-bromonaphthalen-2-yl)thio)-2-methylpropanoyl chloride

(1.05 g, 3.07 mmol) as confirmed by 1H NMR spectroscopy as a brownish oil. The acyl chloride was used

directly in the following step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.79

(s, 1H), 7.67 (dd, J = 23.9, 8.7 Hz, 2H), 7.57 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 3.49–3.40 (m,

1H), 3.15–3.01 (m, 2H), 1.43 (d, J = 6.9 Hz, 2H).

The residue was re-dissolved in CH2Cl2 (20 mL) and the solution was cooled to -20 °C. Under a stream of

nitrogen AlCl3 (0.58 g, 4.36 mmol, 1.5 equiv) was added in small portions. The mixture was stirred for 2 h

at -20 °C, then was allowed to warm up to rt and quenched with aq. 1M HCl (40 mL) at 0°C. The aqueous

layer was separated and extracted into CH2Cl2 (3 x 30 mL) and the combined organic extracts were washed

with sat. aq. NaHCO3 (60 mL), brine (60 mL), dried over MgSO4, filtered and concentrated under reduced

pressure. The crude solid was purified by recrystallization from EtOH to provide the title compound 8-

bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-one 21 (0.85 g, 2.77 mmol, 95%) as light brown

crystals. m.p. 113.7-115.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 9.3 Hz, 1H), 7.88 (d, J = 2.2 Hz,

Chapter 3

100

1H), 7.66 (d, J = 8.7 Hz, 1H), 7.63 (dd, J = 9.3, 2.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 3.29–3.15 (m, 2H),

3.15–3.04 (m, 1H), 1.39 (d, J = 6.6 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 198.9, 144.51, 132.9, 132.1,

132.0, 130.9, 130.23, 127.6, 126.3, 125.2, 119.5, 42.7, 32.7, 15.2; HRMS (APCI, m/z): calcd for

C14H12BrOS [M+]: 308.9764, found: 308.9787.

(E)-(8-Bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)hydrazone (22)

To a mixture of 8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-one

21 (500 mg, 1.6 mmol) and hydrazine monohydrate (5 mL, 100 mmol, 65 equiv)

in EtOH (20 mL) was added Sc(OTf)3 (20 mg, 0.04 mmol). The mixture was

heated to 100 °C for 3 d and subsequently concentrated to ~5 mL. CH2Cl2

(200 mL) and H2O (150 mL) were added and the layers were separated. The

water layer was extracted with CH2Cl2 (3 x 60 mL) and the combined organic

layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column

chromatography (SiO2, CH2Cl2 in pentane, gradient 50–100%) to yield (E)-(8-bromo-2-methyl-2,3-dihydro-

1H-benzo[f]thiochromen-1-ylidene)hydrazone 22 (353 mg, 68%) as a pale yellow gum. 1H NMR (300

MHz, CDCl3) δ 8.32 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.52 (m, 2H), 7.34 (d, J = 8.6 Hz, 1H),

5.60 (bs, 2H), 3.46 (m, 1H), 3.16 (dd, J = 12.8, 5.9 Hz, 1H), 2.68 (dd, J = 12.8, 9.5 Hz, 1H), 1.27 (d, J = 6.8

Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 151.2, 149.1, 136.5, 134.4, 131.1, 130.9, 130.1, 128.4, 127.5, 126.9,

119.5, 36.5, 33.8, 15.0; HRMS (ESI, m/z): calcd for C14H14BrN2S [M+H+]: 321.0038, found: 321.0056.

(E)-9-(8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-

2-amine ((E)-25) and (Z)-9-(8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-

dimethyl-9H-fluoren-2-amine ((Z)-25)

A 100 mL two-necked round bottom flask equipped

with a vacuum/nitrogen inlet was charged with (8-

bromo-2-methyl-2,3-dihydro-1H-

benzo[f]thiochromen-1-ylidene)hydrazone 22

(600 mg, 1.87 mmol). Dry N,N-dimethylformamide

(30 mL) was added via syringe and cooled to -50 °C.

A solution of [bis(trifluoroacetoxy)iodo]benzene

(0.80 g, 1.90 mmol, 1 equiv) in dry N,N-dimethylformamide (15 mL) was then added at this temperature

via syringe. The resulting solution was stirred for 1 min, followed by the addition of a solution of 2-

(dimethylamino)-9H-fluorene-9-thione 5 (0.62 g, 2.80 mmol, 1.5 equiv) in N,N-dimethylformamide

(15 mL) via syringe. The resulting mixture was stirred at this temperature for 1 h and then allowed to warm

slowly to rt and stirred at this temperature for a further 16 h. After this time the reaction mixture was

diluted with EtOAc and washed with sat. aq. NH4Cl (30 mL), water (2 x 30 mL), brine (30 mL), dried over

MgSO4, filtered and concentrated under reduced pressure. The residue was then dissolved in toluene

(15 mL) and treated with tri(dimethylamino)phosphine (0.45 g, 0.50 mL, 2.80 mmol, 1.5 equiv). The

resulting solution was then heated to reflux and allowed to stir at this temperature for 16 h. After this time

the reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude

residue was then analyzed by 1H NMR spectroscopy, indicating the presence of the title compounds (E)-9-

(8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-2-amine

(E)-25 and (Z)-9-(8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-

fluoren-2-amine (Z)-25 in a 0.9 : 1.0 ratio. The crude reaction mixture was then purified by flash column

chromatography (SiO2, EtOAc in pentane, gradient 5–10%). The early fractions were combined,

concentrated under reduced pressure and recrystallized from hot EtOH to provide the title compound (Z)-9-

(8-bromo-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-2-amine

(Z)-25 (147 mg, 0.29 mmol, 16%) as red crystals. The later fractions were combined, concentrated under

reduced pressure and recrystallized from hot EtOH to provide the title compound (E)-9-(8-bromo-2-methyl-



101

2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-25 (130 mg,

0.26 mmol, 14%) as red crystals.

(E)-25: Rf (EtOAc in pentane, 5%): 0.30; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 2.0 Hz, 1H), 7.78–7.71

(m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.27–7.23 (m, 2H),

6.99 (t, J = 7.4 Hz, 1H), 6.84 (t, J = 8.5 Hz, 1H), 6.44 (t, J = 7.7 Hz, 1H), 5.59 (d, J = 7.9 Hz, 1H), 4.75

(app. sext, J = 6.7 Hz, 1H), 3.37 (dd, J = 12.4, 7.2 Hz, 1H), 3.10 (s, 6H), 2.59 (dd, J = 12.4, 7.4 Hz, 1H),

1.38 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 139.0, 137.3, 137.0, 135.4, 134.5, 133.2, 131.93,

130.4, 130.1, 128.4, 127.3, 127.1, 126.6, 125.0, 124.9, 124.7, 120.6, 120.3, 119.5, 117.8, 116.9, 113.0,

110.2, 41.3, 38.9, 37.4, 18.3, two signals (C) were not observed; HRMS (EI): calcd. for C29H25BrNS

[M+H]+: 498.0886, found 498.0877.

(Z)-25: Rf (EtOAc in pentane, 5%): 0.40; m.p. 289.4-291.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J =

1.2 Hz, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.62–7.57 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H),

7.37–7.28 (m, 2H), 7.23 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.19 (br. s, 1H), 4.76 (app. sext, J =

7.1 Hz, 1H), 3.35 (dd, J = 12.3, 7.3 Hz, 1H), 2.59 (dd, J = 12.3, 7.4 Hz, 1H), 2.30 (s, 6H), 1.35 (d, J = 6.8

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 149.7, 142.4, 140.3, 138.6, 137.5, 137.2, 134.9, 134.5, 133.4,

131.8, 130.7, 129.8, 128.8, 128.1, 126.8, 126.7, 125.1, 125.1, 119.5, 119.4, 118.5, 112.2, 110.2, 105.0, 40.3,

38.7, 37.3, 18.6, two signals (C) were not observed; HRMS (EI): calcd. for C29H25BrNS [M+H]+: 498.0886,

found 498.0876.

(E)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-N-(diphenylmethylene)-2-methyl-2,3-dihydro-1H-

benzo[f]thiochromen-8-amine ((E)-26) and (E)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-

2,3-dihydro-1H-benzo[f]thiochromen-8-amine ((E)-27)

A flame dried Schlenk tube

with stirring bar under

nitrogen was charged with

palladium acetate (0.45 mg,

2 µmol, 0.10 equiv), DPPF

(1.67 mg, 3 µmol,

0.15 equiv), (E)-9-(8-bromo-

2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-25

(10 mg, 20 µmol) and sodium tert-butoxide (3.86 mg, 40 µmol, 2 equiv), followed by toluene (1.0 mL).

The mixture was then purged with argon for 5 min. After this time benzophenone imine (9.10 mg, 50 µmol,

2.5 equiv) was added via syringe. The reaction mixture was then heated to 100 °C and allowed to stir at this

temperature for 16 h. After this time the reaction mixture was cooled to rt, diluted with CH2Cl2 (10 mL),

washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced

pressure. The crude reaction mixture was then purified by flash column chromatography (SiO2, EtOAc in

pentane, gradient 5–10%) to provide a crude mixture of (E)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-

N-(diphenylmethylene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-amine (E)-26, which contained

an inseparable excess of benzophenone imine as determined by 1H NMR spectroscopy but was used in the

subsequent reaction without further purification. (E)-26: 1H NMR (400 MHz, CDCl3) δ 7.84–7.78 (m, 3H),

7.74 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.24–7.09 (m, 4H), 7.08–6.98 (m, 3H), 6.83 (dd, J = 8.4,

2.2 Hz, 1H), 6.67 (dd, J = 8.9, 2.2 Hz, 1H), 6.41 (t, J = 7.6 Hz, 1H), 5.54 (d, J = 8.0 Hz, 1H), 4.69 (app.

sext, J = 7.2 Hz, 1H), 3.32 (dd, J = 12.3, 7.3 Hz, 1H), 3.08 (s, 6H), 2.55 (dd, J = 12.4, 8.0 Hz, 1H), 1.39 (d,

J = 6.7 Hz, 3H); note: 4 aromatic proton signals are postulated to lie under the residual benzophenone

imine signals within the range 7.65–7.36 ppm; HRMS (ESI): calcd. for C42H35N2S [M+H]+: 599.2516,

found 599.2507.

The crude fraction of (E)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-N-(diphenylmethylene)-2-methyl-

2,3-dihydro-1H-benzo[f]thiochromen-8-amine (E)-26 was re-dissolved in THF (1.5 mL) and aq. 2M HCl

(0.05 mL, 0.10 mmol, 5.0 equiv) was dropwise via syringe. The solution was stirred at 65 °C over 3 h.

Chapter 3

102

After cooling to rt the reaction mixture was diluted by the addition of aq. 0.5M HCl (2 mL). Reaction

mixture was then basified by the addition of solid Na2CO3 (pH > 10) and then extracted into EtOAc. The

combined organic extracts were then dried over MgSO4, filtered and concentrated. The crude reaction

mixture was then purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 10–50%) to

provide the title compound (E)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-

benzo[f]thiochromen-8-amine (E)-27 (7 mg, 16 µmol, 80%) as a red solid. (E)-27: Rf (EtOAc in pentane,

10%): 0.20; m.p. decomposition above 226 °C; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 9.0 Hz, 1H),

7.61 (dd, J = 18.5, 8.5 Hz, 2H), 7.55–7.49 (m, 1H), 7.46 (dd, J = 18.8, 8.1 Hz, 2H), 7.01–6.96 (m, 2H),

6.89–6.83 (m, 1H), 6.66 (dd, J = 9.0, 2.4 Hz, 1H), 6.46 (t, J = 7.7 Hz, 1H), 5.72 (d, J = 8.0 Hz, 1H), 4.70

(app. sext, J = 7.3 Hz, 1H), 3.31 (dd, J = 12.3, 7.5 Hz, 1H), 3.10 (s, 6H), 2.52 (dd, J = 12.3, 8.2 Hz, 1H),

1.40 (d, J = 6.7 Hz, 3H); 13

C NMR (100 MHz, CD2Cl2) δ 144.2, 143.7, 139.2, 134.8, 133.80, 132.6, 130.0,

129.0, 127.94, 127.0, 126.3, 126.2, 124.9, 120.2, 119.3, 117.6, 110.8, 108.9, 76.7, 41.3, 40.0, 37.7, 18.6;

note: five 13

C signals were not identified due to the low intensity of the spectra, as a result of the low

amount of isolated compound; multiple signals observed in the range 40.0-15.0 ppm that cannot be

accounted for; HRMS (ESI): calcd. for C29H27N2S [M+H]+: 435.1890, found 435.1886.

(Z)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-N-(diphenylmethylene)-2-methyl-2,3-dihydro-1H-

benzo[f]thiochromen-8-amine ((Z)-26)

A flame dried Schlenk tube with stirring bar under nitrogen was charged

with palladium acetate (1.80 mg, 8 µmol, 0.10 equiv), DPPF (6.65 mg,

12 µmol, 0.15 equiv), (Z)-9-(8-bromo-2-methyl-2,3-dihydro-1H-

benzo[f]thiochromen-1-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-

25 (40 mg, 80 µmol) and sodium tert-butoxide (15.40 mg, 160 µmol,

2 equiv), followed by toluene (1.5 mL). The mixture was then purged

with argon for 5 min. After this time benzophenone imine (36.2 mg,

200 µmol, 2.5 equiv) was added via syringe. The reaction mixture was then heated to 90 °C and allowed to

stir at this temperature for 16 h. After this time the reaction mixture was cooled to rt, diluted with CH2Cl2

(10 mL), washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated


(SiO2, EtOAc in pentane, gradient 1–5%) to provide the title compound (Z)-1-(2-(dimethylamino)-9H-

fluoren-9-ylidene)-N-(diphenylmethylene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-amine (Z)-26

(42 mg, 70 µmol, 88%) as red needles. Rf (EtOAc in pentane, 10%): 0.40; m.p. 188.2-190.0 °C; 1H NMR

(400 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 1H), 7.76–7.70 (m, 3H), 7.60–7.53 (m, 2H), 7.51–7.36 (m, 6H),

7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.29–7.06 (m, 12H), 6.70 (dd, J = 9.0, 2.1 Hz, 1H), 6.47 (dd, J = 8.4, 2.3 Hz,


12.3, 8.0 Hz, 1H), 2.32 (s, 6H), 1.36 (d, J = 6.8 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 168.3, 149.6, 148.5,

142.4, 141.2, 139.7, 138.9, 137.3, 135.9, 135.1, 134.9, 134.5, 133.0, 130.7, 130.31, 129.5, 129.6, 129.0,

128.6, 128.2, 128.2, 128.0, 127.9, 127.8, 127.3, 125.39, 124.9, 124.9, 123.3, 119.2, 118.3, 117.5, 111.6,

109.8, 40.3, 39.5, 37.6, 18.8; HRMS (ESI): calcd. for C42H35N2S [M+H]+: 599.2516, found 599.2509.

(Z)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-

amine (Z)-27

To a solution of (Z)-1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-N-

(diphenylmethylene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-amine

(Z)-26 (28 mg, 46 µmol) in THF (1.5 mL) was added aq. 2M HCl 0.05 mL,

0.10 mmol, 2.0 equiv) dropwise via syringe. After stirring for 1 h at rt the

reaction mixture was diluted by the addition of aq. 0.5M HCl (2 mL). The

reaction mixture was then basified by the addition of solid Na2CO3 (pH > 10) and

then extracted into EtOAc. The combined organic extracts were then dried over



103

MgSO4, filtered and concentrated. The crude reaction mixture was then purified by flash column

chromatography (SiO2, EtOAc in pentane, gradient 20–50%) to provide the title compound (Z)-1-(2-

(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-amine (Z)-27

(15 mg, 35 µmol, 75%) as a yellow solid. Rf (EtOAc in pentane, 10%): 0.10; m.p. decomposition above 206

°C; 1H NMR (400 MHz, CDCl3) δ 8.18–8.03 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.82–7.71 (m, 2H), 7.66–

7.54 (m, 3H), 7.52–7.38 (m, 3H), 5.58 (s, 1H), 4.77 (app. sext, J = 7.1 Hz, 1H), 3.39 (dd, J = 12.3, 7.0 Hz,

1H), 2.64 (dd, J = 12.4, 7.6 Hz, 1H), 2.49 (s, 6H), 1.40 (d, J = 6.7 Hz, 3H); note: minor quantities of

solvents (THF and Et2O) signals observed; 13

C NMR (125 MHz, CDCl3) δ 143.6, 140.4, 140.0, 138.4,

138.1, 137.7, 137.3, 136.8, 135.3, 133.8, 132.3, 132.2, 128.6, 128.3, 127.5, 125.4, 123.4, 122.4, 121.4,

120.0, 119.8, 119.6, 118.76, 110.6, 109.5, 40.6, 37.7, 30.4, 18.6; note: multiple signals observed in the

range 65–15 ppm that cannot be accounted for; HRMS (ESI): calcd. for C29H27N2S [M+H]+: 435.1889,

found 435.1885.

(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-2,3-

dihydro-1H-benzo[f]thiochromen-8-yl)thiourea ((E)-2)

To a solution of (E)-1-(2-(dimethylamino)-9H-fluoren-9-

ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-

8-amine (E)-27 (15 mg, 37 µmol) in CH2Cl2 (1.5 mL)

cooled to 0 °C under nitrogen was added a solution of 3,5-

bis(trifluoromethyl)phenyl isothiocyanate (15 mg, 10 µL,

55 µmol, 1.4 equiv) in CH2Cl2 (0.5 mL) via syringe. The

reaction mixture was then allowed to warm up to rt and

was stirred at this temperature for 18 h. After this time the reaction mixture was concentrated under reduced

pressure and purified by flash column chromatography (SiO2, EtOAc in pentane, 15%) to provide the title

compound (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-

methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-yl)thiourea (E)-2 (7 mg, 10 µmol, 27%) as red crystals. Rf

(EtOAc in pentane, 15%): 0.25; m.p. 138.4-140.2 °C; 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 7.98 (d, J

= 9.0 Hz, 1H), 7.93 (s, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.67 (s, 1H), 7.64 (d, J = 8.6

Hz, 1H), 7.63–7.58 (m, 2H), 7.47 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.07 (dd, J = 9.0, 2.2 Hz,

1H), 6.95 (t, J = 7.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.1 Hz, 1H), 6.38 (t, J = 7.6 Hz, 1H), 5.55 (d, J = 8.0 Hz,

1H), 4.78 (app. sext, J = 7.0 Hz, 1H), 3.43 (dd, J = 12.4, 7.0 Hz, 1H), 3.10 (s, 5H), 2.67 (dd, J = 12.4, 7.2

Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H); 13

C NMR (125 MHz, CDCl3) δ 180.1, 150.9, 141.3, 140.2, 139.9, 139.2,

138.9, 137.3, 136.1, 134.5, 132.9, 132.8, 132.4, 132.3 (q, JC-F = 33.8 Hz), 131.2, 129.2, 128.2, 128.1, 127.9,

124.9, 124.8, 124.7, 124.7 124.5, 123.3 (q, JC-F = 272.8 Hz), 120.8, 119.7 (m), 118.3, 113.4, 110.4, 41.6,

38.7, 37.6, 18.4; 19

F NMR (376 MHz, CD2Cl2) δ -63.31; HRMS (ESI): calcd. for C38H30F6N2S2 [M+H]+:

706.1780, found 706.1771.

(Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-methyl-2,3-

dihydro-1H-benzo[f]thiochromen-8-yl)thiourea ((Z)-2)

To a solution of (Z)-1-(2-(dimethylamino)-9H-fluoren-9-

ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-

amine (Z)-27 (24 mg, 55 µmol) in CH2Cl2 (1.5 mL) cooled to

0 °C under nitrogen was added a solution of 3,5-

bis(trifluoromethyl)phenyl isothiocyanate (18.8 mg, 12.7 µL,

70 µmol, 1.3 equiv) in CH2Cl2 (0.5 mL) via syringe. The

reaction mixture was then allowed to warm up to rt and was

stirred at this temperature for 18 h. After this time the reaction mixture was concentrated under reduced

pressure and purified by flash column chromatography (SiO2, EtOAc in pentane, 15%) to provide the title

compound (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-9-ylidene)-2-

Chapter 3

104

methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-yl)thiourea (Z)-2 (29 mg, 41 µmol, 75%) as an orange

solid. Rf (EtOAc in pentane, 15%): 0.25; m.p. 134.1-135.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.37 (br. s,

1H), 8.01 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.92 (br. s, 2H), 7.82 (d, J = 2.2 Hz, 1H), 7.80 (br. s,

1H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 (br. s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.61–7.57 (m, 1H), 7.40 (d, J = 8.4

Hz, 1H), 7.37–7.31 (m, 1H), 7.30–7.23 (m, 1H), 7.07 (dd, J = 9.0, 2.2 Hz, 1H), 6.46 (dd, J = 8.4, 2.3 Hz,


12.3, 7.1 Hz, 1H), 2.26 (s, 6H), 1.37 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 179.8, 149.6,

142.2, 140.0, 139.6, 138.6, 138.6, 137.1, 135.3, 134.0, 132.6, 132.4, 132.3, 132.0 (q, JC-F = 33.8 Hz, 19

F-13

C

coupling), 130.0, 129.2, 128.3, 127.4, 125.4, 125.1, 124.5, 124.5, 124.4, 123.5, 123.0 (q, JC-F = 272.8 Hz, 19

F-13

C coupling), 119.6, 119.4 (m), 118.6, 112.6, 110.1, 40.4, 38.1, 37.3, 18.5; 19

F NMR (376 MHz,

CD2Cl2) δ -63.33; HRMS (ESI): calcd. for C38H30F6N2S2 [M+H]+: 706.1780, found 706.1784.

6-bromo-4-(9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromane (28)

Under nitrogen, Lawesson‘s reagent (3.00 g, 7.40 mmol) was added to a stirred

solution of 9-fluorenone (2.00 g, 11.1 mmol) in dry toluene (50 mL). Three cycles

of vacuum and nitrogen backfill were applied to the reflux setup. The mixture was

then heated at 85 ºC for approximately 2 h, until TLC (CH2Cl2in pentane, 10%)

started showing degradation. The mixture was diluted with a 1:1 solution of

pentane:CH2Cl2 (70 mL) to precipitate most of the Lawesson‘s reagent and filtered.

The liquid fraction was concentrated under reduced pressure and the residue was

purified by a quick column chromatography (SiO2, CH2Cl2in pentane, 10%). The green fraction was

concentrated under reduced pressure to yield 9H-fluorene-9-thione (1.150 g, 5.85 mmol) as dark green

needles. A Schlenk tube was charged with a solution of (E)-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)hydrazone 10 (299 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and cooled to

–30 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene (430 mg, 1.0 mmol, 1.0 equiv) in N,N-

dimethylformamide (2 mL) was then added at this temperature via syringe. The resulting solution was

stirred for approximately 1 min followed by the addition of a solution of 9H-fluorene-9-thione (0.236 g,

1.2 mmol, 1.2 equiv) in N,N-dimethylformamide (3 mL) via syringe. The resulting solution was stirred at

this temperature for 1 h and then allowed to warm slowly to rt and stirred at this temperature for a further

16 h. After this time the reaction mixture was diluted with EtOAc and washed sequentially with sat. aq.

NH4Cl (30 mL), water (2 x 30 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered

and concentrated under reduced pressure. The residue was dissolved in toluene (5 mL) and treated with

tri(dimethylamino)phosphine (0.21 g, 0.19 mL, 1.0 mmol, 1.0 equiv). The resulting solution was heated at

60 °C and allowed to stir at this temperature for 20 h. After this time the reaction mixture was cooled to rt

and the solvent was removed under reduced pressure. The crude reaction mixture was then purified by flash

column chromatography (SiO2, EtOAc in pentane, gradient 2–10%) to provide a red solid which was

further recrystallized from EtOH to provide the title compound 6-bromo-4-(9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochromane 8 (229 mg, 53%) as a bright yellow solid. m.p. 187.2–187.9 °C; 1H NMR (400

MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 1H), 7.78 (dd, J = 6.9, 1.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.53 (s,

1H), 7.47–7.33 (m, 2H), 7.21 (t, J = 7.5 Hz, 1H), 6.93 (td, J = 7.7, 1.2 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H),

4.58 (app. sext, J = 7.6 Hz, 1H), 3.23 (dd, J = 12.5, 7.9 Hz, 1H), 2.42 (s, 3H), 2.38–2.31 (m, 1H), 2.23 (s,

3H), 1.37 (d, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 143.8, 141.2, 139.8, 139.3, 138.7, 137.9,

137.6, 136.7, 135.7, 133.7, 132.81, 127.9, 127.7, 127.3, 127.1, 125.0, 123.4, 123.4, 119.8, 119.1, 40.2, 37.2,

20.2, 19.7, 18.6; HRMS (ESI): calcd. for C25H22BrS [M+H]+: 433.0620, found 433.0621.

3.5.4 Identification of (E)- and (Z)-isomers of stable and metastable forms by 1H NMR

spectroscopy

The configuration of (E)- and (Z)-isomers of both stable and metastable forms could be easily assigned by

the difference in chemical shift of the absorption corresponding to the dimethylamine-substituent and



105

protons in position 1 and 8 on the fluorenyl half in the 1H NMR spectra (Error! Reference source not

found. 8).

Figure 3.8. Identification of (E)- and (Z)-isomers by 1H NMR spectroscopy.

In particular, for compounds (E)-13/14/15/16 and both stable and metastable (E)-1, the chemical shift of the

absorption corresponding to the dimethylamine-substituent is located in the range 3.00–3.20 ppm, while the

absorption corresponding to the proton in position 8 on the fluorenyl half is located within the range 5.70–

6.40 ppm. Similarly, for compounds (Z)-13/14/15/16 and both stable and metastable (Z)-1, the chemical

shift of the absorption corresponding to the dimethylamine-substituent is located in the range 2.60–2.80

ppm, while the absorption corresponding to the proton in position 1 on the fluorenyl half is located within

the range 5.20–6.20 ppm. Regarding the alternative switch scaffold, for compounds (E)-25/26/27 and both

stable and metastable (E)-2, the chemical shift of the absorption corresponding to the dimethylamine-

substituent is located in the range 3.00–3.25 ppm, while the absorption corresponding to the proton in

position 8 on the fluorenyl half is located within the range 5.50–5.80 ppm. Similarly, for compounds (Z)-

25/26/27 and both stable and metastable (Z)-2, the chemical shift of the absorption corresponding to the

dimethylamine-substituent is located in the range 2.25–2.50 ppm, while the absorption corresponding to the

proton in position 1 on the fluorenyl half is located within the range 5.20–5.60 ppm. These uncommon

chemical shifts are caused by the specific electronic environment ((de-shielding) experienced by the

aforementioned protons in each isomer when placed close to the aromatic part of the ‗upper‘ half.

3.5.5 Photoisomerization experiments monitored by UV-vis absorption spectroscopy

Solutions of stable forms of (E)-1, (Z)-1, (E)-2 and (Z)-2 in THF, CH2Cl2, toluene or MeCN (UV-vis

absorption concentrations, 1.0-2.5·10-5

M) were transferred in a quartz cuvette with stirring bar and

degassed with nitrogen under stirring for 5 min. The samples were positioned into the spectrophotometer

fluorescence cuvette holder and irradiated (perpendicularly to the instrument measurement direction) under

stirring (5-10 min at 312/365 nm, 15–30 min at 395/420 nm) while UV-vis absorption spectra were

recorded over the reported time with steps of 15 s. To ensure the PSS was reached, irradiation was

continued until no further changes in the spectra were observed. Similar results were also obtained when

CH2Cl2, toluene or MeCN were used as solvent.

Chapter 3

106

3.5.6 Photoisomerization experiments: characterization of the metastable forms and determination

of the composition of the photostationary states of compounds 1-2 by 1H and

19F NMR

spectroscopy

Irradiation experiment on stable-(E)-1 to generate metastable-(Z)-1

Stable-(E)-1 (~0.5 mg) was dissolved in CD2Cl2 (0.7 mL). This sample was placed in an NMR tube and

irradiated (365 nm) at a distance of 3 cm from the center of the lamp, with periodic mixing of the solution

to facilitate diffusion. 1H NMR spectra of the sample were taken before, during and after irradiation at rt.

No further changes were observed after 15 min of irradiation. The relative integration of the absorptions

peaks of the two isomers (dimethylamine-substituent) revealed a PSS ratio (312 nm) in CD2Cl2 of Stable-

(E)-1 : Metastable-(Z)-1 = 18:82.

Stable-(E)-1: 1H NMR (400 MHz, CD2Cl2) δ 8.80 (s, 1H), 7.82 (s, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.4 Hz,

1H), 7.47 (d, J = 7.4 Hz, 1H), 7.37 (s, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.28 (s, 1H), 6.95 (td, J = 0.8, 7.4 Hz,

1H), 6.81 (dd, J = 2.3, 8.4 Hz, 1H), 6.50 (td, J = 1.2, 7.4 Hz, 1H), 5.94 (d, J = 8.2 Hz, 1H), 4.57 (app. sext,

J = 7.1 Hz, 1H), 3.33 (dd, J = 7.8, 12.7 Hz, 1H), 3.08 (s, 6H), 2.47 (s, 3H), 2.43 (dd, J = 8.9, 12.7 Hz, 1H),

2.11 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ -63.22.

Metastable-(Z)-1: 1H NMR (400 MHz, CD2Cl2) δ 7.89–7.82 (m, 2H), 7.74 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H),

7.39 (d, J = 10.6 Hz, 3H), 7.35–7.27 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 6.83 (d, J = 11.7 Hz,

1H), 6.07 (s, 1H), 4.38 (s, 1H), 2.92 (dd, J = 12.6, 1.9 Hz, 1H), 2.81 (dd, J = 12.3, 3.8 Hz, 1H), 2.47 (s,

3H), 2.37 (s, 6H), 2.03 (s, 3H), 1.60 (d, J = 6.3 Hz, 3H), 19

F NMR (376 MHz, CD2Cl2) δ -63.01.

Irradiation experiment on stable-(Z)-1 to generate metastable-(E)-1

Stable-(Z)-1 (~0.5 mg) was dissolved in CD2Cl2 (0.7 mL). This sample was placed in an NMR tube and




peaks of the two isomers (dimethylamine-substituent in 1H NMR and fluorine peak in

19F NMR) revealed a

PSS ratio (312 nm) in CD2Cl2 of Stable-(Z)-1 : Metastable-(E)-1 = 10:90.

Stable-(Z)-1: 1H NMR (400 MHz, CD2Cl2) δ 8.26 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.61 (s,

2H), 7.60 (d, J = 7.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.24 (td, J =

1.3, 7.8 Hz, 1H), 7.20 (s, 1H), 6.29 (dd, J = 2.2, 8.5 Hz, 1H), 5.34 (d, J = 2.3 Hz, 1H), 4.54 (app. sext, J =

7.3 Hz, 1H), 3.33 (dd, J = 7.6, 12.5 Hz, 1H), 2.45 (dd, J = 9.0, 4.5 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 6H), 2.13

(s, 3H), 1.41 (d, J = 6.8 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ

-63.11.

Metastable-(E)-1: 1H NMR (400 MHz, CD2Cl2) δ 7.71 (s, 1H), 7.64 (s, 1H), 7.57 (s, 2H), 7.53 (d, J = 8.5

Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.15 (s, 1H), 6.99 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (t, J

= 7.5 Hz, 1H), 6.40 (t, J = 7.5 Hz, 1H), 5.88 (d, J = 7.8 Hz, 1H), 4.37–4.28 (m, 1H), 3.05 (s, 6H), 2.88 (dd,

J = 12.4, 1.8 Hz, 1H), 2.76 (dd, J = 12.8, 4.1 Hz, 1H), 2.46 (s, 3H), 1.92 (s, 3H), 1.62 (d, J = 6.3 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ -63.13.

Irradiation experiment on stable-(E)-2 to generate metastable-(Z)-2

Stable-(E)-2 (~0.5 mg) was dissolved in CD2Cl2 (0.7 mL). This sample was placed in an NMR tube and



No further changes were observed after 15 min of irradiation. Due to the low concentration of the sample,

solvent peaks were suppressed by WET-1H NMR experiment to highlight compound peaks. The relative

integration of the absorptions peaks of the two isomers (dimethylamine-substituent) revealed a PSS ratio

(365 nm) in CD2Cl2 of stable-(E)-2 : metastable-(Z)-2 = 20 : 80.

Stable-(E)-2: 1H NMR (400 MHz, CD2Cl2) δ 8.07 (s, 1H), 8.04–8.01 (m, 3H), 7.90 (d, J = 8.7 Hz, 1H),



107

7.88 (s, 1H), 7.77 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.18 (dd, J = 9.1,

2.2 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.43 (t, J = 7.7 Hz, 1H), 5.58 (d, J = 8.0 Hz,

1H), 4.82 (app. sext, J = 7.0 Hz, 1H), 3.46 (dd, J = 12.4, 7.2 Hz, 1H), 3.14 (s, 6H), 2.68 (dd, J = 12.4, 7.4

Hz, 1H), 1.44 (d, J = 6.7 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ -63.31.

Metastable-(Z)-2: 1H NMR (400 MHz, CD2Cl2) δ 8.03 (d, J = 7.7 Hz, 1H), 8.00 (br s, 1H), 7.95–7.90 (m,

2H), 7.75–7.70 (m, 2H), 7.70–7.66 (m, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.48 (s, 1H), 7.35–7.23 (m, 2H), 6.98

(d, J = 9.3 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H), 5.09 (s, 1H), 4.73–4.63 (m, 1H), 2.99 (d, J = 12.4 Hz, 1H),

2.88 (d, J = 11.3 Hz, 1H), 2.30 (s, 6H), 1.65 (d, J = 6.4 Hz, 2H); 19

F NMR (376 MHz, CD2Cl2) δ -63.20.

Irradiation experiment on stable-(Z)-2 to generate metastable-(E)-2

Stable-(Z)-2 (~0.5 mg) was dissolved in CD2Cl2 (0.7 mL). This sample was placed in an NMR tube and




peaks of the two isomers (dimethylamine-substituent in 1H NMR and fluorine peak in

19F NMR) revealed a

PSS ratio (365 nm) in CD2Cl2 of Stable-(Z)-2 : Metastable-(E)-2 = 16:84.

Stable-(Z)-2: 1H NMR (400 MHz, CD2Cl2) δ 8.10–8.03 (m, 1H), 8.03–7.99 (m, 3H), 7.90–7.84 (m, 2H),

7.83 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.3 Hz,

1H), 7.36 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.20 (dd, J = 9.1, 2.1 Hz, 1H), 6.54–6.48 (m, 1H),

4.78 (h, J = 7.1 Hz, 1H), 3.41 (dd, J = 12.4, 7.3 Hz, 1H), 2.65 (dd, J = 12.3, 7.4 Hz, 1H), 2.31 (s, 6H), 1.39

(d, J = 6.8 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ -63.33.

Metastable-(E)-2: 1H NMR (400 MHz, CD2Cl2) δ 8.01 (d, J = 19.4 Hz, 2H), 7.94 (s, 1H), 7.83 (d, J = 9.2

Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.43 (s,

1H), 7.34 (d, J = 7.9 Hz, 1H), 6.92 (dd, J = 9.1, 2.3 Hz, 1H), 6.84 (s, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.29 (t, J

= 7.6 Hz, 1H), 5.49 (d, J = 7.9 Hz, 1H), 4.66 (s, 1H), 3.11 (s, 6H), 3.00 (dd, J = 12.2, 1.7 Hz, 1H), 2.89 (dd,

J = 12.4, 3.9 Hz, 1H), 1.71 (d, J = 6.4 Hz, 3H); 19

F NMR (376 MHz, CD2Cl2) δ -63.30;

3.5.7 Irradiation experiment at 420 nm on PSS mixture (365 nm) of stable-(Z)-2 : metastable-(E)-2

Stable-(Z)-2 (~2.0 mg) was dissolved in MeCN-d3 (0.5 mL). This sample was placed in an NMR tube and



No further changes were observed after 2 h of irradiation. The relative integration of the absorptions peaks

in 1H NMR spectra of the two isomers revealed a PSS ratio (365 nm) in CD2Cl2 of Stable-(Z)-2 :

Metastable-(E)-2 = 7:93. Similarly, the sample was consequently irradiated over 4 h with longer

wavelength (420 nm) towards the initial stable isomer. The relative integration of the absorptions peaks of

the two isomers revealed a PSS ratio (420 nm) in MeCN-d3 of Stable-(Z)-2 : Metastable-(E)-2 = 14:86.

3.5.8 Photoisomerization experiments of compounds 13-16-28 monitored by UV-vis absorption

spectroscopy

To further investigate in depth the role of the substituents in the lack of reversible photoswitching, solutions

(~10-5

M in THF) of five different intermediates or substructures of the target compound 1 (Figure 3.9)

were subjected to UV irradiation at 312 nm (forward) and 395 nm (backward). Irradiation was continued

until no further changes in the spectra were oberved. Similarly to (E)-1 and (Z)-1, (E)-13 and (Z)-13

showed slow but clear photoswitching at 312 nm towards the metastable states (illustrated on the left in

Figure 3.10 and Figure 3.11, respectively), while they showed no change upon irradiation at 395 nm

towards the metastable states (illustrated on the right in Figure10 and Figure 3.11, respectively). The same

behavior was encountered with (E)-16 and (Z)-16 (illustrated in Figure 3.12 and Figure 3.13, respectively),

which may suggest that neither the amine nor the thiourea substituents in the upper half are responsible for

the lack of back-switching. However, after testing compound 28 in the same conditions, rapid and

Chapter 3

108

reversible photoisomerization was observed upon irradiation at 312 and 395 nm (Figure 3.14). It appears

that the dimethylamine substituent in the lower half has a detrimental effect in the efficiency of the photo-

switching process, slowing down the forward isomerization (longer irradiation time was required for

compounds 1, 13 and 16 to reach the PSS) and deactivating the backward process. Similar results were also

obtained when CH2Cl2 or toluene were used as solvent (not shown).

Figure 3.9. The different intermediates or substructures of target compound 1 studied to investigate the role

of the amine substituents in the reversibility of the photoswitching process.

Figure 3.10. UV-vis absorption spectra of compound (E)-13 (~10-5

M in THF) upon irradiation at 312 nm

(left) and subsequent exposure to 395 nm light (right).

Figure 3.11. UV-vis absorption spectra of compound (Z)-13 (~10-5





109

Figure 3.12. UV-vis absorption spectra of compound (E)-16 (~10-5



Figure 3.13. UV-vis absorption spectra of compound (Z)-16 (~10-5



Figure 3.14. UV-vis absorption spectra of compound 28 (~10-5

M in THF) upon irradiation at 312 nm (left)

and subsequent exposure to 395 nm light (right).

Chapter 3

110

3.5.9 Procedures for catalyzed Morita-Baylis-Hillman reactions

Catalytic reactions using (E)-1:

A 4 mL vial was charged with (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-

9-ylidene)-3,5,8-trimethylthiochroman-6-yl)thiourea (E)-1 (3.4 mg, 0.005 mmol, 0.10 equiv), followed by

the addition of CH2Cl2, MeCN or toluene (0.25 mL) and cyclohexanone (14.5 μL, 0.15 mmol, 3.0 equiv).

The reaction mixture was then stirred vigorously for 10 min at rt, prior to the addition of 3-

phenylpropionaldehyde (6.6 μL, 0.05 mmol) via syringe. The reaction mixture was then allowed to stir at rt

for 3 d, after which it was concentrated under reduced pressure and analyzed by 1H NMR spectroscopy. No

evidence of the desired Michael adduct was observed.

Catalytic reactions using (Z)-1:

A 4 mL vial was charged with (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-

9-ylidene)-3,5,8-trimethylthiochroman-6-yl)thiourea (Z)-1 (3.4 mg, 0.005 mmol, 0.10 equiv), followed by

the addition of CH2Cl2, MeCN or toluene (0.25 mL) and cyclohexanone (14.5 μL, 0.15 mmol, 3.0 equiv).

The reaction mixture was then stirred vigorously for 10 min at rt, prior to the addition of 3-

phenylpropionaldehyde (6.6 μL, 0.05 mmol) via syringe. The reaction mixture was then allowed to stir at rt

for 3 d, after which it was concentrated under reduced pressure and analyzed by 1H NMR spectroscopy. No

evidence of the desired Michael adduct was observed.

Catalytic reactions using (E)-2:

A 4 mL vial was charged with (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-

9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-yl)thiourea (E)-2 (3.5 mg, 0.005 mmol, 0.10

equiv), followed by the addition of CH2Cl2, MeCN or toluene (0.25 mL) and cyclohexanone (14.5 μL,

0.15 mmol, 3.0 equiv). The reaction mixture was then stirred vigorously for 10 min at rt, prior to the

addition of 3-phenylpropionaldehyde (6.6 μL, 0.05 mmol) via syringe. The reaction mixture was then

allowed to stir at rt for 3 d, after which it was concentrated under reduced pressure and analyzed by 1H NMR spectroscopy. No evidence of the desired Michael adduct was observed.

Catalytic reactions using (Z)-2:

A 4 mL vial was charged with (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-(dimethylamino)-9H-fluoren-

9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-8-yl)thiourea (Z)-2 (3.3 mg, 0.005 mmol, 0.10

equiv), followed by the addition of CH2Cl2, MeCN or toluene (0.25 mL) and cyclohexanone (14.5 μL,

0.15 mmol, 3.0 equiv). The reaction mixture was then stirred vigorously for 10 min at rt, prior to the

addition of 3-phenylpropionaldehyde (6.6 μL, 0.05 mmol) via syringe. The reaction mixture was then

allowed to stir at rt for 3 d, after which it was concentrated under reduced pressure and analyzed by 1H NMR spectroscopy. No evidence of the desired Michael adduct was observed.

3.5.10 Procedures for the catalyzed Michael addition reactions

Blank reaction:

(E)-3-bromo-β-nitrostyrene (13.68 mg, 0.06 mmol) was dissolved in 0.60 mL of a 12.50 mM stock solution

of triethylamine in d8-toluene (0.76 mg, 7.5 μmol, 0.12 equiv) and transferred into an NMR tube. Then, 2,4-

pentanedione (19.22 mg, 20 μL, 0.19 mmol, 3.2 equiv) was added and the reaction mixture was heated at

40 ºC in the NMR apparatus while registering 1H NMR spectra every 20 min over the course of 18 h.



111

Catalytic reaction using stable-(E)-1:

Catalyst (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochroman-6-yl)thiourea (E)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) and (E)-3-bromo-β-nitrostyrene

(13.68 mg, 0.06 mmol) were dissolved in 0.60 mL of a 12.50 mM stock solution of triethylamine in d8-

toluene (0.76 mg, 7.5 μmol, 0.12 equiv) and transferred into an NMR tube. Then, 2,4-pentanedione (19.22

mg, 20 μL, 0.19 mmol, 3.2 equiv) was added and the reaction mixture was heated at 40 ºC in the NMR

apparatus while registering 1H NMR spectra every 20 min over the course of 18 h.

Catalytic reaction using PSS mixture of stable-(E)-1 and metastable-(Z)-1:


trimethylthiochroman-6-yl)thiourea (E)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) was dissolved in analytical grade

CH2Cl2 (3.5 mL), transferred into a quartz cuvette equipped with stirring bar and septa screw cap and

degassed with nitrogen under stirring at rt over 5 min to remove traces of oxygen. The sample was then

irradiated to the photostationary state (stable-(E)-1 : metastable-(Z)-1 = 20 : 80) with 312 nm UV light at rt

under stirring over 45 min. After evaporation of the solvent, the catalyst and (E)-3-bromo-β-nitrostyrene


toluene (0.76 mg, 7.5 μmol, 0.12 equiv) and transferred into an NMR tube. The ratio of the mixture of

isomers of catalyst was determined by and 1H

19F NMR spectroscopy before adding the second substrate.

Then, 2,4-pentanedione (19.22 mg, 20 μL, 0.19 mmol, 3.2 equiv) was added and the reaction mixture was

heated at 40 ºC in the NMR apparatus while registering 1H NMR spectra every 20 min over the course of

18 h.

Catalytic reaction using stable-(E)-1 with intermediate irradiation:


trimethylthiochroman-6-yl)thiourea (E)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) and (E)-3-bromo-β-nitrostyrene




apparatus while registering 1H NMR spectra every 20 min over the course of 4 h. The NMR tube was then

removed from the NMR apparatus and irradiated (312 nm) over 1 h at rt a distance of 3 cm from the center

of the lamp, with periodic mixing of the solution to facilitate diffusion. The tube was reintroduced in the

NMR apparatus and the sample was heated at 40 ºC in the NMR apparatus while registering 1H NMR

spectra every 20 min over the course of further 12 h.

Catalytic reactions using stable-(Z)-1:

Catalyst (Z)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-(dimethylamino)-9H-fluoren-9-ylidene)-3,5,8-

trimethylthiochroman-6-yl)thiourea (Z)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) and (E)-3-bromo-β-nitrostyrene




apparatus while registering 1H NMR spectra every 20 min over the course of 18 h.

Catalytic reaction using PSS mixture of stable-(Z)-1 and metastable-(E)-1:


trimethylthiochroman-6-yl)thiourea (Z)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) was dissolved in analytical grade

CH2Cl2 (3.5 mL), transferred into a quartz cuvette equipped with stirring bar and septa screw cap and

degassed with nitrogen under stirring at rt over 5 min to remove traces of oxygen. The sample was then

irradiated to the photostationary state (stable-(Z)-1 : metastable-(E)-1 = 12 : 88). After evaporation of the

Chapter 3

112

solvent, the catalyst and (E)-3-bromo-β-nitrostyrene (13.68 mg, 0.06 mmol) were dissolved in 0.60 mL of a

12.50 mM stock solution of triethylamine in d8-toluene (0.76 mg, 7.5 μmol, 0.12 equiv) and transferred into

an NMR tube. The ratio of the mixture of isomers of catalyst was determined by 1H and

19F NMR

spectroscopy before adding the second substrate. Then, 2,4-pentanedione (19.22 mg, 20 μL, 0.19 mmol, 3.2

equiv) was added and the reaction mixture was heated at 40 ºC in the NMR apparatus while registering 1H

NMR spectra every 20 min over the course of 18 h.

Catalytic reaction using stable-(Z)-1 with intermediate irradiation:


trimethylthiochroman-6-yl)thiourea (Z)-1 (1.23 mg, 1.8 μmol, 0.03 equiv) and (E)-3-bromo-β-nitrostyrene




apparatus while registering 1H NMR spectra every 20 min over the course of 4 h. The NMR tube was then

removed from the NMR apparatus and irradiated (312 nm) over 1 h at rt a distance of 3 cm from the center

of the lamp, with periodic mixing of the solution to facilitate diffusion. The tube was reintroduced in the

NMR apparatus and the sample was heated at 40 ºC in the NMR apparatus while registering 1H NMR

spectra every 20 min over the course of further 12 h.

3.5.11 Calculation of the conversion of the Michael addition reactions from the 1H NMR spectra

array

During the progress of the Michael addition the olefinic proton absorption peak # from (E)-3-bromo-β-

nitrostyrene at δ 6.78 ppm decreases and a doublet at δ 3.72 ppm corresponding to the aliphatic proton

absorption peak * of the final product appears and increases while the reaction proceeds (illustrated for

stable-(E)-1 in Figure 15, for PSS mixture (312 nm) of stable-(E)-1 : metastable-(Z)-1 = 18 : 82 in Figure

16, for stable-(Z)-1 in Figure 17, and for PSS mixture (312 nm) of stable-(Z)-1 : metastable-(E)-1 = 18 : 82

in Figure 18). To ensure reliable and proportional values from the integration of each corresponding

absorption peak, each 1H NMR spectrum was recorded with 8 scans (nt = 8) and a t1 of 5 s (t1 = 5) over the

course of 57 s. The conversion of 3-(1-(3-bromophenyl)-2-nitroethyl)pentane-2,4-dione was calculated

from the integration values (I* and I#) of * and # peaks: Conv. = [I*/(I# + I*)]×100.



113

Figure 3.15. Evolution of the Michael reaction using stable-(E)-1 (3 mol%), 60% conversion was reached

after 18 h at 40 °C.

Figure 3.16. Evolution of the Michael reaction using PSS mixture (312 nm) of stable-(E)-1 : metastable-

(Z)-1 = 20 : 80 (3 mol%), 19% conversion was reached after 18 h at 40 °C.

Chapter 3

114

Figure 3.17. Evolution of the Michael reaction using stable-(Z)-2 (3 mol%), 40% conversion was reached

after 18 h at 40 °C.

Figure 3.18. Evolution of the Michael reaction using PSS mixture (312 nm) of stable-(Z)-2 : metastable-

(E)-2 = 12 : 88 (3 mol%), 16% conversion was reached after 18 h at 40 °C.



115

3.5.12 1H NMR,

13C NMR,

19F NMR and 2D NMR Spectra of New Compounds

Full NMR spectra can be found in the Supplementary material of the published version at doi:

10.1002/chem.201604966.

3.5.13 Cartesian coordinates of the computational study

Full Cartesian coordinates can be found in the Supplementary material of the published version at doi:

10.1002/chem.201604966. SCF energy in Hartree, number of imaginary frequencies and Cartesian

coordinates in Ångströms. Cartesian coordinated of DFT optimized structures of the trans and cis

conformations adopted by the thiourea substituent for each stable and metastable isomer of 1: St-(E)-1, MS-

(Z)-1, St-(Z)-1, and MS-(E)-1.

3.6 References

(1) Stoll, R. S.; Hecht, S. Angew. Chem. Int. Ed. 2010, 49, 5054–5075.


(3) Imahori, T.; Kurihara, S. Chem. Lett. 2014, 43, 1524–1531.


(5) Vlatkovic, M.; Collins, B. S. L.; Feringa, B. L. Chemistry - A European Journal. 2016, 17080–17111.

(6) Würthner, F.; Rebek, J. Angew. Chem. Int. Ed. 1995, 34, 446–448.

(7) Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. J. Am. Chem. Soc. 2003, 125, 2224–2227.

(8) Sud, D.; Norsten, T. B.; Branda, N. R. Angew. Chem. Int. Ed. 2005, 44, 2019–2021.



(11) Samanta, M.; Siva Rama Krishna, V.; Bandyopadhyay, S. Chem. Commun. 2014, 50, 10577–10579.


(13) Ueno, A.; Takahashi, K.; Osa, T. J. Chem. Soc. Chem. Commun. 1980, No. 17, 837–838.

(14) Lee, W.-S.; Ueno, A. Macromol. Rapid Commun. 2001, 22, 448–450.

(15) Sugimoto, H.; Kimura, T.; Inoue, S. J. Am. Chem. Soc. 1999, 121, 2325–2326.


(17) Berryman, O. B.; Sather, A. C.; Lledó, A.; Rebek, J. Angew. Chem. Int. Ed. 2011, 50, 9400–9403.

(18) Stoll, R. S.; Peters, M. V; Kuhn, A.; Heiles, S.; Goddard, R.; Bühl, M.; Thiele, C. M.; Hecht, S. J. Am.

Chem. Soc. 2009, 131, 357–367.

(19) Stoll, R. S.; Hecht, S. Org. Lett. 2009, 11, 4790–4793.


(21) Niazov, T.; Shlyahovsky, B.; Willner, I. J. Am. Chem. Soc. 2007, 129, 6374–6375.

(22) Wilson, D.; Branda, N. R. Angew. Chem. Int. Ed. 2012, 51, 5431–5434.

(23) Neilson, B. M.; Bielawski, C. W. J. Am. Chem. Soc. 2012, 134, 12693–126939.

(24) Neilson, B. M.; Bielawski, C. W. Chem. Commun. (Camb). 2013, 49, 5453–5455.

(25) Neilson, B. M.; Bielawski, C. W. Organometallics 2013, 32, 3121–3128.

(26) Chen, C.-T.; Tsai, C.-C.; Tsou, P.-K.; Huang, G.-T.; Yu, C.-H. Chem. Sci. 2017, 8, 524–529.

(27) Lemieux, V.; Spantulescu, M. D.; Baldridge, K. K.; Branda, N. R. Angew. Chem. 2008, 120, 5112–5115.

(28) Samachetty, H. D.; Branda, N. R. Chem. Commun. 2005, 100, 2840–2842.

(29) Sud, D.; McDonald, R.; Branda, N. R. Inorg. Chem. 2005, 44, 5960–5962.

(30) Lemieux, V.; Gauthier, S.; Branda, N. R. Angew. Chemie Int. Ed. 2006, 45, 6820–6824.

(31) Shi, M.; Ma, G.-N.; Gao, J. J. Org. Chem. 2007, 72, 9779–9781.

(32) Erno, Z.; Asadirad, A. M.; Lemieux, V.; Branda, N. R. Org. Biomol. Chem. 2012, 10, 2787–2792.

(33) Sud, D.; Wigglesworth, T. J.; Branda, N. R. Angew. Chemie Int. Ed. 2007, 46, 8017–8019.

(34) Dai, Zhongran; Cui, Yaqin; Chen, Changjuan; Wu, J. Chem. Commun. 2016, 44, 1–4.

(35) Sashuk, V.; Danylyuk, O. Chem. Eur. J. 2016, 22, 6528–6531.

(36) Teator, A. J.; Lastovickova, D. N.; Bielawski, C. W. Chem. Rev. 2016, 116, 1969–1992.


(38) Wezenberg, S. J.; Vlatković, M.; Kistemaker, J. C. M.; Feringa, B. L. J. Am. Chem. Soc. 2014, 136,

16784–16787.


(40) Horspool, W. M.; Lenci, F. CRC Handbook of Organic Photochemistry and Photobiology, Volumes 1 &

2, Second Edition; CRC Press: Boca Raton, 2003.

(41) Kottas, G. S.; Clarke, L. I.; Horinek, D.; Michl, J. Chem. Rev. 2005, 105, 1281–1376.

Chapter 3

116

(42) Feringa, B. L. J. Org. Chem. 2007, 72, 6635–6652.

(43) Ikariya, T.; Shibasaki, M. Bifunctional Molecular Catalysis; Springer-Verlag: Berlin, 2011.

(44) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298–1310.

(45) Serdyuk, O. V; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051–7071.

(46) Allen, A. E.; Macmillan, D. W. C. Chem. Sci. 2012, 2012, 633–658.

(47) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.



124, 5037–5051.

(50) Klok, M.; Walko, M.; Geertsema, E. M.; Ruangsupapichat, N.; Kistemaker, J. C. M.; Meetsma, A.;

Feringa, B. L. Chemistry 2008, 14, 11183–11193.

(51) Geertsema, E. M.; van der Molen, S. J.; Martens, M.; Feringa, B. L. Proc. Natl. Acad. Sci. U. S. A. 2009,

106, 16919–16924.

(52) Ruangsupapichat, N.; Pollard, M. M.; Harutyunyan, S. R.; Feringa, B. L. Nat. Chem. 2011, 3, 53–60.

(53) Kudernac, T.; Ruangsupapichat, N.; Parschau, M.; Maciá, B.; Katsonis, N.; Harutyunyan, S. R.; Ernst, K.-

H.; Feringa, B. L. Nature 2011, 479, 208–211.

(54) Bauer, J.; Hou, L.; Kistemaker, J. C. M.; Feringa, B. L. J. Org. Chem. 2014, 79, 4446–4455.

(55) Kistemaker, J. C. M.; Pizzolato, S. F.; van Leeuwen, T.; Pijper, T. C.; Feringa, B. L. Chem. - A Eur. J.

2016, 22, 13478–13487.


5166–5169.

(57) Blanco, V.; Leigh, D. A.; Lewandowska, U.; Lewandowski, B.; Marcos, V. J. Am. Chem. Soc. 2014, 136,

15775–15780.

(58) Lewandowski, B.; De Bo, G.; Ward, J. W.; Papmeyer, M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P.

M. E.; Heckmann, D.; Goldup, S. M.; D‘Souza, D. M.; Fernandes, A. E.; Leigh, D. A. Science 2013,

339, 189–193.


Chem. Sci. 2015, 6, 140–143.

(60) Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A. J. Am. Chem. Soc. 2016, 138, 1749–1751.

(61) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520–1543.

(62) Takemoto, Y. Chem. Pharm. Bull. (Tokyo). 2010, 58, 593–601.

(63) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem. Eur. J. 2010, 16, 13068–13071.

(64) Yu, C.; Zhang, Y.; Song, A.; Ji, Y.; Wang, W. Chem. Eur. J. 2011, 17, 770–774.

(65) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner, P. R. European J.

Org. Chem. 2012, 2012, 5919–5927.

(66) Li, X.; Xue, X.-S.; Liu, C.; Wang, B.; Tan, B.-X.; Jin, J.-L.; Zhang, Y.-Y.; Dong, N.; Cheng, J.-P. Org.

Biomol. Chem. 2012, 10, 413–420.

(67) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–4296.

(68) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964–8965.

(69) Barton, D. H. R.; Willis, B. J. J. Chem. Soc. D. 1970, No. 19, 1225–1226.

(70) Kellogg, R. M.; Wassenaar, S. Tetrahedron Lett. 1970, 11, 1987–1990.

(71) Wang, Z. In Comprehensive Organic Name Reactions and Reagents; John Wiley & Sons, Inc.: Hoboken,

NJ, USA, 2010; pp 575–581.

(72) This atypical behavior can be attributed to the presence of the dimethylamino group, since the non-

functionalized scaffolds did not exhibit this behavior . Also, it was observed that a longer irradiation time

was required to reach PSS compared to systems, This atypical behavior can be attributed to the presence

of the dimethylamino group, since the non-functionalized scaffolds did not exhibit this behavior . Also, it

was observed that a longer irradiation time was required to reach PSS compared to systems.

(73) A photoequilibrium is established; in fact a small change in isomer ratio was observed upon irradiation at

longer wavelength (λ> 390 nm): e.g. for stable-(Z)-2 to metastable-(E)-2 isomers ratio‘s; 7:93 at 365 nm

to 14:86 at 420 nm (by 1H NMR in MeCN-d3). A photoequilibrium is established; in fact a small change

in isomer ratio was observed upon irradiation at longer wavelength (λ> 390 nm): e.g. for stable-(Z)-2 to

metastable-(E)-2 isomers ratio‘s: 7:93 at 365 nm to 14:86 at 420 nm (by 1H NMR in MeCN-d3).

(74) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659–6690.

(75) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589–5592.

(76) Berkessel, A.; Roland, K.; Neudörfl, J. M. Org. Lett. 2006, 8, 4195–4198.

(77) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem. Int. Ed. 2007, 46, 4614–4628.

(78) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1–48.

(79) Bryantsev, V. S.; Hay, B. P. J. Phys. Chem. A 2006, 110, 4678–4688.



117

(80) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani,

G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;

Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;

Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.,

J.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;

Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;

Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;

Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;

Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;

Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;

Fox, D. J. Gaussian, Inc., Wallingford CT 2013.

(81) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.

(82) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.

(83) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.

(84) Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2006, 128, 1434–1435.

(85) Grunder, S.; Huber, R.; Wu, S.; Schönenberger, C.; Calame, M.; Mayor, M. European J. Org. Chem.

2010, No. 5, 833–845.

Chapter 3

118

Chapter 4 Chapter 4

Studies towards a Trifunctionalized Molecular

Switch for Light-assisted Tandem Catalytic

Processes

This chapter describes the study towards a trifunctionalized molecular photoswitch based on an

overcrowded alkene for light–assisted tandem catalytic processes. We proposed a two-step sequence of

Morita–Baylis–Hillman (MBH) reaction and enamine catalyzed aldol reaction by merging two pairs of

orthogonal bifunctional catalytic groups. Alternative designs, compared to those described in chapter 3,

aimed to improve the catalytic activity in the MBH reaction and related attempted syntheses, are presented.

Finally, screening of other transformations that could be mediated by the initially proposed

photoswitchable catalysts design is reported.

Chapter 4

120

4.1 Introduction

Catalysis is unarguably the most powerful tool to efficiently and effectively transform readily available

building blocks into highly complex molecules and materials. Research focused for decades on the

development of highly selective catalysts to fulfill any possible synthetic task via careful optimization to

achieve high conversions and selectivities. While new synthetic methodologies are still under investigation,

the novel field of switchable catalysis has recently emerged as a promising platform to further extend our

control via more complex catalytic systems.1–6

Inspired by Nature, chemists are now crafting dynamically

responsive catalysts whose activity and selectivity can be tuned or reversed by an external stimulus.

Potential applications include the ability to control ‗one-pot‘ multi-component and multi-step synthetic

processes, thus providing access to a variety of valuable products from a pool of building blocks depending

on the order and type of stimuli provided. A brief selection of the most relevant systems for

photoswitchable catalysis has already been presented in Chapter 3. For a comprehensive view of the field,

the reader may refer to the recent reviews.1–6

Many systems have been demonstrated to achieve reversible control of the catalytic activity by external

input, either by altering the reaction rate or by effectively switching ON/OFF the substrate conversion.7–15

More limited in number and variety are the examples through which dynamic chemoselectivity11,15–17

or

stereoselectivity18–22

were accomplished. Our group largely established the potential of molecular motors23–

26 as versatile light-responsive central units for dynamic stereoselective catalysts,

19,22,27,28 harnessing their

unique tunable stereochemistry. Indeed, stimuli-responsive control of the activity and enantioselectivity

displayed by chiral catalysts was achieved via dynamic conformational changes of a first generation

molecular motor core equipped with two functional groups able to cooperatively accelerate a reaction. Such

responsive organocatalysts (ROC1 and ROC2) and coordination ligands (RCL) were successfully applied,

respectively, in the 1,4-addition of thiols to enones (Scheme 4.1a),19

the Henry reaction20

(Scheme 4.1b),

and palladium-catalyzed enantioselective allylic substitution (Scheme 4.1c).22

Leigh and co-workers reported a multi-tasking rotaxane catalyst RC1 featuring a concealable secondary

amine unit with which catalytic activity in an organocatalyzed reaction can be controlled by changes in pH

(Scheme 4.2a).29

Effective control of the rate of 1,4-addition of an aliphatic thiol to trans-cinnamaldehyde

was achieved via switchable iminium organocatalysis (Scheme 4.2b). Notably, further application of the

same catalyst was accomplished due to the versatility of secondary amines in organocatalysis through other

activation pathways, of which the non-protonated rotaxane (‗ON-state‘) displayed higher catalytic activity

as a general trend.15

Effective β-functionalization of carbonyl compounds with S-nucleophiles (Scheme

4.2b) or C-nucleophiles (Scheme 4.2c) were reported through iminium activation and nucleophilic addition

while substitution reactions were achieved via enamine catalysis (Scheme 4.2d). The rotaxane catalyst is

even able to promote tandem iminium-enamine reaction sequences (Scheme 4.2e) and the Diels–Alder

reaction of a dienal through a trienamine activation pathway (Scheme 4.2f). This concept of switchable

catalyst was further extended to an asymmetric organocatalytic rotaxane that features an acyclic chiral

secondary amine housed within a rotaxane framework.30

This system was able to control the rate of

catalyzed asymmetric Michael addition of 1,3-diphenylpropan-1,3-dione to aliphatic α,β-unsaturated

aldehydes. Good enantioselectivities (up to 93:7 er) were reported, however no dual stereocontrol could be

afforded due to the fixed stereoinduction provided by the catalytic center.

Studies towards a Trifunctionalized Molecular Switch for Light-assisted Tandem Catalytic Processes

121

Scheme 4.1. Stimuli-responsive control of catalytic activity and enantioselectivity achieved by dynamic

conformational changes of a bifunctional first generation molecular motor derivatives in organo- and metal-

catalyzed transformations: a) 1,4-addition of thiol,19

b) Henry reaction20

, c) palladium-catalyzed

enantioselective allylic substitution.22

Chapter 4

122

Scheme 4.2. Activation mode and scope of switchable rotaxane organocatalyst RC1 developed by Leigh

and co-workers.15,29


123

Noteworthy, Leigh and co-workers also developed a switchable rotaxane system featuring two different

organocatalytic sites: a squaramide moiety and a dibenzylamine group (Scheme 4.3a).11

When the rotaxane

is protonated, the macrocycle preferentially interacts with the ammonium unit revealing the squaramide

unit, which can promote the conjugated addition of 1,3-diphenylpropan-1,3-dione to trans-β-nitrostyrene

through hydrogen bonding catalysis (75% conversion after 18 h). In basic media, the macrocycle

preferentially resides over the squaramide, revealing the secondary amine which promotes the Michael

addition of 1,3-diphenylpropan-1,3-dione to crotonaldehyde via iminium ion catalysis (40% conversion

after 40 h). In this way, the catalyst state controls which building blocks react together and which product is

formed from a mixture of reactants (Scheme 4.3b).

Scheme 4.3. Activation mode and substrate-selective switchable rotaxane organocatalyst RC2 developed

by Leigh and co-workers.11

Despite the numerous approaches reported which are extensively reviewed in the literature,1–6

an artificial

system based on a multitasking switchable catalyst or combination of multiple switchable catalysts able to

control sequences of transformations has not yet been reported. The future impact and possible application

of such challenging quest are definitely not easy to predict, as it may lead to the development of highly

complex synthetic methodologies in a biomimetic-like fashion. An atom-efficient scenario achieved by

performing several consecutive reactions in a ‗one-pot‘ (single reactor) is an attractive target. Greater

economy of time and energy maximize resources and overall process simplicity, as well as decreasing

materials loss from multiple iterations of reaction, workup and purification.31–35

Moreover, the use of light

as a non-invasive external input allows for precise frequency, spatial and temporal control over functional

groups response and chemical transformations, providing an artificial alternative to the feedback loops and

trigger-induced effects typical of enzyme activity modulation.36

Chapter 4

124

In this context, we engaged in the challenge of developing a prototype for a dynamically responsive

multitasking catalyst,37–41

based on a second generation molecular motor core (Scheme 4.4). An interesting

aspect of such a motor scaffold is the possibility of functionalizing the otherwise symmetrical lower half

with two different catalytically active moieties (depicted as A and B, respectively), which could

dynamically cooperate with the single functionality (C) located on the upper half in a trifunctionalized

responsive core. Through this design two distinct bifunctional catalytic pairs could be alternatively

activated, thus selectively and orthogonally promoting a two-step transformation sequence upon external

input.

X

Y

C

BA

h1

(P)-[AC]

THI THI

h2

(M)-[BC]

R

R S

aryl

X

Y

C

A B

X

Y

C

BA

(M)-[AC] (P)-[BC]

aryl

X

Y

C

A B

aryl

aryl

R

S R

h1

h2

Scheme 4.4. Proposed design of a trifunctionalized light- and heat-responsive organocatalyst for diastereo-

and enantioselective ‗one-pot‘ assisted tandem catalysis. The catalyst is envisioned to be switchable

between four different states, each displaying a different combination of active cooperative catalytic pair

(AC or BC) and helicity (P or M). In the scheme are displayed only two of the four possible products

accessible by combining three starting components (depicted as different shapes) in a chemo- and

enantioselective fashion (suggested handedness of the newly generated stereogenic centers indicated on the

connecting bond). By triggering the proper catalyst states, both enantiomers of each diastereoisomer could

be accessed.

Notably, each of these two cooperative catalytic pairs could also be selectively addressed in two pseudo-

enantiomeric conformations (i.e. (P)-(AC) and (M)-(AC), (P)-(BC) and (M)-(BC), respectively) upon

triggering the correct light and thermally induced isomerization processes. Indeed, the 4-step isomerization

cycle featured by molecular motors provides access to two distinct catalyst configurations (E or Z), each of

them displaying opposite helical chirality (P or M). Hence, we envision such a design as a feasible future

route for developing the first responsive multi-tasking catalytic system capable of mediating ‗one-pot‘

multi-component transformations in a diastereo- and enantio-selective fashion. The complexity of the ideal

target system is clearly grasped by listing the various critical requirements for such a design (Scheme 4.4).

a) The two catalytic steps must be promoted by two orthogonal distinct bifunctional catalytic pairs

(AC and BC).

b) The shared catalytic moiety of the rotor (C) must be active in both bifunctional pockets.

c) The product of the first catalytic step must be an active substrate for the second step.


125

d) The rate of the intermolecular cooperative catalysis, via interaction of two molecules of catalyst,

should be negligible compared with the intramolecular cooperative mechanism, to efficiently

suppress the undesired catalytic event.

e) In order to avoid further complexity of the catalyst design and restrict the provided stereoinduction

to the sole dynamic chirality of the switch core, the catalytic moieties should not comprise

additional stereogenic centers. The presence of additional chiral elements would in fact increase

the number of possible diastereoisomeric forms of the catalyst, otherwise limited to the four

isomers depicted in Scheme 4.4. Moreover, matched-mismatched effects caused by the different

interaction between the distinct chirality of the switch core and the chirality of the functional

groups A-B-C could be expected, thus further complicating the tandem catalysis development.

f) The two steps of the tandem process should be performed in the same reaction conditions (solvent,

temperature, concentration, catalyst loading, etc.) in order to truly satisfy the requirements for

‗one-pot‘ multi-component transformation; alternatively, the modification of the conditions should

not interfere with the system‘s performance.

g) The catalytic switch should be switched efficiently, reversibly and robustly, i.e. featuring high PSS

ratios towards either the stable and metastable isomer, while displaying limited switching fatigue

or decomposition.

h) The photo-generated metastable state should be highly thermally stable, i.e. feature a long half-life,

thus retaining the desired configuration for extended time intervals (up to days) and non-cryogenic

temperatures (up to 50 °C and above). This feature would ensure a limited variation of the catalyst

mixture composition (ratio of stable vs. metastable) throughout the entire catalytic reaction, open

the application to catalyzed processes characterized by long reaction times and allow higher

working temperatures.

i) Substrates and products of the catalytic cycle should not be affected by photo-induced

decomposition, nor interfere with the switching process of the catalyst, for instance via their own

distinct light absorption or via quenching of the switch‘s excited state by intermolecular energy

transfer.

j) The catalyst inhibition caused by substrates or products should be negligible.

k) The catalyst must be chemically stable at the working catalysis conditions.

l) The synthesis of the trifunctionalized catalyst must be practically feasible and viable on a

reasonably large laboratory scale, to eventually allow for proper screening of the catalysis

conditions and optimization of the ultimate light-triggered tandem process.

m) If the product of the tandem catalyzed synthesis features newly formed stereogenic center(s), the

catalyzed tandem sequence could be performed in an enantioselective fashion by use of a non-

racemic catalyst mixture. Thanks to the inherent and dynamic helicity of the molecular motor

design, asymmetric induction may be achieved with both stable and metastable isomers of the

catalyst. However, asymmetric synthesis or resolution of the photoresponsive catalyst would be

required.

n) The assisted tandem transformation may be composed of two processes generating distinct

stereogenic centers. Noteworthy, the configuration of the secondly generated stereogenic center

may be subject to stereospecific substrate control exerted by the previously generated stereogenic

center rather than by stereoselective induction from the chiral catalyst.

Since the final goal of the project was to develop a catalytic molecular switch able to orthogonally mediate

two distinct catalyzed transformations, we undertook a careful investigation of precedent literature for

recent developments in catalyzed multicomponent ‗one-pot‘ reactions. ‗One-pot‘ reaction types include, but

are not limited to: cascade (domino) processes;42

tandem catalysis (catalysts performing sequential

transformations);43

multifunctional catalysts having more than one active site;44

dual catalyst systems where

one catalyst enhances or alters the properties of the other catalytic cycle;45

and ‗one-pot‘ reactions

involving isolated catalytic cycles, for example where a second catalyst is added after the first has

Chapter 4

126

completed its transformation, or where the first catalyst is selectively deactivated later by addition of a

second reagent.46

Mechanistically distinct from cascade or domino catalysis, in which a single catalytic

transformation occurs sequentially, orthogonal tandem catalysis47

is a ‗one-pot‘ reaction in which

sequential catalytic processes occur through two or more functionally distinct, and preferably non-

interfering, catalytic cycles. Tandem catalysis has also been subcategorized into auto- and assisted-tandem

catalytic cycles.43

Auto-tandem catalysis uses a single precatalyst to effect two or more mechanistically

distinct catalytic cycles, typically by cooperative interaction between the various species in the system. In

contrast, assisted tandem catalysis requires deliberate intervention in the system to switch between one

catalytic cycle and another. Several examples of multi-catalyst promoted tandem or cascade reactions have

been already described in literature,35

showcasing systems based on multiple metal-catalyzed

transformations,43

organocatalytic domino reactions,48

and the combination of metal catalysts and

organocatalysts.49,50

Marks and Lohr recently reported a perspective on orthogonal tandem catalysis, with

particular focus on recent strategies to address catalyst incompatibility.51

They also highlighted the concept

of thermodynamic leveraging by coupling multiple catalyst cycles to effect challenging transformations not

observed in single-step processes, encouraging application of this technique to energetically unfavorable or

demanding reactions. Noteworthy, this perspective mainly describes systems based on metal-catalyzed

reactions, either using homogeneous or heterogeneous catalysts. Reviewed systems include examples

applied to hydrocarbon upgrading via metal catalyzed olefin isomerization/metathesis, metal-catalyzed

tandem arylation/heterocoupling, and enzyme- and acid-catalyzed glucose conversion to

hydroxymethylfurfural. However, no examples of orthogonal tandem organocatalytically promoted

transformations were described.


4.2.1 Design

The design of a switchable trifunctionalized catalytic system proposed hereto entails the reversible

formation and activation of two distinctive catalytic pockets. It is worth mentioning that the ability to retain

the switching properties should not be affected by individual electronic properties nor the cooperative

interactions between the catalytic moieties. Despite the wide variety and solid background of metal-

catalyzed processes, the formation of a metal-complex by cooperation of two ligating moieties (e.g.

phosphines, amines, heterocycles) might have dramatic influence on the switching properties of molecular

motor or switch. A preformed bidentate complex might be too stable to accommodate the isomerization of

the overcrowded alkene bond, especially if each of the two ligating moieties was located on one half of the

motor scaffold. It should be noted that previously reported examples of switchable coordination ligands

based on first generation molecular motor for palladium-catalyzed transformation were changed upon

irradiation of the responsive ligand not in presence of the metal source.22

However, in the case of labile

metal-complexes the reversible coordination of the bidentate ligand may still permit the isomerization of

mono- or non-coordinated species upon irradiation even in presence of the metal source, as demonstrated

subsequently for an analogous responsive core displaying dynamic control of chirality and self-assembly of

double-stranded helicates.28

On the other hand, a different molecular switch design based on a photo-

responsive core of which one half fully contains a flexible bidentate ligand unit may constitute a promising

approach (see Chapters 6 and 8).

We decided to focus our attention on the fast-growing field of organocatalysis (i.e. the catalysis with small

organic molecules in the absence of metals or metal ions) with the prospect of designing the first molecular

motor-based multi-catalyst based purely on organocatalyzed processes. A plethora of organocatalyzed

transformations have been developed in the last decades,52

which witnessed the rise of numerous catalytic

systems based for instance on enamine53

or iminium54

activated intermediates, phosphoric acids, N-

heterocyclic carbenes55

or H-bond donors in asymmetric catalysis.56

We envisioned that small molecule H-

bond donors in combination with Lewis-acid/base mediated catalysis could be implemented in our target

system, while preserving its switching properties. This is also supported by our precedent successful


127

applications of first generation molecular motor based smart systems to achieve reversible stimuli-

controlled catalytic transformation and anion binding.19,20,27

The Aldol reactions,57

conjugated additions,58

cycloadditions,59

Strecker reactions,60

Morita–Baylis–Hillman reactions,61

Mannich reactions,49

Henry

reactions62

and nucleophilic additions to nitroolefins63

are only a few of the organocatalyzed

transformations successfully developed so far.64

Several privileged catalytically active functional groups

have been harnessed in effective organocatalysts, ranging from amines to phosphines, alcohols, thioureas,

guanidines, amides, thiols, carboxylic acids, carbenes, the well-established proline and its related

derivatives. While all these topics support our expectations to find multiple reactions which might be

catalyzed by our goal multi-catalytic switches, it also generated doubts about their plausible selectivity and

specificity.62

It may go without mentioning that all the reported organocatalyzed transformations harness

the reactivity of particularly susceptible functional groups (e.g. imine, aldehyde, indole, α,β-unsaturated

carbonyl group, keto-esters, etc.) already at mild reaction conditions, as opposed for example to more

robust functional groups (e.g. aromatic halides, non-activated alkenes, non-activated allylic groups, etc.)

converted via harsher metal-catalyzed processes. Conversion of a substrate into a product inherently entails

a decrease in functional group reactivity (e.g. secondary amine, secondary alcohol, substituted heterocycles,

non-activated carbonyl group, etc.). Subsequent derivatization would often be required to increase the

intermediate reactivity towards a consecutive organocatalyzed process, unless a proper tandem or domino

sequence is applied. However, it should be noted that most of the reported ‗one-pot‘ tandem

organocatalyzed transformations in fact rely on an auto-tandem catalysis mechanism.43

Hannedouche and

co-workers recently reported the first use of a multitask chiral ligand in an asymmetric assisted tandem

catalysis protocol that successively combines a metal-catalyzed alkyne hydroamination followed by an

asymmetric organocatalyzed Friedel–Crafts alkylation.65

To the best of our knowledge, no examples of

fully organocatalyzed assisted tandem transformations have been reported to date.

In this context, we selected the Morita–Baylis–Hillman reaction (or MBH reaction, Scheme 4.5) as a

starting point for the development of our multi-catalytic system. The classical MBH reaction is a carbon-

carbon bond forming reaction yielding α-methylene-β-hydroxycarbonyl compounds by addition of α,β-

unsaturated carbonyl compounds to aldehydes.

Scheme 4.5. General scheme of Morita–Baylis–Hillman reaction.

Instead of aldehydes, imines can also participate in the reaction if they are appropriately activated: such

process is commonly referred to as the aza-Morita−Baylis−Hillman (aza-MBH) reaction. In either case, this

reaction provides a densely functionalized product, yielding a carbonyl-derived allylic alcohol or secondary

allylic amine upon addition to an aldehyde or an imine, respectively. Such characteristics had a strong

influence during the design of our proposed tandem process, as it retains a potentially reactive α,β-

unsaturated carbonyl motif in the product. Therefore, further functionalization could potentially be

conducted via a second organocatalyzed process in a ‗one-pot‘ fashion. Most effective catalysts for MBH

reactions are nucleophilic unhindered tertiary amines, such as DABCO and quinuclidine, or tertiary

phosphines like tributylphosphine.66–68

In particular the specificity of tertiary amines as catalysts in the

MBH reaction held good promise for our studies, as such functions may provide the orthogonality required

for an efficient assisted tandem catalysis process achieved by a switchable multiple organocatalyst.

Reaction conditions are often mild (temperature ranging from -20 °C to 40 °C), however reaction rates are

notoriously low (reaction times from hours to weeks). The catalytic cycle consists of three steps: 1)

Chapter 4

128

conjugate addition of the nucleophilic trigger catalyst to the β-position of the activated alkene motif; 2)

nucleophilic addition of the α-position of the resultant zwitterionic adduct to the carbonyl or imine

functionality of the electrophilic partner, also referred to the electrophilic quench; 3) proton transfer and

elimination of the catalyst, thus restoring the α,β-unsaturated carbonyl functional group.69

According to the

commonly established mechanism, the electrophilic quench is the rate determining step (second order in

aldehyde and first order in nucleophilic catalyst and enone).70,71

Rate enhancement can be achieved by

stabilizing the zwitterionic intermediate or by activating the aldehyde, for instance by a H-donor co-

catalyst.72

In more elaborate designs, the reported catalyst system comprises both catalytic partners linked

by a rigid chiral scaffold. The bifunctional catalysts based on the popular Cinchona alkaloid scaffold are a

clear example.69

In summary, the MBH reaction features critical advantages for the current study: (i) the

MBH products are flexible and multi-functionalized, retaining an inherent reactivity potentially exploitable

in a tandem sequence; (ii) the recently reported methodologies often involve the use of a bifunctional

organocatalytic systems; (iii) the MBH reaction is usually conducted under mild reaction conditions, which

well suit the very slow thermal relaxation process displayed at room temperature by our chosen switch

scaffolds (six-membered ring thiopyranyl upper half, five-membered ring fluorenyl lower half, see Chapter

2 and 3).

Recently, urea/thiourea-based bifunctional catalysts have emerged as powerful catalysts in a wide range of

asymmetric transformations. 39,73–78

Their high activities as well as their selectivities were attributed to their

ability of activating both electrophilic and nucleophilic centers of the reacting partners.40

Wang and co-

workers reported the use of a chiral binaphthyl-derived amine-thiourea catalyst 1 for asymmetric MBH

reaction (Scheme 4.6), proposing a synergy between the nucleophilic activation of the 2-cyclohexen-1-one

via reversible conjugated addition of the tertiary amine and the dual H-bond stabilization of the generated

enolate anion by the thiourea moiety.38,79

Scheme 4.6. Binaphthyl amine-thiourea catalyst 1 for enantioselective MBH reactions by Wang and co-

workers.79

Previously introduced, photoresponsive stereoselective catalysts based on a first generation molecular

motor ROC1 and ROC2 feature the combination of DMAP and thiourea functional moieties (Figure 4.1).7

These precedents indicate that a thiourea group and an aromatic amine conjugated to the motor core may be

well tolerated by our target trifunctionalized switch. Similarly, a tertiary aromatic amine substituent was

successfully implemented in a nitro-amine disubstituted chiroptical molecular switch 2, which displayed

efficient reversible photoswitching by use of UV and visible light (Figure 4.1).26

Inspired by these

preceding results, we opted for a thiourea substituent as a hydrogen-donor moiety in the upper half and a

basic dimethyl amine group in the lower half of molecular switches 3 and 4 to design the first bifunctional

cooperative catalytic pair (see Chapter 3).


129

Figure 4.1. DMAP-thiourea substituted molecular motor ROC1-2 and nitro-amine substituted chiroptical

switch 2 previously developed in our group. Proposed design of bifunctional molecular switches 3-4

described in Chapter 3.

The second active site of our photoswitchable trifunctionalized catalyst was proposed to harness the

cooperation of the shared thiourea moiety, linked to the upper half, together with a primary or secondary

aliphatic amine, linked to the lower half. In the general mechanism, amine catalysts activate carbonyls by

the formation of either an enamine or an iminium ion intermediate. Enamine formation raises the HOMO

energy, increases nucleophilicity, and facilitates nucleophilic addition and substitutions reactions (Scheme

4.7a).53,80

Conversely, iminium ion formation increases the electrophilicity of the carbonyl carbon and

lowers the LUMO energy.54

This allows access to pericyclic reactions and electrophilic addition reactions,

particularly conjugate additions (Scheme 4.7b).

Scheme 4.7. Enamine and iminium ion activation of saturated and α,β-unsaturated carbonyls.

The obtained bifunctional cooperative catalyst could then be employed, for instance, in an aldol-type

reaction with electrophiles (Scheme 4.8a) by activation of the carbonyl partner via enamine catalysis and

hydrogen-bond activation of the electrophile provided by the upper thiourea substituent.38,39,53,58,81

Alternatively, the α,β-unsaturated carbonyl motif could also be activated via iminium catalysis for

cycloaddition or nucleophilic 1,4-addition reactions (Scheme 4.8b).54

A cyclic aliphatic amine substituent could be considered a promising option in terms of catalytic activity

and versatility for the design of a catalyst for aldol-type reactions. Scheme 4.8c illustrates the proposed

design for bifunctional catalyst 5 featuring an imidazoline or imidazolidinone substituent directly attached

by one of the nitrogen atoms to the fluorenyl lower-half. MacMillan and co-workers developed an efficient

imidazolidinone-based catalyst for enantioselective aldol methodology.40

Chapter 4

130

Scheme 4.8. a) General scheme of an enamine-mediated aldol condensation. b) General scheme of an

enamine-mediated conjugated addition of ketones to activated olefins.

Inspired by their work, we considered such a structure as a solid starting point for our bifunctional catalyst.

First, such imidazolidin(on)e groups could simplify the synthesis through a straightforward Buchwald-

Hartwig coupling with a halogen-substituted fluorenyl lower half. Second, it would also avoid the

complication of generating a stereocenter within the bridging unit (vide supra). An alternative cyclic

pyrrolidine/pyrrolidinone substituent would in fact be connected to the switch lower half by a chiral tertiary

carbon, thus potentially resulting in a diastereomeric mixture of the target catalyst.

The concept design of a trifunctionalized photo-responsive organocatalyst for ‗one-pot‘ multi-step synthesis

via Morita–Baylis–Hillman and subsequent enamine mediated aldol condensation is presented in Scheme

4.9. Merged together, the two catalysts 3 or 4 and 5 would constitute the first multi-catalytic molecular

switch, able to perform a MBH-aldol reactions sequence in a ‗one pot‘ orthogonal tandem process upon

light-assisted isomerization of the catalyst. When the catalyst is switched to the E-isomer, the cooperative

activation by thiourea and tertiary amine groups is envisioned to promote the organocatalytic MBH reaction

of enones and aldehydes to generate the intermediate MBH adducts. Upon photoisomerization, the catalyst

could be switched to the Z-isomer, allowing the conversion of the MBH adduct to more complex final

products, e.g. via thiourea and primary/secondary amine cooperative catalyzed aldol-type transformation or

Michael 1,4-addition via iminium catalysis (not shown in scheme) upon activation of the second catalytic

pair.

S

N

HN

S

NH

N

organocatalyticBaylis-Hillman

reaction

O

R'

OH

organocatalyticenamine alkylation reaction

O

R'El

OH

h1

h2

El

NH

NH

S

CF3

F3C

S

NH

CF3

CF3

O

NR3

H

O

NR3

H

R'

O

H H

H

R' H

O

N

R'

OHR R

N

R'

OHR R

Etertiary amine

+ thiourea catalysis

secondary aliphatic amine

+ thiourea catalysis

O

ThioureaThiourea

HH

Thiourea

aryl aryl

E-isomer Z-isomer

RHN R

Scheme 4.9. Proposed design of a trifunctional photo-responsive organocatalyst for ‗one-pot‘ light-assisted

tandem catalysis via MBH reaction (E-isomer, thiourea + tertiary amine) and subsequent enamine mediated

aldol condensation (Z-isomer, thiourea + primary/secondary aliphatic amine).


131

4.2.2 Preliminary testing of bifunctional overcrowded alkenes as switchable catalysts

Morita–Baylis–Hillman reaction

Before starting the challenging synthesis of a multicatalytic molecular switch, we engaged a more

systematic approach by testing the basic concept of a photo-activated reversible ‗ON/OFF‘ catalyst on a

simpler prototype. The trifunctionalized catalytic switch design was split into the two corresponding

catalytic bifunctional components. Therefore, we suggested two initial designs 3 and 4 for a catalytic

molecular switch for MBH reactions (Figure 4.1). They feature a thiourea substituent as hydrogen-donor

moiety in the upper half and a basic aromatic dimethylamine group in the lower half. In our previous study

we showed that the combination of a 5-membered ring in the lower half (fluorene) with a sulphur

containing 6-membered ring in the upper half (5,8-dimethylthiochromene and benzo[f]thiochromene)

resulted in distinctive high energy activation barriers for the thermal relaxation step in the rotary cycle of

the second generation molecular motors and consequently long half-lives of the corresponding metastable

species. Moreover, by comparison of two structurally different upper halves we envisioned to investigate

the influence of the distance between the two cooperative catalytic functionalities on the catalytic

performance. Despite the literature claims by Wang and co-workers,79

our attempts to catalyze the model

reaction between 2-cyclohexen-1-one and 3-phenylpropionaldehyde by either (E)-3, (Z)-3, (E)-4, (Z)-4 or

the original literature catalyst 1 did not lead to any conversion to the desired MBH adduct as determined by

GC-MS and 1H NMR spectroscopy analysis (Scheme 4.10).

Scheme 4.10. Attempted catalysis of the MBH reaction between 2-cyclohexen-1-one and 3-

phenylpropionaldehyde using 1, stable isomers (E)-3, (Z)-3, (E)-4 or (Z)-4 as catalyst; no conversion to the

desired Michael adduct was observed by 1H NMR. Conditions according to literature.

79. Conversion

monitored by GC-MS and 1H NMR spectroscopy analysis of crude mixture.

We postulate that these disappointing results are due to the limited catalytic activity of the dimethylaniline

moiety, both in terms of the low nucleophilicity of the aryl amine and the structurally constrained nature of

the tertiary amine within the catalyst‘s structure. In order to sustain our hypothesis, the influence of both

nucleophilic and H-bond donor partners as separate co-catalyst units was addressed (Table 4.1). Notably,

no conversion to the MBH product was observed upon use of DABCO (1,4-diazabicyclo[2.2.2]octane) or 6

in neat conditions (entries 1-2). When the two components were combined, only the reaction conducted

without addition of solvent provided a moderate conversion to the expected product (entries 3-4), as proven

by comparison with precedent reported 1H NMR spectral data. To further support the hypothesis of lower

reactivity of the aromatic dimethylamine substituent, N,N‘-dimethylaniline (DMA) was tested alone and in

combination with thiourea 6 resulting in no conversion in either cases (entries 5-6).

Chapter 4

132

Table 4.1. Influence of Lewis-base (co-catalyst A) and thiourea 6 (co-catalyst B) in the MBH reaction

between 2-cyclohexen-1-one and 3-phenylpropionaldehyde.

Conjugated addition of 2,4-pentadione to trans-β-nitrostyrene

Compound 1 was also reported to catalyze the conjugated addition of 2,4-pentadione to trans-β-

nitrostyrene.82

Similar to the original study on catalyst for MBH reaction by Wang,79

the proposed

mechanism entails the acid-base cooperative activation by the bifunctional chiral catalyst of both reaction

partners. 2,4-pentadione is coordinated in its nucleophilc enolic form by the dimethylamine group. The

Michael acceptor trans-β-nitrostyrene is coordinated and activated by the thiourea group via double H-bond

donation. Wang‘s catalyst 1 and switches (E)-3, (Z)-3, (E)-4 and (Z)-4 were eventually tested in such

transformation by following the reported procedure. Similarly to the test results for the MBH reaction, no

conversion towards the Michael addition product was detected in any of the cases as determined by GC-MS

and 1H NMR spectroscopy analysis (Scheme 4.11).

Scheme 4.11. Literature reported82

and tested results for conjugated addition of 2,4-pentadione to trans-β-

nitrostyrene using Wang‘s catalyst and bifunctional switches (E)-3, (Z)-3, (E)-4 and (Z)-4. Conversion

monitored by GC-MS and 1H NMR spectroscopy analysis of crude mixture.

4.2.3 Attempted synthesis of alternative bifunctionalized switches

The initially proposed and subsequent alternative designs of a bifunctional switchable catalyst for MBH

reaction are presented in Figure 4.1. In accordance to more commonly encountered functional groups

featured by previously reported catalysts for MBH reactions, a small selection of alternative Lewis base

motifs was proposed (Figure 4.2). The stronger nucleophilic character of aliphatic tertiary amines featured

by 7, 8 and 9 and tertiary phosphines featured in 10 should ensure the desired higher catalytic activity.

Entrya Co-catalyst A (mol%) Co-catalyst B (mol%) Neat - Solvent Conversion (%)

b

1 DABCO (20) / neat No conversion

2 / 6 (20) neat No conversion

3 DABCO (20) 6 (20) neat 60

4 DABCO (10) 6 (10) acetonitrile No conversion

5 DMA (20) / neat No conversion

6 DMA (20) 6 (20) neat No conversion

[a] Conditions: 2-cyclohexen-1-one (0.75 mmol, 3 equiv), 3-phenylpropionaldehyde (0.25 mmol, 1 equiv), neat or in acetonitrile (1 mL) as specified, room temperature, 4 d. [b] Conversion monitored by GC-MS and

1H NMR

spectroscopy analysis of crude mixture.


133

Figure 4.2. Initial and alternative proposed designs of bifunctional switchable catalyst.

Scheme 4.12 illustrates the proposed retrosynthetic analysis of catalysts C and D. Similarly to 3 and 4, the

more sensitive thiourea motif in the upper half is to be installed after the construction of the tetrasubstituted

alkene and amination of the upper half via a Buchwald-Hartwig coupling.

Scheme 4.12. Retrosynthetic analysis of 7 and 8 starting from bromo-substituted diazospecies 12 and

tertiary amine-substituted thioketone 13.

The lower half coupling partner was synthesized from commercially available 2-carboxaldehyde-fluorene

14 (Scheme 4.13). Reductive amination of the carboxaldehyde moiety was conducted with a commercial

solution of dimethylamine (2M in MeOH) in presence of titanium(IV) isopropoxide and sodium

borohydride to afford 15 (87%). Oxidation of the fluorene core to ketone 16 (83%) was then achieved

under an atmosphere of air using the trialkyl ammonium salt Triton B as a phase transfer catalyst in

pyridine. The conversion of fluorenone 16 into the reactive thioketone 17 was subsequently unveiled to be

the weak link of the proposed synthetic route. Reaction with either P4S10 (Scheme 4.13a) or Lawesson‘s

reagent (Scheme 4.13b) resulted in rapid conversion of substrate 16, as observed by TLC analysis of the

reaction mixture with disappearance of any spot other than at the baseline already after few minutes.

However, no fraction resembling neither the substrate nor the product was collected upon flash column

chromatography of the residual crude. By comparison with the synthesis of 2-(dimethylamino)-9H-

fluorene-9-thione, the thionation of 16 appears to be detrimentally affected by the stronger

basicity/nucleophilicity of the aliphatic tertiary amine substituent. TLC analysis of the reaction mixture

showed a byproduct‘s spot (Rf < 0.05) at a very low elution speed in various mixtures of dichloromethane,

ethyl acetate and methanol. This may suggest the formation of a stable nitrogen-phosphorus adduct or salt

rapidly generated in the tested conditions, thus preventing the conversion towards the desired thioketone. In

a study conducted by Bergman and co-workers, the alternative thionating reagent P4S10·Py4 complex was

studied and employed for thionations of carbonyl functional groups in polar solvents such as acetonitrile

and dimethyl sulfone, displaying excellent selectivity and substrate versatility.83

Its properties have been

compared with the established Lawesson‘s reagent. Particularly interesting are the results from thionations

in dimethyl sulfone at high temperatures (∼165–175 °C), at which Lawesson‘s reagent is inefficient due to

rapid decomposition. The reported methodologies were successfully applied to a large variety of aliphatic

and aromatic ketones, amides and ketamines, containing scaffolds such as lactams, nicotinamides,

quinolones, indoles and oxindoles, to afford the corresponding thioketones and thioamides. Notably, no

Chapter 4

134

aliphatic amine was included in the procedure scope, with the exception of glycine which afforded 2,5-

piperazinedithione upon dimerization. Despite the lack of precedence, the thionation of 2-

((dimethylamino)methyl)-9H-fluoren-9-one 16 with P4S10·Py4 complex in acetonitrile (Scheme 4.13c) and

dimethyl sulfone (Scheme 4.13d) were both attempted by following reported procedures. In either case, no

trace of product was detected upon NMR analysis of the reaction crude. While the reaction in acetonitrile

gave no visible conversion, reacting in dimethyl sulfone caused a sudden change from yellow to vivid

purple color, a common indication of the presence of successfully thionated fluorenones. However, the

reported workup step involves the use of boiling water to hydrolyze the excess of P4S10·Py4 complex, which

in our case rapidly caused the mixture to turn brown and may have also decomposed the expected product.

When the procedure was subsequently repeated without the addition of water but using direct flash column

chromatography of the solidified melted, no purple fraction was isolated. Eventually the herein proposed

synthetic route towards 7, 8 and 9 via thionation of amine-substituted fluorenones and subsequent Barton-

Kellogg coupling with diazo compound 12 was abandoned in favor of an alternative approach.

Scheme 4.13. Attempted synthetic route to tertiary aliphatic amine-substituted thioketone 17.

An alternative retrosynthetic analysis was proposed, as illustrated in Scheme 4.14. Secondary amine-

substituted switches 7, 8 and 9 could potentially be obtained from a common dihalogenated intermediate

21, synthesized from the corresponding coupling partner bromo-diazochromane 12 and iodofluorenthione

22. Due to the expected higher reactivity of the iodo-substituted fluorenyl lower half, a plausible

chemoselectivity was envisioned upon lithiation and subsequent quenching with DMF to afford

carboxaldehyde intermediate 20, or upon phosphination to yield phosphine intermediate 19, respectively.

Similarly, quinuclidine-derived switch 18 may be obtained from intermediate 20 via condensation with 3-

quinuclidone and subsequent reduction of the carbonyl group (for instance via a Wolff–Kishner-type

reduction). Derivatization via Buchwald-Hartwig amination and subsequent introduction of the thiourea

substituent would afford the target compounds 7, 8, 9 and 10.


135

Scheme 4.14. Retrosynthetic analysis of switches 7-10 starting from bromo-substituted diazothiopyran 12

and iodo-substituted thioketone 22.

The attempted synthesis of bromo-iodo-substituted alkenes 25 and 27 started with the generation of 2-

iodofluoren-9-thione 22 upon reaction with Lawesson‘s reagent (Scheme 4.15). The unstable thioketone 22

was rapidly reacted in a Barton–Kellogg coupling with hydrazones 10 and 22 upon generation of the

corresponding highly reactive diazo compounds with PIFA at low temperature. However, after sulfur

extrusion with PPh3 or HMPT only small amounts of alkenes 25 and 27 were obtained by flash column

chromatography as inseparable mixtures of E- and Z-isomers. Separation of the stereoisomers could be

achieved in a later stage of the synthesis. However, due to the discouraging results from these Barton

Kellogg couplings and high catalyst loading often required in common organocatalytic transformations for

final application of the target compounds as catalysts, the synthesis of 7-10 along this path was

discontinued.

Scheme 4.15. Attempted synthesis of bromo-iodo-substituted overcrowded alkene 25 and 27 as precursors

of proposed catalysts 7-10.

Chapter 4

136

4.2.4 Investigation of catalytic performance in alternative organocatalyzed transformations

The project was eventually redirected to a different approach in order to optimize the time left. As

compounds 3 and 4 were already fully characterized, alternative reactions were tested to investigate their

catalyst performance in different types of transformations other than the MBH. The proposed applications

would harness either the basic and nucleophilic character of the dimethylamine substituent or its steric

hindrance in combination with the hydrogen-bond donor nature of the thiourea motif. It should be noted

that due to the very small quantities of 3 and 4 obtained, the screening tests described herein were

performed by using Wang‘s catalyst 1 as a model. Due to its inherent similarity with Z-isomers of 3 and 4,

the latter would have been tested once the successful reaction conditions were unveiled.

Alkylation of α-carboxypiperidones ethyl esters

The first investigated reaction was the synthesis of benzomorphan analogues by intramolecular Buchwald–

Hartwig cyclization developed by Khartulyari and co-workers.84

In their study, the key bond formation was

based on an intramolecular Buchwald–Hartwig enolate arylation reaction, to provide tricyclic

benzomorphan derivatives. Thus, alkylation of α-carboxypiperidones ethyl esters with ortho-bromobenzyl

bromides provides the necessary substrates. N-benzyl substituted piperidones were alkylated directly with

substituted benzyl bromides (Scheme 4.16a). N-methyl substituted piperidone required alkylation via

benzyl transfer by a pre-formed ammonium intermediate due to higher nucleophilicity of the nitrogen atom

in the piperidone ring (Scheme 4.16b). Despite the elegant synthetic approach to pharmaceutically valuable

targets, the described methodology provides only racemic products.

Scheme 4.16. Synthesis of benzomorphan analogues by intramolecular Buchwald–Hartwig cyclization

developed by Khartulyari and co-workers: a) N-benzyl protected piperidones directly alkylated with

substituted benzyl bromides; b) N-methyl protected piperidone required alkylation via benzyl transfer from

a pre-formed ammonium intermediate.84

It should be noted that the stereoselective event is the formation of the quaternary carbon via benzyl

transfer to the enolate intermediate of the starting piperidones. Upon intramolecular Buchwald–Hartwig

enolate arylation reaction, the tricyclic benzomorphane derivatives are subsequently constructed in a

stereospecific fashion. We envisioned that a chiral inductor able to coordinate via hydrogen-bonding the

prochiral enolate intermediate would give access to the corresponding enantioselective benzylation.

Scheme 4.17 illustrates the proposed mechanism mediated by chiral benzyl ammonium derivatives of 1 in

stoichiometric quantities. Similarly, using 3 or 4 as alkylating agents could allow achieving activity control

upon photoswitching. The E-isomers would in fact characterized by a less efficient intramolecular transfer


137

due to the larger distance between the functional group compared with Z-isomers, possibly resulting in a

lower alkylation rate. In alternative, a combination of activity and stereoselectivity control could be

expected in the case of enantioenriched 3 or 4. Similarly to the dynamic control of stereoselectivity reported

for catalyst ROC1 by Wang and co-workers,19

different enantioselectivity and reaction rate could be

expected between the distinct of E- and Z-isomers of 3 or 4 as benzyl ammonium salts.

Scheme 4.17. Proposed asymmetric synthesis of benzomorphan analogues via asymmetric alkylation of N-

protected piperidones with a pre-formed benzyl ammonium chiral intermediate (derivatives of 1 and

bifunctional switches 3 and 4) in stoichiometric quantities and subsequent palladium-catalyzed cyclization.

The initial investigation was approached by using 1 as model compound. The tertiary amine moiety of 1

was successfully converted upon reaction with benzyl bromide to the corresponding ammonium salt 28

(Scheme 4.18a). Surprisingly, 28 was found to be particularly unreactive in the benzyl transfer to

piperidone 29, despite the screening in toluene of temperatures from 50 °C up to reflux (Scheme 4.18b).

Upon careful monitoring of the reaction by 1H NMR spectroscopy analysis over time, compound 28 was

found to be slowly degraded to 1 and benzyl alcohol, as confirmed upon subsequent spiking of the sample

with commercial benzyl alcohol for reference. The reaction was repeated according to the literature using

the ammonium salt of dimethylaniline and benzyl bromide 31, which successfully yielded the expected

alkylated piperidone 30 already at 50°C (Scheme 4.18c). While the aromatic dimethylamine substituent of

1 displayed the required nucleophilic character to generate the alkyl ammonium salt, 28 was found too

unreactive towards the alkyl transfer. It could be hypothesized the nucleophilicity of the naphthalenyl

amine is higher than aniline, causing a greater stability of the corresponding ammonium salt. Alternatively,

the high steric hindrance caused by the thiourea group may prevent instead the efficient approach of the

piperidone enolate, thus impeding the alkylation. The bifunctional catalyst 1 was found again inactive

under the tested conditions and our proposed enantioselective approach of the reported synthesis of

benzomorphans derivatives was r unsuccessful.

Chapter 4

138

Scheme 4.18. Preliminary test with 1. a) Synthesis of chiral benzyl transfer intermediate 28. b) Attempted

asymmetric alkylation of piperidone 30 by stoichiometric benzyl transfer with 29. c) Repeating literature

procedure with dimethylamine-derived benzyl ammonium bromide.

Decarboxylative protonation of α-aminomalonates

Due to the unsatisfactory nucleophilic properties of the amine substituent of 1 and switches 3 and 4, we

decided to test their catalytic performance as a Brønsted base. Asymmetric decarboxylative protonation of

substituted aminomalonates in the presence of a chiral base is a synthetically convenient and

straightforward route to synthesize a variety of natural and unnatural optically pure α-aminoacids. This

synthetic methodology is based on the more general malonic acid synthesis where the chirality of the

product can be generated during the enolate protonation step (Scheme 4.19a). Thiourea derived cinchona

alkaloids promote the asymmetric decarboxylative protonation of cyclic, acyclic, or bicyclic α-

aminomalonate hemiesters under mild and metal-free conditions to afford enantioenriched aminoesters in

high yields and enantioselectivities. In particular, Rouden and co-workers reported the synthesis of both

enantiomers of the aminoesters starting from racemic substrates using cinchona alkaloid 32 and its

pseudoenantiomer derived from quinine (Scheme 4.19b).85]

However, it requires stoichiometric amount of

base (1 equiv) and long reaction times (7 d). In the proposed mechanism, the amine function could act as a

chiral proton shuttle whereas the urea/thiourea group, a strong hydrogen-bond donor, would anchor the

substrate to bring the chiral protonating agent in a close proximity to the prochiral enolate. An alternative

mechanism may involve the interaction of carboxylate anion with thiourea that facilitates the

decarboxylation step whereby protonation preferably occurs in a stereocontrolled fashion with the

ammonium moiety of promoter 32. Despite the difference in basicity between an aliphatic amine featured

by the cinchona alkaloids and the aromatic amine of 1, 3 and 4, we did envision the deprotonation process

of aminomalonates not to be largely affected. Indeed, the subsequent decarboxylation could be triggered by

the basic aniline motif, providing the target chiral amino-esters. Photoisomerization of switches 3 and 4

could give access to external control of activity or enantioselectivity depending on the selected catalyst

isomer.


139

Scheme 4.19. a) Proposed mechanism of enantioselective decarboxylative protonation of α-

aminomalonates. b) Enantioselective decarboxylative protonation of α-aminomalonates mediated by

thiourea cinchona alkaloid 32 developed by Rouden and co-workers.85

Preliminary tests on the decarboxylative protonation of 1-acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic

acid 33 to ethyl 1-acetylpiperidine-2-carboxylate 34 are presented in Table 4.2. The tested conditions are

according to the literature precedent.85

Both in absence or presence of DMA, conversion of the substrate

was observed only at temperature above room temperature (entries 1-4). Upon addition of a

substoichiometric amount of DMA, full conversion was still obtained only at higher temperature (entries 5-

6). The use of the more basic DABCO as base gave full conversion already at rt (entries 7-8).

Table 4.2. Influence of temperature, base and thiourea catalyst in the decarboxylative protonation of 1-

acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic acid.

Entrya Catalyst (mol%) Temperature (°C) Time (d) Conversion (%)

b

1 / rt 4 No conversion

2 / 40 2 60

3 DMA (110) rt 4 No conversion

4 DMA (110) 40 2 Full conversion

5 DMA (20) rt 4 No conversion

6 DMA (20) 40 2 Full conversion

7 DABCO (110) rt 1 Full conversion

8 DABCO (110) 40 1 Full conversion

9 DMA (20) + 6 (20) rt 1 No conversion

10 DMA (20) + 6 (20) 40 1 25

11 1 (50) rt 4 No conversion

12c 1 (50) 40 1 45

(racemic)

[a] Conditions: 33 (0.09 mmol) in THF (0.5 mL), catalyst loading, temperature and time as reported. [b] Conversion monitored by GC-MS and

1H NMR spectroscopy analysis of crude mixture. [c] Product was obtained as a racemic mixture as determined by

chiral HPLC analysis (OB-H, hept:2-propanol = 95:5, flow 0.5 mL/min, 40 °C, Rt 21.2 min and 26.0 min).

Chapter 4

140

Compound 6 was then used in combination with DMA in substoichiometric amounts, to investigate the

possibility of synergistic effects. Contrary to our expectations, low conversion was observed also at higher

temperature (entries 9-10). Eventually, 1 was tested affording similar results to the blank reactions (entries

11-12). No enantiomeric excess was observed for the isolated product. Compared with the higher activity of

DABCO, the large difference in pKb between the aliphatic amine in the cinchona alkaloid 32 and the

aromatic amine of 1 might be the cause of lack of catalytic activity of the latter. Alternatively the acidity of

the thiourea protons86

and the close proximity to the amine group might be responsible for its low basicity

and poor catalyst activity, as suggested by the control experiment using DMA in presence of 6.

Alcoholysis of styrene oxides

Finally, we tested the binding properties of our thiourea-substituted switches. Numerous studies have been

conducted on the supramolecular recognition of anions with ureas and thioureas derivatives.87

The success

of this class of systems lies in their hydrogen bonding ability to a variety of reactants and intermediates in

close similarity to those found in the active sites of enzymes. After the seminal reports by Wilcox88

and

Hamilton,89,90

appropriate incorporation of the (thio)urea motif in acyclic, cyclic or polycyclic frameworks

has become one of the prevailing strategies in the design of synthetic anion receptors.91

Recent advances in

supramolecular recognition allowed chemists to design a wide range of synthetic receptors matching the

requirements for inorganic and organic anion binding, such as halide anions, oxyanion, cyanide, nitronate,

enolate anions and nitro-groups, with remarkable application as powerful organocatalysts.92,93

In particular,

thiourea derivatives have been shown to effectively bind Y-shaped oxoanions such as carboxylates in polar

solvents,94

achieving selective recognition of amino acids95

and synergistic effect in catalysis.85,93,96

Schreiner and co-workers reported a method for mild and regioselective alcoholysis of styrene oxides via

cooperative Brønsted acid-type organocatalytic system comprised of mandelic acid 37 and N,N′-bis-[3,5-

bis-(trifluoromethyl)phenyl]-thiourea 38 (Scheme 4.20a).97

Scheme 4.20. a) Method for mild and regioselective alcoholysis of styrene oxides via cooperative Brønsted

acid-type organocatalytic system comprising mandelic acid 37 and N,N′-bis-[3,5-bis-

p(trifluoromethyl)phenyl]-thiourea 38 developed by Schreiner and co-workers.97

b) Reported Proposed

mechanism.


141

Various styrene oxides 35 are readily transformed upon addition of alcohols 36 into their corresponding β-

alkoxy alcohols 39 in good to excellent yields. Simple aliphatic and sterically demanding, as well as

unsaturated and acid-sensitive alcohols can be employed. The experimental findings suggested an H-

bonding-mediated cooperative Brønsted-acid catalysis mechanism (Scheme 4.20b). It is likely that co-

catalyst 38 coordinates to the acid 37 through double H-bonding, stabilizes the latter in the chelate-like cis-

hydroxy conformation, and acidifies the secondary alcoholic proton via an additional intramolecular H-

bond. The epoxide then is activated by a single-point hydrogen bond that facilitates regioselective

nucleophilic attack of the alcohol at the benzylic position. The incipient oxonium ion reprotonates the

mandelate ion and affords the β-alkoxy alcohol product. In this context, we envisioned switches 3 and 4 to

potentially exhibit selective reversible cooperative effects with mandelic acid 37 upon photoisomerization.

While E-isomers would provide effective binding of the acid and subsequent efficient catalytic activity, Z-

isomers were expected to display either lower activity or strong asymmetric preference due to the steric

hindrance generated by the amine substituent. Thioureas 1 and 6 were then tested beforehand to establish

such potential. More precisely, 1 was used as always to mimic the Z-isomers of 3 and 4, while 6 might have

provided insights on the use of E-isomers of 3 and 4, due to a reduce steric hindrance from the aromatic

tertiary amine envisioned for the latter. The influence of thiourea and Lewis-base catalyst in the alcoholysis

of styrene oxide 40 in presence of ethanol was investigated under conditions similar to those given for the

work of Schreiner as presented in Table 4.3.

Table 4.3. Influence of thiourea and base in the catalyzed alcoholysis of styrene oxide.

Entry

a Catalyst (mol%) Conversion (%)

b Comment

1 / <5 Traces of 41

2 (R)-37 (1) 20 42 obtained, no traces of 41

3 (R)-37 (1) + DMA (4) No conversion /

4 DMA (4) No conversion /

5 (R)-37 (1) + 6 (1) 26 42 main product, 41 in traces

6 (R)-37 (1) + DMA (4) + 6 (1) No conversion /

7 (R)-37 (1) + 1 (1) 50 42 obtained, no traces of 41

8 (S)-37 (1) + 1 (1)) 30 42 obtained, no traces of 41

[a] Conditions: 40 (0.30 mmol), ethanol (1.80 mL), catalyst as reported, room temperature, 3 d. [b] Conversion monitored by GC-MS and

1H NMR spectroscopy analysis of crude mixture. [c] Product was

obtained as a racemic mixture as determined by chiral HPLC analysis (AD-H, hept:2-propanol = 95:5, flow 0.5 mL/min, 40 °C, Rt 14.5 min and 15.0 min).

Chapter 4

142

Surprisingly, no conversion to the expected product 41 was observed in any case. The blank reaction gave

conversions to hydrolysed product 42 in traces (entry 1). The use of mandelic acid 37 alone only provided a

higher conversion to 42 (entry 2). Notably, the addition of co-catalyst 6 resulted in no significant variation

(entry 5). In any test where DMA was added, no conversion of 40 was detected (entries 3,4,6). It appears

that an additional base suppresses the hydrolysis to sideproduct 42. The use of 1 in combination with either

enantiomer of 37 resulted in conversion towards 42 to different extents. Noteworthy, Schreiner and co-

workers reported that parallel reference experiments without 38, as well as experiments using 38 without

acid co-catalyst 37 under identical reaction conditions, which showed no conversion to products 39.97

As

opposed to 38, thioureas 1 and 6 feature a single 1,3-bis(trifluoromethyl)benzyl substituent. From the

experimental evidence it appears that such structural difference causes a detrimental decrease in catalytic

activity, possibly due to the large difference in acidity of and non-covalent interaction provided by the

thiourea derivatives (compound, pKa in DMSO: 38, 8.5±0.1; 6, 12.1±0.1; 1, 10.72±0.02). Indeed, Schreiner

and co-workers reported a study on the acidities of popular (thio)urea organocatalysts in DMSO, which

showed the incremental effect of trifluoromethyl groups (-CF3) on acidic strength as associated to

established catalytic activity in noncovalent organocatalysis.98

Due to complete lack of effective catalytic

activity of 1 and 6 in such transformation, the investigation of the current project was eventually interrupted

without testing 3 and 4. Eventually compounds (E)-3 and (Z)-3 were found to provide successful control of

catalytic activity in the Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-

pentanedione upon irradiation of the stable isomers towards the corresponding metastable forms (see

Chapter 3). Due to the insurmountable complications encountered during the development of an effective

switchable organocatalyst based on a reversibly photo-responsive bifunctional overcrowded alkene, the

venture of designing a switchable trifunctional catalyst for dynamic control of light-assisted tandem

synthetic transformations was interrupted in favor of more practicable research proposals.

4.3 Conclusions

This chapter describes the study towards a trifunctionalized molecular photoswitch based on an

overcrowded alkene for ‗one-pot‘ multi-catalytic systems. A detailed analysis of the requirements implied

by such complex design is given. We proposed a two-step sequence of Morita-Baylis Hillman reaction and

enamine catalyzed aldol or conjugated addition reaction catalyzed by merging two orthogonal bifunctional

catalytic group pairs. As a preliminary investigation, we have presented the design and attempted synthesis

of various photoresponsive bifunctionalized catalysts 7-10 for MBH reaction featuring combinations of

thiourea and tertiary amine or phosphines groups. As opposed to compounds 3 and 4, the synthesis of

compounds 7 failed due to incompatibility of the aliphatic tertiary amine with the thionation step required

to obtain one of the coupling partners for the Barton-Kellogg reaction. An alternative route towards 7-10

from a common dihalogenated intermediate 27 was proposed. However, it was affected by particularly low

yielding Barton–Kellogg couplings, after which the availability of small quantities of product would have

complicated the subsequent stages of the study. Eventually, alternative reactions were tested to investigate

the performance of 3 and 4 in mediating different types of transformations other than the MBH. More

precisely, we explored their application in: conjugated addition of 2,4-pentadione to trans-β-nitrostyrene;

alkylation of α-carboxypiperidones ethyl esters via benzyl transfer by a pre-formed ammonium

intermediate; decarboxylative protonation of α-aminomalonates; and alcoholysis of styrene oxides. In all

instances, the screening tests described herein were performed by using compound 1 as a model catalyst,

due to its inherent similarity with the Z-isomers of 3 and 4. As opposed to our initial assumption, no activity

was observed in any case. As demonstrated in this work, an aromatic amine substituent was shown to be a

poorly active catalytic moiety. These studies provide valuable insight into the requirements for the design

of more effective and complex trifunctionalized molecular switches, which may allow the photocontrol of

catalyst activity and selectivity in multicomponent reactions. Key to the successful development of these

future catalysts will be a deeper understanding of the compatibility of ancillary functional groups with the

overcrowded alkene syntheses and the introduction of more active catalytic groups to ensure higher catalyst

performance.


143


The author would like to thank Dr. B. S. L. Collins for her fundamental contribution to this work.



General experimental details can be found in Chapter 3. Wang‘s catalyst 1 was synthesized starting from

(R)-BINAM according to the reported procedure.79

P4S10·Py483

, N-benzyl-N,N-dimethylbenzenaminium

bromide84

, piperidones 2984

and 1-acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic acid 3399

were

synthesized according the reported procedures. 2-iodo-9H-fluoren-9-one 23 was synthesized by Jort

Robertus.100


1-(9H-fluoren-2-yl)-N,N-dimethylmethanamine (15)

Compound 15 was prepared from commercially available fluorene-2-

carboxaldehyde by a modified procedure previously reported.101

Titanium(IV) isopropoxide (2.65 mL, 10.30 mmol) was added dropwise to a

commercially available 2M solution of dimethylamine in methanol (8.3 mL,

16.5 mmol, 3.2 equiv) followed by the addition of fluorene-2-carboxaldehyde 14 (1.0 g, 5.15 mmol). The

reaction mixture was stirred at ambient temperature for 4 h, after which sodium borohydride (200 mg, 5.15

mmol, 1.0 equiv) was added and the resulting mixture was further stirred for another period of 1.5 h. The

reaction was then quenched by the addition of water (3 mL), the resulting inorganic precipitate was filtered,

washed with diethyl ether (20 mL) and the aqueous filtrate was extracted with diethyl ether (20 mL x 2).

The combined organic extracts were dried on K2CO3, filtered and concentrated under reduced pressure. The

solid residue was recrystallized form EtOH : toluene (~10 mL) to yield 15 (1.10 g, 4.92 mmol, 95%) as

light brown solid. m.p. 182-184 °C. 1H NMR (200 MHz, CDCl3) δ 7.76 (t, J = 7.9 Hz, 1H), 7.62–7.47 (m,

1H), 7.43–7.21 (m, 2H), 3.90 (s, 1H), 3.51 (s, 1H), 2.29 (s, 3H). 13

C NMR (50 MHz, CDCl3) δ 143.4,

143.3, 141.6, 140.8, 137.5, 127.8, 126.7, 126.5, 125.8, 125.0, 119.8, 119.5, 64.6, 45.4, 36.8. HRMS (ESI,

m/z): calcd for C16H18N [M+H]+: 224.1434, found: 224.1434.

2-((dimethylamino)methyl)-9H-fluoren-9-one (16)

A 100 mL two-necked round bottom flask fitted with a reflux condenser was

charged successively with 1-(9H-fluoren-2-yl)-N,N-dimethylmethanamine 15

(970 mg, 4.34 mmol), pyridine (50 mL) and benzyltrimethylammonium

hydroxide (40 wt% solution in EtOH, 0.20 mL, 0.1 equiv). An air inlet was

then introduced through the septum and a stream of air was allowed to pass

through the reaction mixture. The reaction mixture was then allowed to stir at rt for 3 h under this set-up.

After this time the pyridine was removed under reduced pressure. The residue was then dissolved in CH2Cl2

(30 mL) and washed with water (3 x 30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated


(SiO2, NEt3 in pentane, gradient 10–25%) to provided the title compound 2-((dimethylamino)methyl)-9H-

fluoren-9-one 16 (860 mg, 3.62 mmol, 83%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (dt, J = 7.3,

0.9 Hz, 1H), 7.61 (t, J = 1.1 Hz, 1H), 7.54–7.45 (m, 4H), 7.29 (td, J = 7.0, 1.6 Hz, 1H), 3.45 (s, 2H), 2.28

(s, 7H). 13

C NMR (100 MHz, CDCl3) δ 193.9, 144.4, 143.4, 140.4, 135.3, 134.6, 134.4, 134.3, 128.9, 125.1,

124.3, 120.2, 120.2, 63.8, 45.3. 13

C NMR (100 MHz, CDCl3) δ 195.0, 151.2, 145.9, 135.7, 134.8, 134.2,

126.8, 124.1, 121.2, 118.9, 116.6, 108.4, 40.7. HRMS (ESI, m/z): calcd for C16H16NO [M+H]+: 238.1226,

found: 238.1228.

Chapter 4

144

2-((dimethylamino)methyl)-9H-fluorene-9-thione (17)

Synthesis of compound 17 was attempted by following the procedure

described for 2-(dimethylamino)-9H-fluorene-9-thione (a, see Chapter 3) and

other previously reported procedures (b)102

, (c-d).83

(a) A 25 mL two-necked round bottom flask fitted with a reflux condenser and

nitrogen inlet was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one

16 (300 mg, 1.265 mmol), dry toluene (8 mL) and phosphorus pentasulfide (422 mg, 1.90 mmol, 1.5 equiv)

under nitrogen. The reaction mixture was then stirred at 110 °C for approximately 2 h, while the conversion

was monitored by TLC (EtOAc in pentane, 50%). The mixture was concentrated under reduced pressure

and the residue was filtrated by quick column chromatography (Al2O3, EtOAc in pentane, 50%). Analysis

by 1H NMR spectroscopy indicated that none of the collected fractions contained the desired product.

(b) A 25 mL two-necked round bottom flask fitted with a reflux condenser and nitrogen inlet was charged

with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (200 mg, 0.843 mmol), dry toluene (8 mL) and

Lawesson‘s reagent (510 mg, 12.65 mmol, 1.5 equiv) under nitrogen. The reaction mixture was then stirred

at 80 °C for approximately 30 min, at which point TLC (EtOAc in pentane, 20%) showed complete

disappearance of the substrate. The mixture was concentrated under reduced pressure and the residue was

filtrated by quick column chromatography (SiO2, MeOH in CH2Cl2, 10%). As analyzed by 1H NMR

spectroscopy, none of the collected fractions contained the desired product.

(c) A Schlenk tube was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (250 mg, 1.05

mmol), P4S10 · Py4 (240 mg, 0.32 mmol, 0.3 equiv) and acetonitrile (5 mL). The reaction mixture was

heated at reflux for 2 h and then allowed to cool down to room temperature. The two-phase system was

concentrated under reduced pressure to ca. 2 mL and water (5 mL) was added. A solid was quickly formed

which was filtered and washed with water. As analyzed by 1H NMR spectroscopy, the obtained crude

residue did not contain the desired product.

(d) A Schlenk tube was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (250 mg, 1.05

mmol), P4S10·Py4 (240 mg, 0.32 mmol, 0.3 equiv) and dimethyl sulfone (1.0 g). The solid mixture was

heated at 170-175 °C for 15 min until changed to a vivid purple color. After cooling, boiling water (4 mL)

was added to the solidified melt. The color of the mixture rapidly changed to brown. Analysis by 1H NMR

spectroscopy indicated that the obtained crude residue did not contain the desired product.

(E/Z)-6-bromo-4-(2-iodo-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromene (25)

Synthesis of compounds 25 was attempted by following the

procedure described for compound 3 (see Chapter 3).

A 25 mL two-necked round bottom flask fitted with a reflux

condenser and nitrogen inlet was charged with 2-iodo-9H-

fluoren-9-one 23 (306 mg g, 1.0 mmol), dry toluene (10 mL)

and Lawesson‘s reagent (600 mg, 1.5 mmol, 1.5 equiv). The

mixture was then heated at 95 ºC for approximately 6 h, until

TLC (CH2Cl2 in pentane, 15%) started showing degradation. The mixture was diluted with a 1:1 solution of

pentane:CH2Cl2 (70 mL) to precipitate most of the Lawesson‘s reagent and filtered. The liquid fraction was

concentrated under reduced pressure and the residue was purified by a quick column chromatography

(SiO2, CH2Cl2 in pentane, 15%). The early yellow fraction was concentrated under reduced pressure to

yield 2-iodo-9H-fluorene-9-thione as a brown residue, which was used directly in the following step. A

Schlenk tube was charged with a solution of (E)-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)hydrazone 24 (50 mg, 0.167 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and cooled

to –40 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene (80 mg, 0.18 mmol, 1.1 equiv) in N,N-

dimethylformamide (1 mL) was then added at this temperature via syringe. The resulting solution was

stirred for approximately 1 min followed by the addition of a solution 2-iodo-9H-fluorene-9-thione 22

(70 mg, 0.217 mmol, 1.3 equiv) in N,N-dimethylformamide (1.5 mL) and CH2Cl2 (1.5 mL) via syringe. The


145

resulting solution was stirred for 16 h while allowed to warm slowly to rt. After this time the reaction

mixture was diluted with EtOAc (15 mL) and washed sequentially with sat. aq. NH4Cl (10 mL), water (2 x

10 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under

reduced pressure. Analysis of the crude residue by TLC (SiO2, CH2Cl2 in pentane, 10%) and 1H NMR

spectroscopy confirmed the presence of episulfide intermediate. The residue was transferred to a 10 mL

round bottom flask, dissolved in toluene (3 mL) and treated with tri(dimethylamino)phosphine (0.07 g, 0.06

mL, 0.33 mmol, 2.0 equiv). The resulting solution was heated at 70 °C and allowed to stir at this

temperature for 2 d. After this time the reaction mixture was cooled to rt and the solvent was removed


(SiO2, CH2Cl2 in pentane, 4%) to provide in the early fraction an inseparable (E/Z)-mixture of compound 6-

bromo-4-(2-iodo-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromene 25 (13 mg, 0.025 mmol, 15%) as a

red solid. 1H NMR (300 MHz, CDCl3, mixture of E and Z isomers) δ 8.67 (d, J = 5.5 Hz, 1H), 8.32 (dd, J =

19.6, 7.8 Hz, 1H), 7.82 (s, 2H), 7.69 (t, J = 8.4 Hz, 4H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.8 Hz, 4H),

7.33 (d, J = 9.4 Hz, 3H), 7.13 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 5.83 (d, J = 7.8 Hz, 1H), 3.46 –

3.22 (m, 3H), 2.75–2.65 (m, 7H), 2.22 (dd, J = 12.5, 6.8 Hz, 2H), 1.89 (d, J = 9.2 Hz, 6H), 1.40–1.32 (m,

2H), 0.92–0.80 (m, 6H).

(E/Z)-8-bromo-1-(2-iodo-9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromene (27).

Synthesis of compounds 27 was attempted by

following the procedure described for compound 25,

starting from hydrazone 26 (160 mg, 0.5 mmol). The

crude reaction mixture was then purified by flash

column chromatography (SiO2, CH2Cl2 in pentane,

5%) to provide in the early fraction a complex

mixture mainly composed of bis-fluorenyl by-products as an orange residue. 1H NMR spectroscopy of the

residue showed diagnostic peaks of a mixture of the title compound (E/Z)-8-bromo-1-(2-iodo-9H-fluoren-9-

ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromene 27 as minor component (traces). 1H NMR (300

MHz, CDCl3, mixture of E and Z isomers) δ 10.10 (s, 1H), 9.76–9.61 (m, 1H), 7.99 (d, J = 7.7 Hz, 1H),

7.93 (d, J = 7.4 Hz, 1H), 6.85–6.65 (m, 1H), 6.41 (s, 1H), 6.17 (d, J = 7.9 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H),

3.59–3.44 (m, 1H), 2.82–2.65 (m, 1H), 2.46–2.23 (m, 1H), 0.92–0.83 (m, 6H).

(R)-N-benzyl-2'-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,N-dimethyl-[1,1'-binaphthalen]-2-

aminium bromide (28)

A 10 mL round-bottom flask equipped with a stir bar and rubber septum

was charged with a solution of 1 in dry benzene (1.5 mL) under nitrogen. A

2 mL vial equipped with a septa screw-cap was charged with benzyl

bromide (35 mg, 24 µL, 0.205 mmol, 1.2 equiv) and attached to vacuum-

nitrogen inlet with a needle. Three cycles of vacuum and nitrogen were

applied. Dry benzene (0.5 mL) was added and the obtained solution was

transferred to the solution of A. The reaction mixture was stirred at room

temperature over a period of 24 h. Heptane (4 mL) was added to the

mixture, causing the precipitation of the desired ammonium adduct. The slurry was filtered on a P4 fritted

glass funnel under reduced pressure and the solid was washed with a mixture of pentane:Et2O 3:1 (4 mL)

and pentane (4 mL) to yield the title compound (R)-N-benzyl-2'-(3-(3,5-

bis(trifluoromethyl)phenyl)thioureido)-N,N-dimethyl-[1,1'-binaphthalen]-2-aminium bromide 28 (65 mg,

0.086 mmol, 51%) as pink/yellow powder. The product was stored under inert atmosphere in a desiccator

due to its high hygroscopicity and air sensitivity. 1H NMR (400 MHz, CDCl3) δ 11.17 (br s, 1H), 10.86 (br

s, 1H), 8.53 (br s, 2H), 8.29 (br d, J = 7.9 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.07 (br d, J = 7.9 Hz, 1H),

8.02 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 9.1 Hz, 2H), 7.62 (s, 1H), 7.52 (ddd, J = 8.2,

Chapter 4

146

6.9, 1.1 Hz, 1H), 7.48 (br s, 1H) 7.31 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.77 (br s,

1H), 3, 3.39 (br s, 1H), 3.10 (br s, 1H). 13

C NMR (100 MHz, CDCl3) δ 179.9, 133.5, 132.5, 131.7, 131.3,

129.4, 128.8, 128.2, 126.8, 124.5, 123.8, 121.8, 118.5, 48.7, 48.0, 42.0. 19

F NMR (400 MHz, CDCl3) δ -

62.83. HRMS (ESI, m/z): calcd for C38H30F6N3S [M-Br]+: 674.2059, found: 674.2056.

4.5.3 General procedure for screening of conditions for Morita–Baylis–Hillman reactions (Table

4.1)

A 4 mL vial was charged with catalyst (see reported equivalents in Table 4.1), followed by the addition of

MeCN (1 mL, when reported) and 2-cyclohexen-1-one (0.75 mmol, 3 equiv). The reaction mixture was

then stirred vigorously for 10 min at rt, prior to the addition of 3-phenylpropionaldehyde (0.25 mmol, 1

equiv) via syringe. The reaction mixture was then allowed to stir at rt for 4 d, after which it was

concentrated under reduced pressure and analyzed by GC-MS and 1H NMR spectroscopy (CDCl3) to

determine the conversion. No evidence of the desired MBH adduct was observed, as compared with

previously reported physical data.103

Product: 1H NMR (CDCl3) δ 7.29–7.15 (m, 5H), 6.85 (t, J = 4.0 Hz,

1H), 4.32 (1 H, dt, J = 7.0, 5.0 Hz, 1H), 3.04 (d, J = 7.0 Hz, 1H), 3.04 (d, J = 7.0 Hz, 1H), 2.85–2.77 (m,

1H), 2.69–2.62 (m, 1H), 2.43–2.36 (m, 4H), 2.03–1.89 (m, 4H).

4.5.4 General procedure for screening of conditions for conjugated additions of 2,4-pentadione to

trans-β-nitrostyrene (Scheme 4.11)

A 4 mL vial was charged with catalyst (see reported equivalents in Scheme 4.11), followed by the addition

of 2,4-pentadione (0.34 mmol, 2 equiv) and trans-β-nitrostyrene (0.17 mmol, 1 equiv) in Et2O (1 mL) at

room temperature. After 28 h of stirring, the reaction mixture was concentrated in vacuo. The residue was

analyzed by GC-MS and 1H NMR spectroscopy (CDCl3) to determine the conversion. No evidence of the

desired Michael adduct was observed, as compared with previously reported physical data.104

Product: 1H

NMR (CDCl3) δ 7.35–7.26 (m, 3H), 7.21–7.16 (m, 2H), 4.68–4.59 (m, 2H), 4.38 (d, J = 10.5 Hz, 1H),

4.28–4.21 (m, 1H), 2.30 (s, 3H), 1.95 (s, 3H).

4.5.5 General procedure for asymmetric alkylation of N-benzyl-oxopiperidine-3-carboxylate via

benzyl transfer with quaternary ammonium bromides (Scheme 4.18)

A dried Schlenk tube equipped with a stirring bar and rubber septa under nitrogen was charged with NaH

(0.2 mmol, 1.0 equiv, 60 % in mineral oil). A solution of N-benzyl-oxopiperidine-3-carboxylate (0.2 mmol)

in toluene (1.5 mL) was added. The stirred mixture was then kept at 80 °C for 1 h. Then, quaternary

ammonium bromide 28 or 31 (0.22 mmol, 1.1 equiv) was added in one portion to the suspension of the

sodium salt at room temperature. The reaction mixture was subsequently heated at the reported temperature

for the reported time (see Scheme 4.). After cooling, the mixture was poured carefully into water (2 mL).

The organic layer was separated, washed with brine (2 x 2 mL), dried with Na2SO4, filtered, and

concentrated to give an oily residue. The crude product was analyzed by GC-MS and 1H NMR

spectroscopy (CDCl3) to determine the conversion. Substrate: 1H NMR (300 MHz, CDCl3) δ 7.43–7.22

(m, 5H), 4.31–4.11 (m, 2H), 3.64 (s, 3H), 3.21 (t, J = 1.8 Hz, 2H), 2.61 (t, J = 5.9 Hz, 1H), 2.44-2.34 (m,

2H), 1.27 (t, 3H). Product: 1H NMR (300 MHz, CDCl3) δ 7.27–7.05 (m, 8H), 6.71–6.62 (m, 2H), 4.04–

3.94 (m, 2H), 3.49 (d, J = 5.1 Hz, 1H), 3.35 (dd, J = 11.5, 2.6 Hz, 2H), 3.14 (d, J = 13.7 Hz, 1H), 2.86 (s,

2H), 2.80-2.65 (m, 1H), 2.43–2.18 (m, 3H), 1.03 (t, J = 7.1 Hz, 3H).

4.5.6 General procedure for decarboxylative protonation of 1-acetyl-2-(ethoxycarbonyl)piperidine-

2-carboxylic acid (

4.5.7 Table 4.2)

A 4 mL vial was charged with catalyst (see reported equivalents in Table 4.2) and 1-acetyl-2-

(ethoxycarbonyl)piperidine-2-carboxylic acid 33 (0.09 mmol), followed by the addition of THF (0.5 mL).

The reaction mixture was then stirred vigorously (see reported time and temperature). The reaction mixture

was then concentrated under reduced pressure and analyzed by GC-MS and 1H NMR spectroscopy (CDCl3)


147

to determine the conversion. The crude product was purified by flash chromatography (SiO2, MeOH in

CH2Cl2, 1%) and the ee was determined by chiral HPLC analysis (Chiralcel OB-H, hept:2-propanol = 95:5,

flow 0.5 mL/min, 40 °C, Rt (1st) 21.2 min (1

st) and 26.0 min (2

nd)). Substrate:

1H NMR (300 MHz, CDCl3)

δ 4.2–4.3 (m, 2H), 3.6–3.7 (m, 2H), 2.2–2.3 (m, 1H), 2.15 (s, 3H), 1.6–1.9 (m, 4H), 1.29 (t, J = 7.0 Hz, 3H).

Product: 1H NMR (300 MHz, CDCl3, two rotamers a/b: 75/25) 5.3–5.4 (m, 1H, a), 4.4–4.6 (m, 2H, b), 4.1–

4.2 (m, 2H, a+b), 3.6–3.7 (m, 1H, a), 3.30 (dt, J = 12.4, 2.3 Hz, a), 2.6–2.7 (m, 1H, b), 2.2–2.3 (m, 1H,

a+b), 2.14 (s, 3H, a), 2.07 (s, 3H, b),1.2–1.7 (m, 5H, a+b), 1.27 (t, J = 6.8 Hz, 3H, a+b).

4.5.8 General procedure for catalyzed alcoholysis of styrene oxide (Table 4.3)

(R/S)-mandelic acid 37 (3.8 mg, 0.025 mmol, 1 mol%) and thiourea derivative 1 or 6 (0.05 mmol, 1 mol%)

were weighed into an oven-dried, one-necked, 10 mL flask equipped with stir bar and rubber septum.

Where indicated, N,N‘-dimethylaniline (12 mg, 0.012 mL, 4 mol%) was added via syringe. After addition

of styrene oxide 40 (29 mg, 0.28 mL, 2.5 mmol) and dry ethanol (1.80 mL, 30 mmol), the solution was

vigorously stirred at room temperature over 3 d. The conversion was monitored by GC/MS analysis. The

reaction mixture was then concentrated under reduced pressure and analyzed by 1H NMR spectroscopy

(CDCl3) to determine the conversion. The crude product was purified by flash chromatography (SiO2, Et2O

in pentane, 10%) and the ee was determined by chiral HPLC analysis (Chiralpak AD-H, hept:2-propanol =

95:5, flow 0.5 mL/min, 40 °C, Rt: 14.5 min (1st) and 15.0 min (2

nd)). Substrate:

1H NMR (400 MHz,

CDCl3) δ 7.52-7.11 (m, 5H), 3.86 (s, 1H), 3.15 (dd, J = 4.7, 4.7 Hz, 1H), 2.80 (dd, J = 5.2, 2.0 Hz, 1H).

Product: 1H NMR (300 MHz, CDCl3) δ 7.41−7.30 (m, 5H), 4.39−4.32 (dd, J = 12.1, 8.0 Hz, 1H),

3.80−3.58 ( m, 2H), 3.34 (s, 3H), 3.15−3.09 (dd, J = 12.6 Hz, 8.3 Hz, 1H). Hydrolyzed by-product: 1H

NMR (300 MHz, CDCl3) δ 7.54–7.42 (m, 2H), 7.42–7.28 (m, 3H), 4.77 (dd, J = 5.6, 3.3 Hz, 1H), 4.07 (dd,

J = 12.1, 5.6 Hz, 1H), 3.92 (dd, J = 12.1, 3.3 Hz, 1H).

4.6 References








(8) Berryman, O. B.; Sather, A. C.; Lledó, A.; Rebek, J. Angew. Chemie Int. Ed. 2011, 50, 9400–9403.



Chem. Soc. 2009, 131, 357–367.


Chem. Sci. 2015, 6, 140–143.

(12) Schmittel, M.; De, S.; Pramanik, S. Angew. Chemie Int. Ed. 2012, 51, 3832–3836.

(13) De, S.; Pramanik, S.; Schmittel, M. Angew. Chemie - Int. Ed. 2014, 53, 14255–14259.


(15) Blanco, V.; Leigh, D. A.; Lewandowska, U.; Lewandowski, B.; Marcos, V. J. Am. Chem. Soc. 2014, 136,

15775–15780.

(16) Wang, X.; Thevenon, A.; Brosmer, J. L.; Yu, I.; Khan, S. I.; Mehrkhodavandi, P.; Diaconescu, P. L. J.

Am. Chem. Soc. 2014, 136, 11264–11267.


(18) Escorihuela, J.; Burguete, M. I.; Luis, S. V. Chem. Soc. Rev. 2013, 42, 5595–5617.



(21) Mortezaei, S.; Catarineu, N. R.; Canary, J. W. J. Am. Chem. Soc. 2012, 134, 8054–8057.



(24) Horspool, W. M.; Lenci, F. CRC Handbook of Organic Photochemistry and Photobiology, Volumes 1 &

2, Second Edition; CRC Press: Boca Raton, 2003.



Chapter 4

148


16784–16787.

(28) Zhao, D.; van Leeuwen, T.; Cheng, J.; Feringa, B. L. Nat. Chem. 2016, No. November, 1–7.


5166–5169.

(30) Blanco, V.; Leigh, D. A.; Marcos, V.; Morales-Serna, J. A.; Nussbaumer, A. L. J. Am. Chem. Soc. 2014,

136, 4905–4908.

(31) Mata, J. A.; Hahn, F. E.; Peris, E. Chem. Sci. 2014, 5, 1723–1732.

(32) Robert, C.; Thomas, C. M. Chem. Soc. Rev. 2013, 42, 9392–9402.

(33) Oroz-Guinea, I.; García-Junceda, E. Current Opinion in Chemical Biology. 2013, pp 236–249.

(34) José Climent, M.; Corma, A.; Iborra, S. RSC Adv. 2013, 2, 16–58.

(35) Zhou, J. Chem. - An Asian J. 2010, 5, 422–434.

(36) Traut, T. Enzyme Activity: Allosteric Regulation; John Wiley & Sons, Ltd: Chichester, UK, 2014.

(37) Ikariya, T.; Shibasaki, M. Bifunctional Molecular Catalysis; Springer-Verlag: Berlin, 2011.

(38) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298–1310.

(39) Serdyuk, O. V; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051–7071.

(40) Allen, A. E.; Macmillan, D. W. C. Chem. Sci. 2012, 2012, 633–658.


(42) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chemie Int. Ed. 2007, 46, 1570–1581.

(43) Fogg, D. E.; Dos Santos, E. N. Coordination Chemistry Reviews. 2004, pp 2365–2379.

(44) Delferro, M.; Marks, T. J. Chem. Rev. 2011, 111, 2450–2485.

(45) Al-Amin, M.; Roth, K. E.; Blum, S. A. ACS Catal. 2014, 4, 622–629.

(46) Dydio, P.; Ploeger, M.; Reek, J. N. H. ACS Catal. 2013, 3, 2939–2942.

(47) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001–1020.

(48) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chemie Int. Ed. 2007, 46, 1570–1581.

(49) Barber, D. M.; Ďuriš, A.; Thompson, A. L.; Sanganee, H. J.; Dixon, D. J. ACS Catal. 2014, 4, 634–638.

(50) Rueping, M.; Dufour, J.; Bui, L. ACS Catal. 2014, 4, 1021–1025.

(51) Lohr, T. L.; Marks, T. J. Nat Chem 2015, 7, 477–482.

(52) List, B. Chem. Rev. 2007, 107, 5413–5415.

(53) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569.

(54) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.

(55) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655.


(57) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430–3431.

(58) Ban, S.; Zhu, X.; Zhang, Z.; Xie, H.; Li, Q. European J. Org. Chem. 2013, 2013, 2977–2980.

(59) Nishikawa, Y.; Nakano, S.; Tahira, Y.; Terazawa, K.; Yamazaki, K.; Kitamura, C.; Hara, O. Org. Lett.

2016, 18, 2004–2007.

(60) Zhang, G.-W.; Zheng, D.-H.; Nie, J.; Wang, T.; Ma, J.-A. Org. Biomol. Chem. 2010, 8, 1399–1405.


(62) Takemoto, Y. Chem. Pharm. Bull. (Tokyo). 2010, 58, 593–601.

(63) Li, X.; Xue, X.-S.; Liu, C.; Wang, B.; Tan, B.-X.; Jin, J.-L.; Zhang, Y.-Y.; Dong, N.; Cheng, J.-P. Org.

Biomol. Chem. 2012, 10, 413–420.

(64) Mahrwald, R.; Cobb, A. J. A.; Alonso, D. A.; Hong, B.-C.; Guillena, G.; Nájera, C.; Ramón, D. J.

Enantioselective Organocatalyzed Reactions I; Mahrwald, R., Ed.; Springer Netherlands: Dordrecht,

2011.

(65) Aillerie, A.; Rodriguez-Ruiz, V.; Carlino, R.; Bourdreux, F.; Guillot, R.; Bezzenine-Lafollée, S.; Gil, R.;

Prim, D.; Hannedouche, J. ChemCatChem 2016, 8, 2455–2460.

(66) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129–2135.

(67) Garnier, J.-M.; Liu, F. Org. Biomol. Chem. 2009, 7, 1272–1275.

(68) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49, 6262–6264.

(69) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659–6690.

(70) Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980–3987.

(71) Roy, D.; Patel, C.; Sunoj, R. B. J. Org. Chem. 2009, 74, 6936–6943.

(72) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005–1018.

(73) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672–12673.

(74) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chemie Int. Ed. 2005, 44, 4032–4035.

(75) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298.

(76) Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G. G.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2005,

127, 13798–13799.

(77) Berkessel, A.; Mukherjee, S.; Cleemann, F.; Müller, T. N.; Lex, J. Chem. Commun. 2005, No. 14, 1898–


149

1900.

(78) Miyaji, R.; Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2015, 137, 6766–6769.

(79) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–4296.

(80) List, B. Acc. Chem. Res. 2004, 37, 548–557.

(81) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632.

(82) Wang, W. Organocatalysts and methods of use in chemical synthesis. US20090088588 A1, 2006.

(83) Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H. J. Org. Chem. 2011, 76, 1546–1553.

(84) Khartulyari, A. S.; Maier, M. E. European J. Org. Chem. 2007, 2007, 317–324.

(85) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621–2624.

(86) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724–1727.

(87) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.

(88) Smith, P. J.; Reddington, M. V.; Wilcox, C. S. Tetrahedron Lett. 1992, 33, 6085–6088.

(89) Foli, G.; D‘Elia, C. S.; Fochi, M.; Bernardi, L. RSC Adv. 2016, 6, 66490–66494.

(90) Albert, J. S.; Hamilton, A. D. Tetrahedron Lett. 1993, 34, 7363–7366.

(91) Sirikulkajorn, A.; Duanglaor, P.; Ruangpornvisuti, V.; Tomapatanaget, B.; Tuntulani, T. Supramol. Chem.

2009, 21, 486–494.

(92) Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817–824.

(93) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.

(94) Ulatowski, F.; Jurczak, J. J. Org. Chem. 2015, 80, 4235–4243.

(95) Yun, K. K.; Han, N. L.; Singh, N. J.; Hee, J. C.; Jin, Y. X.; Kim, K. S.; Yoon, J.; Myung, H. H. J. Org.

Chem. 2008, 73, 301–304.

(96) Lubkoll, J.; Wennemers, H. Angew. Chem. Int. Ed. 2007, 46, 6841–6844.

(97) Weil, T.; Kotke, M.; Kleiner, C. M.; Schreiner, P. R. Org. Lett. 2008, 10, 1513–1516.

(98) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724–1727.

(99) Seitz, T.; Baudoux, J.; Bekolo, H.; Cahard, D.; Plaquevent, J.-C.; Lasne, M.-C.; Rouden, J. Tetrahedron

2006, 62, 6155–6165.

(100) Ahmed, S. A.-M.; Al-Raqa, S. Y. J. Phys. Org. Chem. 2011, 24, 173–184.

(101) Bhattacharyya, S. Synth. Commun. 2000, 30, 2001–2008.

(102) Pijper, T. C.; Pijper, D.; Pollard, M. M.; Dumur, F.; Davey, S. G.; Meetsma, A.; Feringa, B. L. J. Org.

Chem. 2010, 75, 825–838.

(103) Kataoka, T.; Iwama, T.; Tsujiyama, S. I.; Iwamura, T.; Watanabe, S. I. Tetrahedron 1998, 54, 11813–

11824.

(104) Durmaz, M.; Tataroglu, A.; Yilmaz, H.; Sirit, A. Tetrahedron Asymmetry 2016, 27, 148–156.

Chapter 4

150

Chapter 5

Central-to-Helical-to-Axial-to-Central Transfer of

Chirality with a Photoresponsive Catalyst

Recent advances in molecular design have displayed striking examples of dynamic chirality transfer

between various elements of chirality, e.g. from central to either helical or axial chirality and vice versa.

While considerable progress in atroposelective synthesis has been made, it is intriguing to design chiral

molecular switches able to provide selective and dynamic control of axial chirality with an external

stimulus for functional application. This chapter describes the synthesis and characterization of a

photoresponsive bis(2-phenol)-substituted molecular switch 1. The novel design exhibits a dynamic hybrid

central-helical-axial transfer of chirality. The change of preferential axial chirality in the biaryl motif is

coupled to the reversible switching of helicity of the overcrowded alkene core, dictated by the fixed

stereogenic center. The potential for dynamic control of axial chirality was demonstrated by using (R)-1 as

switchable catalyst to control the stereochemical outcome of the enantioselective addition of diethylzinc to

aromatic aldehydes, with successful reversal of enantioselectivity for several substrates.

This chapter will be published as: S. F. Pizzolato, P. Štacko, J. C. M. Kistemaker, T. van Leeuwen, Prof. E.

Otten, Prof. B. L. Feringa, manuscript in preparation.

The computational studies here reported were performed by J. C. M. K. and T. v. L. For more details, see


Chapter 5

152

5.1 Introduction

Chirality plays a fundamental role in a myriad of biological processes, including information storage and

transmission, gene expression, energy production and cellular motion.1–4

For instance, life has developed on

Earth by optimizing its biological functions using L-amino acids as polypeptide building blocks and D-

glucose as chemical energy source. The chirality of D-deoxyribose is amplified to the (almost) exclusively

right handed helices of DNA.5 The supreme control of directional movement showcased by biological

machine structures like ATP synthase,6 proteasomes,

7 ribosomes,

8 myosin,

9 kinesin

10 and bacterial

flagella11

are astonishing demonstrations of how transfer of chiral information leads to accurate control of

metabolic functions and motion in cells. None of these processes could take place without precise

propagation, amplification and coupling of movement, from the very bottom scale of single molecular

chiral motifs to the fine interplay of large protein sub-units.

While early research on stereochemistry mainly focused on point chirality, other motifs that feature axial

chirality,12,13

helical chirality,14

and planar chirality15,16

have been extensively investigated for their

potential use in synthesis, in asymmetric catalysis, and as chiral dopants. Compared with molecules that

feature fixed central chirality (i.e. point chirality), axially chiral compounds may not comprise stereogenic

center(s) yet exist as enantiomers.17,18

Atropisomers belong to the class of axially chiral compounds: in this

case the enantiomers exist due to the restricted rotation around a single bond. The stereodescriptor for

distinctive axial chirality (Ra, Sa) is assigned according to the CIP rules (Figure 5.1a).19,20

Atropisomers also

display axial helicity (Pa, Ma) similarly to overcrowded alkenes (Figure 5.1b).

Figure 5.1. Schematic representation of biaryl atropisomers chirality: a) axial chirality (Ra/Sa); a) axial

helicity (Pa/Ma), where 0°<α<90°.

The phenomenon of equilibration of stereoisomers about a rotational axis - atropisomerization21

- has

become a main topic of investigation in organic,22

materials,23

and medicinal chemistry.24

Despite a number

of responsive molecular devices based on reversible cis-trans isomerization of double bonds,25–27

cyclizations,28

redox cycles29

and rotation around single bonds,23,30

only limited examples of stimuli

responsive systems featuring elements of axial chirality have been reported.27,31,32

Focused efforts have

produced elegant systems displaying unidirectional aryl–aryl bond rotation of biaryl structures via

sequential addition of chemical stimuli, overcoming the atropisomerization energy barrier inherently

featured by the open structures via more flexible macrocyclic or tricyclic intermediates.23,30,33–36

Among the

atropisomeric chiral inductors, biaryl-type ligands have also played an undisputed central role in the field of

catalytic asymmetric transformation. Crafting from the most common 1,1‘-binaphthyl motif, a myriad of

derivatives, e.g. BINOL, BINAP, BINAM, phosphoramidites, organic phosphoric acids, etc., have been

developed, tuned and tested by chemists to fulfilll nearly any possible stereochemical task. Hence,

Central-to-Helical-to-Axial-to-Central Transfer of Chirality in a Photoresponsive Catalyst

153

atroposelective synthesis and selective functionalization of axially chiral biaryl compounds gained major

attention during the last decades.12,13,37,38

Here we report the photochemical control of axial biaryl chirality by a light-responsive BINOL-type

catalyst based on a chiral molecular switch, which displays dual stereocontrol in an asymmetric addition of

organozinc reagents to aromatic aldehydes. Limited examples of reversible biaryl dihedral angle restriction

based on molecular switching have been reported as a strategy for controlling the degree of extended

conjugation. 39–41

Despite interesting approaches to use external stimuli such as redox modulation of a

disulfide bridge,42

pH-change43

and ion binding,44

stereocontrol of the atropisomerization was not achieved.

Noticeably, an approach to develop an axial chirality switch for application as a responsive ligand was

reported in a study by Breit and co-workers, showing solvent-dependent atropisomerism of a flexible 2,2‘-

biphenol core bridged tricyclic structure,45

however, catalytic application was not included. Therefore, the

major challenge remains to design chiral molecular switches able to selectively and dynamically generate

and exploit axial chirality with an external stimulus.

Combining dynamic chirality, chirality transfer, and photoswitches,46–48

our group has achieved control of

activity and stereoselectivity49

by switchable catalytically active first generation molecular motors (see

Chapter 4 for further details).50–53

These catalysts harness the intra- and intermolecular transfer of chirality

to ultimately control the stereochemical outcome of a catalytic transformation via photochemical and

thermal induced isomerizations of a functionalized unidirectional four-stage rotary motor. We anticipate

that the development of new molecular switches which harness the pairing of hybrid helical-axial chiralities

within chiroptical switchable units could provide unprecedented levels of dual stereoselective induction

with non-invasive control and high spatio-temporal resolution. By combining the fixed point chirality

originating from the two stereocenters on either side of the overcrowded alkene with the dynamic alkene

configuration and helical chirality, the configuration and enantiomeric excess of the catalysis product could

be reversibly controlled.


5.2.1 Design and modeling calculations

Molecular motors of the second generation are helical-shaped overcrowded alkenes consisting of a

symmetric tricyclic lower half and an asymmetric upper half that features a single stereocenter.54–56

Harnessing the hybrid chirality generated by the stereogenic center and the helical structure, the

photochemical E-Z isomerization (PEZI) and thermal helix inversion (THI) of the central alkene bond

allow to achieve unidirectional rotary motion controlled by a light- and heat-driven four-stage cycle

(Scheme 5.1). The combinations of an upper half containing a six-membered ring and a lower half featuring

a five membered ring, are characterized by a high activation energy for the thermal relaxation process and

have been recently reported as a new class of bi-stable photoswitches.55,57

Due to the long half-life at room

temperature, i.e. high thermal stability, of their photo-generated metastable isomers, they allow for the

design of systems capable of displaying dual stereocontrol while retaining the desired configuration for

extended time intervals at elevated temperatures. This property, combined with their unique dynamic

helical chirality, is highly desirable in the field of switchable catalysis. We envisioned that merging a

flexible 2,2‘-biphenol core with the rotor of a rigid second generation overcrowded alkene scaffold would

result in transfer of chirality from the helical core of the overcrowded alkene to the biphenyl unit by steric

interactions (Scheme 5.2). In this way the distinctive dynamic helicity of the switch unit and the versatility

of the substituted biaryl motif are combined. Based on our recent study,57

we envisioned the combination of

a tetrahydronaphthalenyl upper half and a fluorenyl lower half to ensure desirable photoswitching

properties, inversion of helicity and high thermal stability. A similar scaffold (tetrahydrophenanthrenyl

upper half) in fact displayed a long living metastable isomer (t½ at 20°C = 1.3 years) and efficient reversible

photoswitching properties, allowing to selectively address both the stable (S) and metastable (MS) isomer

achieving high photostationary state (PSS) ratios (S:MS = 93:7 at 420 nm; S:MS = 3:97 at 365 nm).

Chapter 5

154

Scheme 5.1. Isomerization processes leading to unidirectional rotation in second generation molecular

motor. Four-stage cycle with only two distinctive stereoisomers in case of symmetrically substituted lower

half (here R = R‘). S = stable isomer, MS = metastable isomer.

Introduction of an additional aryl substituent (R = Ar) in the fjord region of such a molecular switch would

result in a biaryl of which the chirality is governed by the photochemically induced rotation of the

overcrowded alkene. The system described herein features three stereochemical elements (Scheme 5.2).

The first element is the stereogenic center of the switch (highlighted in red), which can exist with either the

R or S configuration. The second element is the helicity of the overcrowded alkene (highlighted in blue),

which is controlled by the configuration at the stereogenic center but can be inverted upon

photoisomerization.

Scheme 5.2. Design of photoswitchable 2,2‘-biphenol-substituted overcrowded alkene 1. Axial helicity and

chirality (green) of the 2,2‘-biphenol core are coupled to axial helicity (blue) and point chirality (red) of the

molecular switch scaffold. Here assigned descriptors are based on the structure of compound (R)-1 (for

explanation of the chiral descriptors, vide infra). Two isomers with opposite coupled helicity can be

selectively addressed by irradiation with UV-light: (R,P,Sa)-1 (S); (R,M,Ra)-1 (MS).


155

More precisely, the more stable diastereoisomer (stable isomer) of the R enantiomer will adopt a P helicity,

while the photo-generated diastereoisomer with higher energy (metastable isomer) will adopt an M helicity.

Third is the axial chirality of the biaryl unit (highlighted in green), which can be assigned to either Ra or Sa

according to the CIP rules.19,20

For biphenyls with an average dihedral angle of 90°, such as ortho

substituted biphenyls, these stereochemistry descriptors are interchangeably used with M and P,

respectively. Depending on the size of the groups and substitution pattern at the ortho positions, the

dihedral angle can be smaller than 90°. Each rotamer with either Ra or Sa absolute configuration possesses

two conformational helical geometries, also assigned as right-handed (P) or left-handed (M) according to

the CIP rules.18

Recently our group reported a study on the tidal locking of an aryl moiety in a molecular

motor, showing that among the four theoretically possible conformations of a biaryl unit only

conformations in which the non-annulated aryl group was parallel to the fluorenyl lower half were

adopted.58

Similarly, the other conformations, with the aryl orientated perpendicular with respect to the

lower half, are expected to induce significant steric strain also in the system describe hereto (see Figure

5.2b). With such a diastereotopic constraint, the true helicity (Pa/Ma) of the biaryl is inextricably connected

to the helicity (P=/M=) of the overcrowded alkene chromophore, and is identical to it in each isomer.

Therefore, three stereodescriptors (R/S, P/M and Ra/Sa) will be sufficient for the assignment of any expected

isomer reported in this work. So for isomer (R,P=,Pa,Sa)-1: R = configuration of stereogenic center, P= =

helicity of alkene, Pa = helicity of biaryl, Sa = axial chirality of biaryl (see Figure 5.2a). The asterisks at the

stereodescriptors throughout the text denote a racemic mixture of isomers with identical relative

stereochemistry (e.g. R*,P*,Sa* means a mixture of R,P,Sa and S,M,Ra). The doubly expressed axial

stereodescriptor (Ra/Sa) throughout the text denote a mixture of rotamers with identical absolute

stereochemistry at the stereocenter and configurational helicity but opposite axial chirality (e.g. R,P,Sa/Ra

means a mixture of atropisomers R,P,Sa and R,P,Ra).

Figure 5.2. a) Example of top-down schematic view and front structural view of (R,P=,Pa,Sa)-1. Upper half

ring (red, methyl substituent omitted); fluorenyl lower half (blue); biaryl moiety (black). Assigned

stereodescriptors based on the structure of compound (R)-1 (see main text for details). b) Depiction of the

four possible conformations of the biaryl moiety as viewed from the top along the central double bond and

biaryl single bond. c) H-bond assisted biaryl rotation of 2,2‘-biphenol with inversion of stereochemistry.

d) Schematic energy vs. biaryl torsional angle profile upon clockwise rotation of lower phenol group

around aryl-aryl bond.

Chapter 5

156

The inversion of axial chirality in biphenols is likely to take place via a coplanar transition state along the

syn-periplanar conformation of the phenol rings taking advantage of the intramolecular hydrogen bonds

between the hydroxyl groups (Δ‡G° = 48.1 kJ mol

-1, T = 298.15 K; Figure 5.2c), based on a DFT study by

Fujimura and co-workers.59

These calculations support the proposal of reversible axial chirality when

applied to our system, as we expected the syn- and anti-conformers (hydroxyl groups in proximity or

pointing away from each other, respectively) to be in equilibrium in solution in the absence of metals or

other coordinating species. A schematic representation of the four possible conformations of 1 upon

rotation of the aryl-aryl bond is presented in Figure 5.2b. We expect conformations with matching helicities

of biaryl and overcrowded alkene units to be highly favored (A and C), while the two conformers with the

aryl perpendicular to the lower half experience steric hindrance (B and D), as shown in the relative energy

vs. torsional angle profile plot based on DFT calculations (vide infra) (Figure 5.2d). Our proposed model

entails a coupled helical-to-axial transfer of helicity, in which the most favored conformation of the rotor

aryl substituent is parallel to the fluorenyl lower half of the switch core. Scheme 5.3 illustrates the delicate

interplay of dynamic stereochemical elements and the switching process between the stable isomer and

metastable isomer of (R)-1 with all the expected conformers. Starting from the stable isomer, rotamers

(R,P,Ra)-1 and (R,P,Sa)-1 interchange via atropisomerization (A) presumably facilitated by an internal

hydrogen bonding between the two phenolic moieties.59

We envisioned that upon irradiation with UV-light

of (R,P,Sa)-1 and (R,P,Ra)-1 into the corresponding conformers of metastable isomer (R,M,Ra)-1 and

(R,M,Sa)-1 the upper half containing the biaryl motif rotates with respect to the fluorenyl lower half

yielding isomers with opposite helicity (P→M. Notably, the metastable isomer was also expected to display

atropisomerization (B). We undertook a theoretical study a priori to verify the design as shown in Figure

5.2, with particular attention to the barrier for biaryl rotation and the relative energy of the four accessible

conformers upon reversible irradiation.

Scheme 5.3. Schematic representation of switching process between the rotamers of stable isomer

(R,P,Sa/Ra)-1 (top and bottom left) and metastable isomer (R,M,Ra/Sa)-1 (top and bottom right). Proposed

ground states of rotamers (top and bottom) and transition states (middle) of atropisomerization processes, as

viewed from the top along the axis given by the double bond. Proposed catalytically active syn-isomers

highlighted in the boxes.


157

The structures of the four ground states were computed via DFT method calculations (see J.C.M.

Kistemaker‘s PhD thesis for further details), which suggested an energetic preference in both biaryl rotation

equilibriums (A and B, Scheme 5.3) for the conformers (R,P,Sa)-1 and (R,M,Ra)-1, respectively. The latter

are characterized by having the lower hydroxyl substituent pointing away from the central overcrowded

alkene in a syn conformation with the upper phenol group. In summary, our design is based on the

following elements: a) the selective and reversible photo-isomerization of the overcrowded alkene; b) the

unique change in helicity governed by the configuration of the stereogenic center; c) the coupled change in

axial chirality of the biaryl core achieved via a central-to-helical-to-axial transfer of chirality, d) application

of the switchable chiral biphenol functionality with potentially manifold applications in catalytic

enantioselective transformations.

5.2.2 Synthesis

Key steps in the synthesis of 1 are the Barton-Kellogg coupling of thiofluoren-9-one 7 and 1-diazo-7-

methoxy-8-(2-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydronaphthalene 6, followed by deprotection of the

bis-phenol moiety and chiral resolution of the target molecule 1 as illustrated in Scheme 5.4.

Scheme 5.4. Synthesis and chiral resolution of 2,2'-biphenol molecular switch 1. Note on resolution of 1: i)

result from first resolution; ii) (S,M,Ra/Sa)-1 obtained by second resolution of the solid fraction: (8S,9R)-

(−)-N-benzylcinchonidinium chloride 10 0.9 equiv, 79% yield, >99% ee (solid); (R,P,Sa/Ra)-1 obtained by

second resolution of the residue from solution: 10 0.3 equiv, 81% ee (residue from solution), followed by

recrystallization from EtOH/H2O = 1:1 of the residue from solution, 15% yield, 96% ee.

Chapter 5

158

Commercially available 7-methoxy-1-tetralone was brominated with N-bromosuccinimide in acetonitrile to

yield 2,60

follow by Suzuki-Miyaura cross-coupling catalyzed by Pd2dba3 and SPhos to provide the

dimethoxy-biaryl motif in ketone 3.61

α-Methylation provided ketone 4 (86%), which was converted to the

corresponding hydrazone 5 (75%) via condensation with hydrazine monohydrate using Sc(OTf)3 as a

catalyst. The diazo coupling partner 6 was accessed via in situ oxidation with [bis(trifluoroacetoxy)iodo]-

benzene at low temperature. Fluorene-9-thione 7, freshly synthesized by thionation of 9-fluorenone with

Lawesson's reagent, was subsequently added to yield a variable mixture of episulfide 8 and overcrowded

alkene 9 (see Experimental section). After separation, the remaining episulfide was desulfurized by

treatment with HMPT at elevated temperature to provide 9 (85%, for the 3-step sequence). The use of

boron tribromide, widely applied for the deprotection of methoxy-substituents, resulted in partial

decomposition of the overcrowded alkene and in an inseparable mixture of target compound and side-

products. Successful deprotection was accomplished using methyl magnesium iodide at 165 °C62

to afford

racemic (R*,P*,Sa/Ra)-1 (86%) as a mixture of two atropisomers in their thermodynamic ratio (60:40 in

CDCl3) according to 1H NMR analysis. Optical resolution of 1 was accomplished by two-step resolution

with (8S,9R)-(−)-N-benzylcinchonidinium chloride (10) in ethyl acetate.62

Both enantiomeric mixtures of

conformers were obtained in high optical purity: (R,P,Sa/Ra)-1 (96% ee, 15%); (S,M,Ra/Sa)-1 (>99% ee,

31%).

The structure of 1 was proven by NMR spectroscopy (see following section), HRMS, as well as by single-

crystal X-ray structure analysis. By means of a high-brilliance Cu IμS microfocus source (Cu Kα radiation

wavelength = 1.54178 Å), the absolute configuration of enantiomerically pure (R)-1 was determined despite

the absence of atoms that show significant anomalous scattering.63–65

The reconstructed unit cell of the

lattice was shown to contain only the syn-conformer (R,P,Sa)-1 (Figure 5.3).

Figure 5.3. a) X-Ray structure of (R,P,Sa)-1. Left: front view; right: top view. Ellipsoids set at 50%

probability. Hydrogen bond lengths (intra: H101–O1 1.874 Å, inter: H100–O1‘ 1.826 Å) and Oxygen-

Oxygen distances (intra: O1–O2 2.629 Å, inter: O1–O2‘ 2.685 Å). b) Newman projections. Left: Left: top

view through overcrowded alkene bond. Right: top view through aryl-aryl bond of biaryl unit. Torsional

angles of alkene unit (13.92°) and biaryl unit (55.71°) are shown.


159

The experimental data confirmed the proposed model of coupled helical-to-axial transfer of helicity,

demonstrating the most favored conformation of the lower aryl substituent to be parallel to the fluorenyl

lower half of the switch core (synclinal) in the crystal lattice. The dihedral angle over the biaryl motif

determined from the X-ray structure in the solid state was found to be 55.7°.

5.2.3 NMR spectroscopy and atropisomer assignment

The 1H NMR spectra of an enantiomerically pure solution of stable (R,P,Sa/Ra)-1 in toluene-d8 (Figure 5.4)

revealed a relative integration of the best resolved absorptions of the atropisomers (R,P,S)-1 (A) and

(R,P,Ra)-1 (B) in a ratio of A:B = 67:33 [Figure 5.5 for proton positions and Figure 5.4 for corresponding

NMR absorptions – fluorenyl proton 37: δ 7.78 ppm (A), 7.70 ppm (B); proton 19 at the stereogenic center:

δ 3.95 ppm (A), 3.86 ppm (B); methyl protons 45-46-47: δ 1.34 ppm (A), 1.22 ppm (B)].

Figure 5.4. 1H NMR spectrum (toluene-d8) of 1, with highlighted sets of characteristic absorptions of major

(A) and minor (B) atropisomers. The same spectrum was obtained from either racemic mixture or

enantiomerically enriched fractions of 1.

Similar behavior with minor variation in the ratio where obtained in other deuterated solvents (solvent, A:B

ratio: CDCl3, 60:40; DMSO-d6, 60:40; MeOD, 63:37; CD3CN, 66:34; benzene-d6, 66:34). Based on

calculated 1H NMR spectra, we assigned the experimental sets of peaks to the corresponding atropisomers

of stable 1 as follows. Figure 5.5a depicts the schematic 2D-representation of the biaryl isomerization

equilibrium of the atropisomers of stable 1, with stereochemical assignment. Figure 5.5b reports the

schematic representation with labeling of carbon atoms of conformer (R,P,Sa)-1. Figures 5.5c-d illustrate

the calculated optimized geometries of conformers (R,P,Sa)-1 and (R,P,Ra)-1, respectively, with labelled

atoms for NMR peak assignment listed in Tables 5.1 and 5.-2. Calculated 1H and

13C NMR spectra of

(R,P,Sa)-1 and (R,P,Ra)-1 (DFT giao mPW1PW91/6-311+G(2d,p) in toluene (SMD)) were compared with

experimental spectra of (R,P,Sa/Ra)-1 (in toluene) (vide infra, Figures 5.6 and 5.7). According to the

calculated chemical shifts, the experimental peaks were assigned to conformers (R,P,Sa)-1 (major) and

(R,P,Ra)-1 (minor), respectively. Despite the difference in absolute chemical shift value, the relative

Chapter 5

160

position of the experimentally assigned absorptions peaks for the major and minor atropisomer in the

experimental 1H NMR spectra are in full agreement with the corresponding calculated absorption peaks for

(R,P,Sa)-1 and (R,P,Ra)-1, respectively (Table 5.1). Notably, every resonance absorption (except the one

assigned to atom 52) of the major isomer (R,P,Sa)-1 resonates at higher frequency than the minor isomer

(R,P,Ra)-1. However, comparison of the 13

C NMR spectra did not display a consistency to such a high

extend in this regard (Table 5.2).

Figure 5.5. a) Schematic 2D-representation of the biaryl isomerization equilibrium of atropisomers of

stable state (R,P,Sa/Ra)-1. b) C-labelled structure of (R)-1. Calculated optimized geometries of (R,P,Sa)-1. c)

Calculated optimized geometries of (R,P,Ra)-1. Calculations and rendering performed by J.C.M.

Kistemaker and T. van Leeuwen.


161

Table 5.1. List of 1H NMR chemical shifts of labelled atoms for atropisomer assignment, obtained and

assigned via experimental 1D- and 2D-NMR and via calculation.

Experimental

1H Chemical Shift Calculated

1H Chemical Shift

Atom label Major Minor (R,P,Sa)-1 (R,P,Ra)-1

39 1.07 1.041 0.930

45/46/47 1.33 1.22 1.258 1.066

38 2.07 1.98 2.193 2.135

50 2.238 2.164

49 2.416 2.379

19 3.94 3.86 3.866 3.766

55 3.914 4.173

56 3.972 3.867

33 6.430 6.438

52 6.13 6.50 6.431 6.813

43 6.40 6.18 6.548 6.340

51 7.00 7.03 6.695 7.110

44 6.57 6.832 7.053

30 6.842 6.944

42 7.17 6.90 6.932 6.814

31 7.122 7.189

36 7.154 7.132

35 7.185 7.200

41 7.283 7.372

32 7.29 7.40 7.573 7.622

34 7.33 7.40 7.580 7.622

37 7.78 7.70 7.689 7.626

Chapter 5

162

Table 5.2. List of 13

C NMR chemical shifts of labeled atoms for atropisomer assignment, obtained and

assigned via experimental 1D- and 2D-NMR and via calculation.

Experimental

13C Chemical Shift Calculated

13C Chemical Shift

Atom label Major Minor (R,P,Sa)-1 (R,P,Ra)-1

40 20.777 19.834

48 30.008 30.263

17 31.75 32.05 31.827 32.111

18 35.16 35.48 38.377 38.703

22 117.98 116.49 112.611 114.023

28 117.34 115.67 114.590 113.796

26 120.61 120.08 116.623 117.417

10 119.77 119.5 118.174 117.939

3 119.33 119.5 118.850 118.227

6 120.769 123.610

24 122.334 117.870

13 123.372 123.874

20 123.898 118.583

12 124.819 125.131

1 125.075 124.847

11 125.734 126.076

2 125.949 125.917

23 126.599 127.861

27 130.30 127.437 129.900

25 133.45 131.55 131.370 131.039

16 134.777 134.333

9 135.43 135.44 135.880 136.071

8 137.714 137.525

5 138.455 138.357

4 139.163 138.732

7 139.287 139.530

15 138.49 138.64 142.184 140.619

14 144.67 144.67 150.561 149.432

21 153.15 153.78 152.959 153.738

29 152.86 153.43 155.032 153.507


163

Figure 5.6. 1H NMR spectra (toluene-d8) comparison of calculated optimized structures of atropisomers

(R,P,Sa)-1 (middle) and (R,P,Ra)-1 (bottom) with experimental spectra of (R,P,Sa/Ra)-1 (top), atom label

assignment as listed in Table 5.1.

Figure 5.7. 13

C NMR spectra (toluene-d8) comparison of calculated optimized structures of atropisomers

(R,P,Sa)-1 (middle) and (R,P,Ra)-1 (bottom) with experimental spectra of (R,P,Sa/Ra)-1 (top), atom label

assignment as listed in Table 5.2.

Chapter 5

164

5.2.4 Atropisomerization process

The chiral resolution and initial characterization of 1 by 1H NMR disclosed a very interesting yet initially

unexpected phenomenon. Although stable isomer 1 could be resolved in two enantiomerically pure

fractions, which by chiral HPLC analysis appeared to comprise single compounds and eluted as sharp

symmetric peaks (see Experimental section, both racemic and enantiopure fractions comprised two

inseparable species, as displayed by 1H NMR spectroscopy analysis. Notably, no variation in the

atropisomers ratio was observed upon 1H NMR spectra comparison of several samples of either racemic or

enantioenriched fractions of 1. Based on our design, we assumed these can be attributed to two

equilibrating syn- and anti-atropisomers (Scheme 5.3).

1H NMR spectroscopy coalescence experiments

Initial attempts to determine the rate of the atropisomerization process via dynamic NMR focused on the

coalescence of the aforementioned diagnostic absorption peaks corresponding to the proton in position 1 of

the fluorenyl stator (H37, see Figures 5.4 and 5.5).66–68

With this technique, dynamic aspects of systems that

are at chemical equilibrium can be studied.69

In particular, the NMR time scale includes a range of reaction

rates that are often encountered in the laboratory, 10-1

-10-5

s-1

. In addition, rotational barriers in the range

12-80 kJ mol-1

can be studied by this method.70

The requirements for the use of dynamic NMR are (a) the

chemical exchange between the proton associated to the inspected peaks and (b) the exchange time scale to

be slow or fast enough to cause broadening of the NMR lines. The coalescence temperature (Tc) is used in

conjunction with the maximum peak separation in the low-temperature (i.e. slow-exchange) limit (∆ν

in Hz) to determine the activation energy parameters.71

The exchange rate constant (kexc) in these

calculations, for nearly all NMR exchange situations, is actually k1+k2 in a system for X exchanging with

Y, where:

( 1 )

and the rate of exchange kexc at the coalescence temperature:

√

⁄ ( 2 )

The equation to estimate ∆‡G using the coalescence temperature is:

* (

) ( )+ * (

)+ ( 3 )

1H NMR spectra (300 MHz) of a sample of stable state (R,P,Sa/Ra)-1 in toluene-d8 were recorded at

temperatures ranging from 50 to 100 °C (highest working temperature allowed for our NMR

spectrometer).72

No coalescence of the aforementioned diagnostic absorption peaks (A-B, see Figures 5.8

and 5.9) was observed, suggesting a high activation barrier for the biaryl rotation process, not evaluable via

this technique.73

Focusing our attention on the diagnostic absorption peaks in the downfield aromatic region

(δA = 7.78 ppm; δB = 7.70 ppm; Δν = 24 Hz), an exchange rate of 53.3 Hz would be required to observe

coalescence, as calculated using equation 2. Since no coalescence was observed at 100 °C, the value of

∆‡GBI at rt could be estimated to be higher than 63 kJ mol

-1 from equation 3 (similarly: ∆

‡GBI > 70 kJ mol

-1

at 50 °C; ∆‡GBI > 80 kJ mol

-1 at 100 °C).


165

Figure 5.8. 1H NMR spectra (full spectrum) from coalescence experiments of (R,P,Sa/Ra)-1 in toluene-d8.

Figure 5.9. 1H NMR spectra (partial spectrum, magnification of aromatic region) from coalescence

experiments of (R,P,Sa/Ra)-1 in toluene-d8.

Chapter 5

166

1H NMR spectra of a sample of stable isomer (R,P,Sa/Ra)-1 in toluene-d8, were recorded at temperatures

ranging from 50 °C to 100 °C.72

No coalescence of the aforementioned diagnostic absorption peaks was

observed, suggesting the activation barrier for the biaryl rotation process to be higher than typical exchange

processes usually determined via Dynamic NMR.74

Hence, the thermodynamic parameters of this

isomerization process could not be determined via this technique at the investigated conditions, as higher

temperatures would be required to display coalescence.73

Dynamic HPLC experiments

Dynamic HPLC (DHPLC) analysis was also considered, as it was previously reported to allow for the

successful determination of rotational barriers for other substituted biphenyl atropisomers.75–78

Dynamic

HPLC on enantioselective stationary phases has become a well-established technique to investigate chiral

molecules with internal motions that result in stereo-inversion and occur on the time scale of the separation

process. Kinetic parameters for the on-column interconversion phenomena can be extracted from

experimental peak profiles by computer simulation or by direct calculation methods. The technique has

been used in a wide range of temperatures and is complementary in scope to dynamic NMR spectroscopy.

The dynamic chromatographic profiles are dependent on the eluent flow rate and column temperature. By

comparison of the experimental separation with computer simulated chromatographic profiles, the

rotational energy barrier of atropisomers (or racemization barrier of enantiomers) can be determined.

Resolution of peaks can be achieved when, at the elution conditions, half-life of racemization t½ is in the

scale of hours or longer, with krac ≈ 10-5

s-1

(see equations 2-3). Complete coalescence is obtained when t½

in the scale of ~10 min or shorter, with krac ≈ 10-3

s-1

.22

Despite the screening of temperatures down to 0 °C

(lowest working temperature allowed by our HPLC instrument and AD-H column used for HPLC analysis

of 1) and various mixtures of hetptane:2-propanol, no splitting of the elution peaks was observed, indicative

of a fast equilibration process even at lower temperatures. As complete coalescence is observed for stable

state (R,P,Sa/Ra)-1 at 0°C, ∆‡G could be estimated, using equation 2, to be lower than 88 kJ mol

-1 at rt

(∆‡GBI < 82 kJ mol

-1 at 0 °C; ∆

‡G < 94 kJ mol

-1 at 40 °C).

Exchange spectroscopy measurements (EXSY)

The rotational process was eventually demonstrated and studied by one dimensional exchange spectroscopy

(EXSY, 1H-

1H nuclear Overhauser enhancement spectra). When two NMR signals are undergoing dynamic

exchange on the timescale of T1, then saturation of one of the signals causes intensity changes in the other,

since saturated nuclei will be transferred between the two forms by the exchange process. These intensity

changes can be used to obtain quantitative rate data, as the change of relative intensities are temperature

and mixing time dependent.69,72

According to the initial rate approximation method proposed by Ernst and

co-workers,79,80

the rate of exchange (rate of atropisomerization k) can be calculated directly from the ratio

of cross- (aAB and aBA) and autopeak integrations (aAA and aBB) and the mixing time using the formula:

(aAA/aAB) = (1-ktm)/ktm ( 4 )

provided a slow exchange situation and absence of scalar spin-spin coupling. This equation can be

transformed into:

k = 1/tm (aAB / (aAA + aAB)) ( 5 )

A plot of tm versus (aAB / (aAA + aAB)) will therefore directly give the rate constant k at a given temperature.

These k-values can be used subsequently to determine the thermodynamic constants, ∆‡G

°, ∆

‡H

° and ∆

‡S

°,

via a direct Eyring plot (k versus T). The absorption peaks assigned to proton (H37) at position 1 of the

fluorenyl stator were also chosen for the EXSY experiments. The measurements were conducted in the

temperature range of 39.2‒60.9 °C, consisting of an arrayed cluster of multiple mixing times (tm from 0.10

s to 2.00 s) per temperature (samples: 10.0 mg of 1 in 0.7 mL of toluene-d8) (Figure 5.10).


167

Figure 5.10. Arrays of 1D-NOESY experiments performed at fixed temperatures (T = 39–61 °C) consisting

of an arrayed cluster of mixing times (tm= 0.10– 2.00 s) per temperature, obtained upon excitation of peak

A (δ 7.78 ppm).

Their difference in chemical shift of the chosen absorptions is sufficiently large, due to the local anisotropy

caused by the different conformation of the lower 2-phenol ring. Their resolved profile allowed successful

monitoring of the exchange process at different temperatures. The biaryl isomerization process of 1

corresponds to an equilibrium process (i.e. comprising a pair of forward and reverse reactions). Thus a

kinetic analysis as two opposite 1st order reactions system can be performed. In a simple equilibrium

between two species:

( 6 )

The constant K at equilibrium is expressed as:

[ ]

[ ] ( 7 )

where [A]e and [B]e are the concentrations of species A and B at equilibrium, respectively. The

concentration of A at time t ([A]t) is related to the concentration of B at time t ([B]t) by the equilibrium

reaction equation:

[ ] [ ] [ ] ( 8 )

This applies as well when time t is at infinity, i.e. when equilibrium has been reached:

[ ] [ ] [ ] ( 9 )

By definition of K, it follows:

Chapter 5

168

[ ]

[ ] (10)

and:

[ ] [ ]

[ ] ( 11)

The rate law for two equilibrating unimolecular reactions is described by the following equation:

[ ]

[ ] [ ] (12)

The derivative is negative because this is the rate of the reaction going from A to B, and therefore the

concentration of A is decreasing. To simplify annotation, let x be [A]t, the concentration of A at time t. Let

xe be the concentration of A at equilibrium. Then:

[ ]

[ ] ([ ] ) ( ) [ ] (13)

Since:

[ ]

(14)

The reaction rate becomes:

[ ]

( ) (15)

which results in:

([ ] [ ]

[ ] [ ] ) ( ) [ ] ([ ] [ ] )

( ) [ ] (16)

If the concentration at the time t = 0 is different from above, the simplifications above are invalid, and a

system of differential equations must be solved. However, this system can also be solved exactly to yield

the following generalized expressions:

[ ] [ ]

(

( ) ) [ ]

( ( ) ) (17)

[ ] [ ]

( ( ) ) [ ]

(

( ) ) (18)

The observed rate constant is the sum of the individual rate constants (kf and kb):

(19)

From the ratio [B]e/[A]e, the ratio of rate constants kf/kb can be calculated as expressed in eq. 9. Each

formation rate constant can then be calculated as follows:

([ ] [ ]

) (20)

([ ] [ ]

) (21)

It should be noted that throughout the entire NMR experiments both atropisomers are always present at the

thermodynamic equilibrium ratio, which can vary with the temperature. However, as the EXSY experiment

allows us to focus the attention on the evolution of single atropisomer upon selective excitation, the kinetic

analysis was performed according to the simplified case as described above. The integral fraction (fAB =

integral fraction of cross-peak B upon excitation of A) of the obtained absorption peaks at δ 7.78 ppm (A)

and δ 7.70 ppm (B), as assigned to the major and minor atropisomers of (R,P,Sa/Ra)-1, respectively, was

calculated for each experiment (temperature and mixing time) as follows:


169

(22)

Exponential growth curves of the absorption peak of the minor atropisomer were obtained by plotting the

integral fraction ( ) vs mixing time at each temperature. Curve fitting provided the total growth constant

(ktot) and associated standard error (σktot) for each temperature, while the atropisomers ratio for each

experiment was determined by 1H NMR spectroscopy. The latter equalled to the kf/kb ratio for each

experiment, from which each isolated rate constant kf and kb could be calculated as described above. The

temperature of the NMR probe compartment during the EXSY experiments was measured with a Pt1000

RTD Temperature Sensor and the error (3σst-T) associated was assumed to be ±1 K. The standard error

associated to each kinetic constant was determined through the quadratic variance of each variable. When a

function used to calculate a value (f) involves multiplications or divisions:

(23)

(24)

the associated standard error (σf) is calculated from the standard errors of the function parameters (σx, σy) as

follows:

(

) (

) (

) (25)

√(

) (

) (26)

As described in eq. 21 or 22, in this work f denotes kf or kb, while x denotes ktot and y denotes the

equilibrium ratios of atropisomers. The standard error associated to the equilibrium ratios was also

determined accordingly, accounting for an error of 5% of the integral ratio value. A least squares analysis

of the rates of isomerization versus the temperature on the original Eyring equation:

(

) (

) (28)

with appropriate weighing (1/k2) afforded the entropies and enthalpies of activation of the forward

isomerization (major into minor atropisomer). The standard errors (σ) were obtained from a Monte Carlo

error analysis on the linearized Eyring equation:

( ) ( (

)

)

(29)

from forty thousand randomly generated samples using calculated standard errors on rates (σk) and

estimated standard errors on temperatures (3 σT = 1 K).57

Integral fraction versus mixing time curves and

Eyring plot are reported in Figure 5.11b-c. The half-life of biaryl isomerization at room temperature (t½ at

rt, 20 °C) is extrapolated to be in order of minutes (1.2±0.4 min), while the ‗hour half-life temperature‘

(temperature at which the half-life equals one hour) is calculated to be equal to -50.5±0.5 °C. This analysis

explains why the isolation of atropisomers was not successful (requiring temperatures of -50 °C), the lack

of coalescence in the 1

H NMR spectrum at high temperatures (extrapolated coalescence temperature: Tc ≈

177 °C) and the unresolved elution profile in the HPLC chromatograms. The value of ∆‡G°BI was

calculated at the average temperature of the EXSY measurements TAVG = 49.7 °C (322.9 K), while ∆‡GBI at

rt was calculated at 20 °C. All the mentioned thermodynamic data are reported in Table 5.3. The value of

∆‡G at rt (78.2 ±1.1 kJ·mol

−J) is within the expected range (63 kJ·mol

−J < ∆

‡G < 88 kJ·mol

−J, vide supra) as

estimated by comparison from the unsuccessful determination via dynamic 1H NMR and dynamic HPLC

techniques.

Chapter 5

170

Figure 5.11. Integral fraction vs. mixing time curves and Eyring plot for the biaryl isomerization process of

stable state (R,P,Sa/Ra)-1. a) Schematic representation of the biaryl isomerization process of (R,P,Sa)-1 to

(R,P,Ra)-1. b) Graph showing the relation between the mixing time (tm) and the integral fraction fAB (see Eq.

3) for stable state (R,P,Sa/Ra)-1 (10.0 mg in 0.7 mL of toluene-d8), obtained by recording, upon excitation of

peak A, 1D-NOESY experiments at fixed temperatures (312.32, 318.00, 322.45, 327.58, and 334.01 K)

consisting of an arrayed cluster of mixing times (tm= 0.10, 0.20, 0.30, 0.40, 0.50, 0.65, 0.80, 0.95, 1.10,

1.30, 1.50, 1.70, 2.00 s) per temperature. c) Least-squares analysis on the original Eyring equation (Eq. 4)

with error bars of 3σ.


171

Table 5.3. Thermodynamic parameters for biaryl isomerization (BI) of stable (R,P,Sa/Ra)-1 determined by

the direct Eyring analysis (Figure 5.11c), with standard errors obtained from a Monte Carlo analysis.

t½ at rt (s) [a]

73.4±23.8

T at t½=1 h (°C) -50.5±0.5

Δ‡H°BI (kJ·mol

−1) 45.0±11.8

Δ‡S°BI (J·K

−1·mol

−1) -113±37

Δ‡G°BI (kJ·mol

−1) [b]

81.6±0.4

Δ‡GBI at rt (kJ·mol

−1) [a]

78.2±1.1

[a] rt: 20 °C (293.15 K). [b] Standard condition: TAVG = 49.7 °C (322.9 K) and atmospheric pressure.

Notably, when the isolated metastable state (R,M,Ra/Sa)-1 (via preparative HPLC, see Experimental section)

was subjected to the same EXSY experiments (5.0 mg in 0.7 mL of toluene-d8), no exchange of the

aromatic peaks (C, δ 7.61 ppm; D, δ 7.47 ppm; see Figure 5.12e) was observed (temperatures up to 60 °C).

This observation, in accordance with the large elution band of the metastable state fraction obtained in the

analytical HPCL run (see Experimental section), suggests a higher activation barrier, hence a slower

isomerization rate, for the biaryl rotation process in the photo-generated state. No further investigation was

performed due to the low signal-to-noise ratio obtained in the NMR spectra, which we hypothesized to be

caused by detrimental convection effects in the toluene solution at high temperatures. As observed in the X-

ray structure analysis and based on the model investigated by Fujimura and co-workers (vide supra), we

proposed a thermodynamically favored cyclic seven-membered ring conformation generated upon internal

coordination via hydrogen bonding of the two hydroxyl substituents (see Figure 5.2 and Scheme 5.3).

Experimental evidence and calculation data suggest that such a conformation provides access to a transition

state with a relatively low barrier for atropisomerization, allowing for a fast exchange of two atropisomers

in solution at room temperature. In these two transition states (TSBI-(R,P,Syn)-1‡ and TSBI-(R,M,Syn)-1

‡,

see J. C. M. Kistemaker‘s PhD thesis for further details)81

the hydrogen bond between the two phenol

moieties is shorter than it is in any other conformation suggesting additional stabilization of the transition

state with respect to its corresponding minima explaining the relatively low barrier for atropisomerization.

Moreover, the barrier for biaryl rotation is sufficiently low to allow the desired syn atropisomer to act as a

thermodynamic sink upon its depletion in a reaction selective for it, for instance by biphenol bidentate

coordination to a metal center (vide infra, Scheme 5.5a). Indeed, the product of a metal bidentate

complexation would require a syn conformation of the biaryl motif and concordant alkene and biaryl

helicity, as the clash of the lower phenol moiety with the fluorenyl lower half in the conformation with

discordant helicities would otherwise lead to very energetically unfavored species (Figure 5.2; vide infra,

Scheme 5.5b).

5.2.5 Photochemical isomerization

NMR spectroscopy

In order to investigate the photochemical behavior of 1 (Figure 5.12a) in more detail, an NMR sample of

stable isomer (R,P,Sa/Ra)-1 in toluene-d8 was irradiated with UV light (365 nm) for 30 min at room

temperature. 1H NMR spectra were taken before (Figure 5.12b), during (Figure 5.12c) and after irradiation

(Figure 5.12d). Upon irradiation two new sets of absorptions C and D with intensities increasing over time

were obtained [proton H37 at fluorenyl stator: δ 7.61 ppm (C), 7.47 ppm (D); proton H19 at the stereogenic

center: δ 3.75 ppm (C), 3.35 ppm (D); methyl protons H45-47: δ 1.22 ppm (C+D, peaks not resolved)], which

is indicative of the photo-induced isomerization to the metastable isomer (R,M,Ra/Sa)-1 comprising of two

distinct atropisomeric species, (R,M,Ra)-1 (C) and (R,M,Sa)-1 (D), respectively.

Chapter 5

172

Figure 5.12. a) Schematic representation of the photochemical E-Z isomerization of stable isomer

(R,P,Sa/Ra)-1 to metastable isomer (R,M,Ra/Sa)-1. 1H NMR spectra of (R)-1 (~5.0 mg, toluene-d8 (0.7 mL),

25 °C): b) stable isomer (R,P,Sa/Ra)-1 (A:B = 67:33); c) after irradiation with UV light (365 nm) over

15 min of stable (R,P,Sa/Ra)-1 to the metastable isomer (R,M,Ra/Sa)-1 (~50% of MS); d) after irradiation

over 30 min (~65% of MS). e) 1H NMR spectra of atropisomers of metastable isomer (R,M,Ra/Sa)-1, (C:D =

55:45), isolated by preparative HPLC (see Experimental section). Note: the codes A-B and C-D indicate the

characteristic sets of absorptions of mixtures of atropisomers for stable and metastable isomer, respectively.


173

Their relative integration revealed a final ratio in toluene-d8 of, (R,P,Sa/Ra)-1 (A+B) : (R,M,Ra/Sa)-1 (C+D)

= 35:65, respectively, upon irradiation over 30 min. Due to the high thermal stability of the metastable

isomers ((R,M,Ra/Sa)-1), isolation of the latter from a crude mixture of an irradiated solution of (R)-1 was

achieved by preparative HPLC (see Experimental section). Analysis by 1H NMR revealed the metastable

isomer to comprise a mixture of atropisomers (R,M,Ra)-1 (C) and (R,M,Sa)-1 (D) in a ratio of C:D = 55:45

(Figure 5.12e).

UV-vis and CD spectroscopy

The switching properties of (R)-1 were monitored by UV-vis absorption and circular dichroism (CD)

spectroscopy (Figure 5.13). A schematic representation of the reversible photochemical E-Z isomerization

process of (R)-1 is shown in Figure 5.13a. A solution of stable (R,P,Sa/Ra)-1 (toluene, 4.5·10−5

M) in quartz

cuvettes was purged with argon and irradiated at room temperature towards either the metastable isomer

using UV light (365 nm, Figure 5.13b, black to red gradient) or the stable isomer using visible light

(420 nm, Figure 5.13c, red to blue gradient). The reversible photochemical E-Z isomerization was found to

be characterized by a clear isosbestic point at 368 nm, indicating the absence of side reactions. A

bathochromic shift of the major absorption band (π→ π*) of about 40 nm was observed, indicative of an

increase in alkene strain and consistent with other second generation motors and switches as is expected for

the metastable form (R,M,Ra/Sa)-1.57

The sample was subsequently subjected to irradiation cycles (see

Experimental section, Figure 5.14), displaying non-perfect switching fatigue resistance with a minor

decomposition, as opposed to the highly resistant unfunctionalized parent compounds studied recently.57

This problem could be solved by irradiation of (R)-1 (solution in toluene, ~4.0·10−5

M) in presence of the

radical scavenger TEMPO (~10−5

M) towards opposite PSS mixtures, which resulted in no evidence of

degradation after six irradiation cycles (Figure 5.13d). This observation suggests that radicals may be

involved in the decomposition process). Lastly, a solution of stable (R,P,Sa/Ra)-1 (toluene, 4.5·10−5

M) was

subjected to CD spectroscopy in order to perform a qualitative analysis of the change in its helical structure

(Figure 5.13e). The CD spectrum displayed a strong Cotton effect in the area of 320–370 nm. Upon

irradiation with 365 nm light an inversion of the absorption band was observed, which is indicative of an

inversion in helicity and shows that the photochemical isomerization of the stable isomers (R,P,Sa/Ra)-1 to

the metastable isomers (R,M,Ra/Sa)-1 has occurred. Upon irradiation with 420 nm light, the original

absorption band could be recovered. The presence of the metastable species was further confirmed by chiral

HPLC analysis of irradiated mixture (see Experimental section). The ratio between the stable and

metastable isomer in the PSS in a toluene solution was determined by a chiral HPLC analysis of the PSS

mixtures using a detection wavelength at the isosbestic point (368 nm). An efficient photoswitching process

was observed upon irradiation with 365 nm light, with a high ratio towards the metastable diastereoisomer

(S:MS = 17:83) at the PSS365. However, the reverse process upon irradiation at 420 nm light was found to

be less selective, affording an equimolar mixture of stable and metastable isomers (S/MS = 50:50) at the

PSS420.

Chapter 5

174

Figure 5.13. a) Schematic representation of photochemical E-Z isomerization of stable isomer (R,P,Sa/Ra)-1

to metastable isomer (R,M,Ra/Sa)-1. b) Experimental UV-vis absorption spectra of stable (R,P,Sa/Ra)-1

(toluene, 4.5·10−5

M, black) and irradiation with UV-light (365 nm) of (R,P,Sa/Ra)-1 towards the metastable

isomer affording a PSS365 mixture (S:MS = 17:83, red) with isosbestic point at 368 nm. c) Experimental

UV-vis absorption spectra of irradiation of the previous PSS365 sample using visible light (420 nm),

resulting in reversed E-Z isomerization towards the stable isomer affording a new PSS420 mixture (S:MS =

50:50). d) Irradiation cycles of (R)-1 (toluene, ~4.0·10−5

M) in the presence of TEMPO (~10−5

M) towards

opposite PSS mixtures (red: 365 nm, 4 min; blue: 420 nm, 15 min). e) Experimental and calculated CD

spectra of (R)-1 (toluene, 5.0·10−1

M): black, starting stable isomer (R,P,Sa/Ra)-1; red: CD spectra of PSS365

mixture; blue: CD spectra of PSS420 mixture; cyan: metastable isomer (R,M,Ra/Sa)-1. Note: PSS ratios

determined by HPLC analysis of the irradiated solutions via quantitative analysis with PDA detector

wavelength set at the isosbestic point (368 nm).


175

5.2.6 Switchable asymmetric catalysis

Having established the reversible switching process between (R,P,Sa/Ra)-1 and (R,M,Ra/Sa)-1, we

investigated their abilities for dual stereocontrol in a model asymmetric catalysis reaction.49

As a proof of

principle, we envisioned to use compound (R)-1 as a switchable bidentate ligand, which could coordinate a

metal center and eventually be applied to an asymmetric transformation acting as a tunable stereoselective

catalyst (Scheme 5.5). We anticipated the isomers of 1 having an anti conformation of the biphenol unit

(torsion angle = ±90°–180°, hydroxyl groups pointing away from each other) to be poor bidentate ligands.

Therefore only the isomers with syn conformation (torsion angle = 0°–±90°, hydroxyl groups in proximity)

were expected to efficiently bind an organometallic center and successfully transfer the chirality within a

catalytically active complex (Scheme 5.5a,b). Hence we proposed that the tunable helicity (P or M) of the

switch core in turn would dictate the preferential axial configuration (Ra or Sa) of the desirable syn

conformation of the biaryl moiety and eventually, for instance, the configuration (R or S) of a newly formed

stereogenic center when applied to an enantioselective catalytic event (Scheme 5.5c).

Scheme 5.5. Schematic representation of mono- and bidentate coordination equilibrium upon reaction of

(R)-1 with organozinc reagents. We anticipated light-assisted dual stereocontrol in a catalyzed

organometallic reaction. a) Depiction of the possible mono-and bidentate coordination species upon

reaction of stable isomers of 1 with ZnR2. b) Only the isomer with syn conformation (torsion angle = 0°–

±90°) were expected to efficiently bind a metal center and successfully transfer the chirality within a

catalytically active complex. c) Light-assisted dual stereocontrol could be achieved in a catalyzed

organometallic reaction upon photoisomerization of (R)-1 and internal transfer of chirality to the

coordinated metal site.

Zn-BINOL-derived complexes have previously been reported to successfully mediate the catalytic

asymmetric aldol82–84

and hetero-Diels-Alder85

reactions. We decided to use compound (R)-1 as a

switchable bidentate ligand in 1,2-addition of diethylzinc to benzaldehydes. Numerous efforts have been

devoted in the past decades to develop new effective chiral ligands for asymmetric addition of diethylzinc

to benzaldehyde.86–90

However, only few cases have been reported in which dual stereocontrol was

achieved by tuning the reaction conditions. The switching of enantioselectivity in the catalytic addition of

diethylzinc to aldehydes was obtained by changes in the reaction conditions (e.g. solvent, temperature)

while using the same chiral additive.91–94

Alternatively, complementary catalytic systems were developed

by the use of distinctive structural derivatives from a common chiral catalyst scaffold to access both

enantiomers of the desired products.95–98

Chapter 5

176

In the representative reaction (see Scheme in Table 5.4), benzaldehyde 11a was added to a mixture of

ligand (R)-1 and a solution of diethylzinc in toluene, yielding a mixture of secondary alcohol 12a and the

side-product benzyl alcohol 13a. The latter is the product of the aldehyde reduction, a known process

occurring in the case of a slow addition process and proposed to derive from the β-hydride elimination of

organozinc species and subsequent reduction of the substrate in case of poorly activated zinc

complexes.99,100

As we anticipated, photo-induced switching of ligand (R)-1 allowed successful reversing of

stereoselectivity in the 1,2-addition of diethylzinc to benzaldehyde. The results of the catalysis experiments

are presented in Table 5.4. 1H NMR analysis allowed determining the conversion and selectivity of

organozinc addition versus aldehyde reduction to benzylic alcohol. The enantiomeric excess (ee) of chiral

secondary alcohols 12a-g was determined by chiral HPLC or GC analysis. In addition to benzaldehyde,

several para- and ortho-substituted aromatic aldehydes bearing electron-withdrawing or electron-donating

groups were tested as substrates. In all cases, when the stable form (R,P,Sa/Ra)-1 was used as a catalyst, the

preferred formation of the (R)-enantiomer of secondary alcohols 12 was observed, with ee‘s up to 68%

(entry 1, Table 5.4).101

Table 5.4. Dynamic enantioselective addition of organozinc to aromatic aldehydes with (R)-1.

Entrya 11 R Catalyst

Conversion of 11 (%)

b

Yield of 12 (%)

d

ee of 12 (%)

c

∆ee of 12 (%)

c

12:13 (%)

b

1

Et (R)-1 >95 86 68 (R)-12a 113

93:7

2 Et (R)-1 + 365 nm >95 87 45 (S)-12a 93:7

3

Et (R)-1 94 80 35 (R)-12b

59

81:19

4 Et (R)-1 + 365 nm >95 80 24 (S)-12b 81:19

5

Et (R)-1 94 87 40 (R)-12c 82

89:11

6 Et (R)-1 + 365 nm >95 86 42 (S)-12c 88:12

7

Et (R)-1 66 37 40 (R)-12d 95

62:38

8 Et (R)-1 + 365 nm >95 76 55 (S)-12d 97:3

9

Et (R)-1 >95 58 48 (R)-12e 98

63:37

10 Et (R)-1 + 365 nm >95 79 50 (S)-12e 85:15

11

Et (R)-1 >95 81 46 (R)-12f 77

89:11

12 Et (R)-1 + 365 nm >95 72 31 (S)-12f 83:17

13

11a

i-Pr (R)-1 95 40 <5 (±)-12g N.A

41:59

14 i-Pr (R)-1 + 365 nm >95 57 <5 (±)-12g 58:42

15 Et / 59 24 N.A. N.A 80:20

a General reaction conditions: 0.0125 mmol of (R,P,Sa/Ra)-1 in 0.5 mL of dry toluene at 0 °C; 0.375 mmol of R2Zn

(Et2Zn, 1.0 M in hexane; i-Pr2Zn, 1.0 M in toluene) added dropwise and stirred over 10 min; 0.125 mmol of 11 added to the mixture. Reaction mixture stirred for 7 d at 0 °C. Reaction with irradiated mixture of (R)-1: 0.00125 mmol of (R,P,Sa/Ra)-1 in 15 mL of dry, degassed Et2O, irradiated with UV-light (365 nm) for 30 min until the PSS was reached (S:MS = 17:83). PSS ratio determined by chiral HPLC analysis. Reaction procedure follows as described above.

b

Determined by 1H NMR analysis of crude.

c Determined by chiral GC or chiral HPLC analysis of isolated product.

d

Isolated yield. Abbreviations: N.A., Not Applicable.


177

In sharp contrast, upon use of the irradiated mixture of catalyst (R,P,Sa/Ra)-1 (365 nm light, PSS ratio S:MS

= 17:83), the addition proceeded with reversed enantioselectivity under the same conditions. Preferred

formation of the (S)-enantiomer of secondary alcohols 12 was observed in all cases after irradiation, with

ee‘s up to 55% (entry 8). The difference in enantioselectivity (∆ee) between non-irradiated and irradiated

catalyst solution was up to 113% (from 68% (R) to 45% (S), entries 1-2). When compared to the stable

(R,P,Sa/Ra)-1 isomer, no significant change in the reaction rate was observed upon use of the irradiated

mixture of the catalyst. Notably, use of diisopropylzinc led to no enantioselectivity in either case (entries

13-14).88

Compared to entry 1, in a control experiment performing the addition of diethylzinc in absence of

stable (R,P,Sa/Ra)-1 led to a marked decrease in conversion, addition vs. reduction selectivity and isolated

yield of 12a (entry 15).102

Addition of tetrabutylammonium bromide did not improve the catalytic activity,

as otherwise observed in previously reported systems (see Experimental section for further details).103

Noticeably, under the reaction conditions no decomposition, racemization or significant thermal relaxation

of the recovered catalyst (90% average catalyst recovery) was observed, as determined by 1H NMR and

chiral HPLC analysis (see Experimental section for further details). Moreover, several times the catalyst

was recovered after an experiment using a non-irradiated reaction mixture and recycled to perform a

subsequent experiment on the same substrate with irradiated catalyst without notable loss of catalytic

performance (see Supplementary material for further details). Point chirality dictates or governs helical

chirality, which in turn is coupled to the axial chirality and with a limitation of a syn conformation in the

ligand. The chirality is eventually transferred to the reagent providing an asymmetric product. The

inversion of enantioselectivity is an indication of the reversed local chirality around the transferring zinc

center and the coordinated aldehyde, achieved by using a ligand with opposite chiral induction.95–97

In the

current case, we suggest that upon irradiation and subsequent inversion of the biaryl axial chirality, the

metastable isomer (R,M,Ra/Sa)-1 resembles the enantiomer of the stable isomer (R,P,Sa/Ra)-1 (Scheme 5.5c).

As the biphenol unit is the chiral ligand for zinc, opposite chiral induction is achieved in the proximity of

the zinc-complexed aldehyde substrate, affording the opposite enantiomers of the 1,2-addition products.

5.3 Conclusions

The synthesis and resolution of a photoresponsive molecular switch featuring a versatile 2,2‘-biphenol

motif in which chirality is transferred across three stereochemical elements has been designed and

successfully executed. The comparison of experimental and computational data confirmed the proposed

model of coupled central-to-helical-to-axial transfer of chirality, demonstrating the most favored

conformation of the lower aryl substituent to be parallel to the fluorenyl lower half of the switch core.

Compared with previously reported molecular motor based systems, the reduction from four to two

isomerization stages featured by the biaryl-functionalized design described herein provides a simpler,

reusable and more efficient dynamic responsive core. Extensive studies with CD and UV-vis absorption

spectroscopy, 1H NMR spectroscopy and chiral HPLC analysis proved the reversible photoswitchability of

1, with no switching fatigue over multiple cycles in presence of substoichiometric amount of TEMPO. The

chirality transfer was successfully applied to creation of another stereogenic element as demonstrated via

dynamic central-to-helical-to-axial-to-central transfer of chirality by using (R)-1 as switchable catalyst in

the enantioselective addition of diethylzinc to benzaldehydes. Clear reversal of enantioselectivity was

accomplished for each substrate, with ee‘s of 12 up to 68%, ∆ee‘s up to 113% and yields up to 87%. These

results achieved in switchable asymmetric catalysis highlight the proof-of principle of a two-stage

dynamically tunable and responsive chiral biaryl-functionalized switch scaffold. The further development

of analogous biaryl-switch designs combined with the established precedence of numerous catalysts based

on biaryl scaffolds may lead to the construction of unprecedented switchable chiral catalysts that could

perform multiple enantioselective transformation in a sequential manner. In addition, this switch system has

considerable potential as chirality selector for a wide range of purposes beyond the field of asymmetric

catalysis, such as control of supramolecular architecture, host-guest interaction, and polymer or liquid

crystal morphology.

Chapter 5

178


The author would like to thank P. Štacko J. C. M. Kistemaker, T. van Leeuwen and Prof. E. Otten for their

fundamental contribution to this work. Design, synthesis and characterization were performed in

collaboration with P. Štacko, J. C. M. Kistemaker and T. van Leeuwen. Computational study was

performed by J. C. M. Kistemaker. X-ray structure determination was performed by Prof. E. Otten. The

authors would like to thank Ing. P. van der Meulen for the technical support during the EXSY experiments.



Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe. Commercially available solutions of

Et2Zn (1.0 M in hexane), i-Pr2Zn (1.0 M in toluene) and EtMgBr (3.0 M in Et2O) were used without

dilution. Solvents were reagent grade and distilled and dried before use according to standard procedures.

Dichloromethane, ether and toluene were used from the solvent purification system using a MBraun SPS-

800 column. Tetrahydrofuran was distilled over sodium under a nitrogen atmosphere prior to use. Column

chromatography was performed on silica gel (Silica Flash P60, 230–400 mesh, mixtures of pentane,

EtOAc, Et2O, CH2Cl2 or MeOH were used as eluent as reported for each case). Components were

visualized by UV and phosphomolybdic acid or potassium permanganate staining. Progress and conversion

of the reaction were determined by GC-MS (GC, HP6890 – MS, HP5973) with an HP1 or HP5 column

(Agilent Technologies, Palo Alto, CA). NMR spectra were recorded on a Varian Gemini-200, a Varian

Mercury 300, a Varian AMX400 or a Varian Unity Plus 500 spectrometer, operating at 200 MHz,

300 MHz, 400 MHz, and 500 MHz for 1H NMR, respectively. EXSY experiments were performed on a

Varian Unity Plus 500 spectrometer. Chemical shifts are denoted in δ values (ppm) relative to CDCl3 (1H: δ

= 7.26; 13C: δ = 77.00) or toluene-d8 (

1H: δ = 2.09). Unless mentioned otherwise, all NMR spectra were

recorded at 25 °C. For 1H NMR, the splitting parameters are designated as follows: s (singlet), d (doublet), t

(triplet), q (quartet), p (pentet), sext (sextet), h (heptet), m (multiplet) and br (broad). When a mixture of

atropisomers is described, the integral value of an absorption assigned to a specific atropisomer is reported

as the corresponding fraction of the total number of nuclei of a specific chemical position. Mass spectra

were obtained with a AEI MS-902 spectrometer (EI+) or with a LTQ Orbitrap XL (ESI+). Melting points

were measured on a Büchi Melting Point B-545 apparatus. Optical rotations were measured on a Perkin

Elmer 241 Polarimeter with a 10 cm cell (c given in g/100 mL). Chiral HPLC analysis was performed using

a Shimadzu LC 10ADVP HPLC equipped with a Shimadzu SPDM10AVP diode array detector using a

Chiralpak (Daicel) AD-H column, Chiralcel OB-H or Chiralcel OD-H column. The elution speed was

0.5 mL/min, with mixtures of HPLC-grade heptane and 2-propanol (BOOM) as eluent and column

temperature of 40 °C. Sample injections were made using a HP 6890 Series Auto sample Injector.

Preparative HPLC was performed on a Shimadzu semi-prep HPLC system consisting of an LC-20T pump,

a DGU-20A degasser, a CBM-20A control module, a SIL-20AC autosampler, a SPD-M20A diode array

detector and a FRC-10A fraction collector, using a Chiralpak (Daicel) AD-H column. Elution speed was

0.5 mL/min with mixtures of HPLC grade heptane and 2-propanol (BOOM) as eluent. Chiral GC analysis

was performed using a HP6890, equipped with capillary column CP-Chirasil-Dex-CB, 25m x 0.25mm, He-

flow 1.0 mL/min, equipped with a flame ionization detector. UV-vis absorption spectra were measured on a

SPECORD S600 Analityk Jena spectrophotometer, equipped with a QUANTUM Northwest TC-1

temperature controller and fluorescence temperature control cell. CD spectra were measured on a Jasco J-

815 CD spectrometer. All spectra were recorded at 20 °C using Uvasol-grade toluene (Merck) as solvent.

Irradiation was performed using Thorlabs M365F1/M420F2 fiber-coupled high power LEDs (at 365 nm

and 420 nm, respectively). Room temperature (rt) as mentioned in the experimental procedures and

characterization sections is to be considered equal to 20 °C.

The chiral descriptors for each species described in this work (e.g. (R,P,Sa)-1) indicate respectively: the

absolute stereochemistry of the stereogenic center (R or S), the configurational helicity of the switch core (P

or M), and the axial stereochemistry of the biaryl unit (Ra or Sa). The asterisks at the stereodescriptors


179

throughout the text denote a racemic mixture with identical relative stereochemistry (S*,M*,Ra* means a

mixture of S,M,Ra and R,P,Sa). The doubly expressed axial stereodescriptor (Ra/Sa) throughout the text

denote a mixture of conformers with identical absolute stereochemistry and configurational helicity, with

the first axial descriptor indicating the major species (R,P,Sa/Ra means a mixture of R,P,Sa, major

conformer, and R,P,Ra, minor conformer).


8-bromo-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (2)

Compound 2 was prepared from 7-methoxy-3,4-dihydronaphthalen-1(2H)-one

following the procedure previously reported.60

To a solution of 7-methoxy-3,4-

dihydronaphthalen-1(2H)-one (3.80 g, 21.40 mmol) in acetonitrile (30 mL) was added

portionwise N-bromosuccinimide (4.20 g, 23.60 mmol, 1.1 equiv) under stirring at rt.

The reaction suspension was stirred over 24 h. Due to a low conversion, more N-bromosuccinimide (1.00 g,

5.62 mmol, 0.25 equiv) was added and the stirring was continued for 24 h. After the volatiles were removed

under reduced pressure, the red crude product was adsorbed on celite and purified by column

chromatography (SiO2, pentane:EtOAc = 5:1) to yield 2 (5.13 g, 20.11 mmol, 94%) as a light yellow solid.

Characterization data according to the literature.104

m.p. 90.3–90.5 °C; 1H NMR (200 MHz, CDCl3) δ 7.17

(d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 2.91 (t, J = 6.1 Hz, 2H), 2.69 (t, J = 6.7 Hz, 2H),

2.20–1.95 (m, 2H); 13

C NMR (75 MHz, CDC13) δ 197.3, 155.5, 138.7, 132.5, 128.4, 115.9, 111.7, 56.8,

40.1, 30.1, 22.8; HRMS (APCI, m/z): calcd for C11H12BrO2 [M+H]+: 255.0015, found: 254.9996.

7-methoxy-8-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one (3)

Compound 3 was prepared from 2 by a modified procedure previously reported.61

A

flame-dried resealable Schlenk tube containing a magnetic stirring bar was charged

with 2 (6.00 g, 23.5 mmol), 2-methoxyphenyl-boronic acid (7.15 g, 47.0 mmol, 2.0

equiv) and powdered, anhydrous K3PO4 (15.00 g, 70.6 mmol, 3.0 equiv). The Schlenk

tube was capped with a rubber septum and then evacuated and backfilled with argon

three times. Dry toluene (50 mL) was added through the septum via a syringe and the

resulting mixture was stirred at rt for 2 min. Subsequently the Schlenk tube was charged with Pd2dba3

(215 mg, 0.235 mmol, 1.0 mol%), SPhos (386 mg, 0.941 mmol, 4.0 mol%), and evacuated and backfilled

with argon three times. The septum was replaced with a Teflon screwcap and the Schlenk tube was sealed.

The reaction mixture was heated at 100 °C over 24 h. The reaction mixture was then allowed to cool to rt,

diluted with EtOAC (50 mL), filtered through a thin pad of silica gel (eluting with EtOAC) and

concentrated under reduced pressure. The crude material obtained was purified by a recrystallization from

toluene (~ 60 mL) and the obtained precipitate was washed with a mixture of heptane:toluene = 1:1,

sonicated with heptane (40 mL) and evaporated at reduced pressure to remove traces of toluene, to yield 3

(6.45 g, 22.8 mmol, 97%) as light brown crystals. m.p. 110.8–111.0 °C; 1H NMR (300 MHz, CDCl3) δ 7.31

(t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.07–6.96 (m, 2H), 6.94 (d, J =

8.2 Hz, 1H), 3.70 (br s, 6H), 2.98–2.89 (m, 2H), 2.60–2.47 (m, 2H), 2.17–2.01 (m, 2H); 13

C NMR

(75 MHz, CDC13) δ 198.8, 156.8, 156.4, 137.2, 133.2, 130.4, 129.2, 128.4, 128.1, 127.4, 120.7, 116.5,

111.1, 56.8, 56.0, 40.5, 30.3, 23.6; HRMS (APCI, m/z): calcd for C18H19O3 [M+H]+: 283.1329, found:

283.1317.

7-methoxy-8-(2-methoxyphenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-one (4)

To a solution of diisopropylamine (3.33 mL, 23.75 mmol, 1.30 equiv) in dry THF

(70 mL) cooled at 0 °C was added dropwise a solution of nBuLi (1.6 M in hexane,

14.28 mL, 22.85 mmol, 1.25 equiv) under argon. The reaction mixture was stirred for

30 min at 0 °C and then cooled to -78 °C. A solution of 3 (5.16 g, 18.28 mmol, 1

equiv) in dry THF (70 mL) was added dropwise to the cooled mixture, which was

Chapter 5

180

stirred over 1 h at −78 °C. Methyl iodide (2.27 mL, 27.4 mmol, 1.5 equiv) was added at -78 °C, the reaction

mixture was stirred for 1 h at rt, quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (3 x

80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent

evaporated at reduced pressure. The crude solid was purified by column chromatography (SiO2,

pentane:EtOAc = 7:1) to yield 4 (4.66 g, 15.72 mmol, 86%, variable mixture of two atropisomers) as a light

brown solid. m.p. 103–105 °C (partial melting of solid residue); 1H NMR (200 MHz, CDCl3, ≈ 1:1 mixture

of two atropisomers) δ 7.52–7.40 (m, 1H), 7.40–7.29 (m, 1.3H), 7.29–7.24 (m, 0.3H), 7.24–7.15 (m, 0.5H),

7.14–7.01 (m, 2H), 3.85 (s, 1.5H), 3.83 (s, 3H), 3.81 (s, 1.5H), 3.30–2.99 (m, 2H), 2.88–2.55 (m, 1H),

2.38–2.20 (m, 1H), 2.11–1.86 (m, 1H), 1.29 (d, J = 6.5 Hz, 1.5H), 1.24 (d, J = 6.5 Hz, 1.5H); 13

C NMR

(50 MHz, CDC13, 1:1 mixture of two atropisomers) δ 201.4, 201.0, 156.6, 156.0, 155.8, 155.7, 136.45,

135.9, 133.4, 132.7, 130.6, 129.7, 128.8, 128.8, 128.0, 128.0, 127.3, 1269.0, 126.6, 120.4, 120.3, 115.9,

110.6, 110.69, 56.4, 56.3, 55.6, 55.4, 43.7, 43.0, 31.8, 31.5, 28.8, 15.9, 15.4; HRMS (APCI, m/z): calcd for

C19H21O3 [M+H]+: 297.1485, found: 297.1473.

(7-methoxy-8-(2-methoxyphenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-ylidene)hydrazine (5)

To a mixture of 4 (2.00 g, 6.75 mmol), hydrazine monohydrate (7 mL) in EtOH

(15 mL) was added Sc(OTf)3 (83 mg, 0.17 mmol, 2.5 mol%). Three cycles of

vacuum and nitrogen backfill were applied to the reflux setup. The mixture was then

heated at reflux for 3 d and subsequently, upon cooling down, concentrated to

~5 mL. CH2Cl2 (50 mL) and H2O (70 mL) were added and the layers separated. The

water layer was extracted with CH2Cl2 (3 x 30 mL) and the combined organic layers

was washed with water (70 mL) and brine (70 mL), dried over Na2SO4, filtered and the solvents were

removed at reduced pressure. The residue was purified by column chromatography (SiO2, CH2Cl2:MeOH =

95:5) to yield 5 (1.57 g, 5.06 mmol, 75 %) as a slight brown solid. m.p. 151.3–151.5 °C; 1H NMR

(300 MHz, CDCl3) δ 7.38–7.16 (m, 2H), 7.13–6.95 (m, 2H), 6.95–6.75 (m, 2H), 3.68 (s, 3H), 3.62 (s, 3H),

2.96–2.80 (m, 1H), 2.72–2.55 (m, 1H), 2.52–2.32 (m, 1H), 2.30–2.12 (m, 1H), 1.41 (dtd, J = 12.8, 9.3,

4.6 Hz, 1H), 1.15 (d, J = 6.9 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 155.9, 155.0, 151.0, 135.4, 133.6,

133.2, 127.3, 126.8, 126.6, 125.1, 119.7, 111.0, 109.9, 56.1, 55.0, 32.4, 29.6, 28.7, 16.7; HRMS (ESI, m/z):

calcd for C19H23N2O2 [M+H]+: 311.1754, found: 311.1752.

Dispiro[(7-methoxy-8-(2-methoxyphenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-1,2’-thiirane-3’,9’’-

9H-fluorene (8) and 9-(7-methoxy-8-(2-methoxyphenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-

ylidene)-9H-fluorene (9)

Under nitrogen, Lawesson‘s reagent (3.00 g, 7.40 mmol) was added to a stirred solution of 9-fluorenone

(2.00 g, 11.1 mmol) in dry toluene (50 mL). Three cycles of vacuum and nitrogen backfill were applied to

the reflux setup. The mixture was then heated at 85 ºC for approximately 2 h, until TLC analysis started

showing degradation (pentane:CH2Cl2 = 10:1, Rf product = 0.8, Rf decomposed product = 0.5, Rf substrate

= 0.15). The mixture was diluted with a solution of pentane:CH2Cl2 = 1:1 (70 mL) to precipitate most of the

Lawesson‘s reagent and filtered. The liquid fraction was concentrated under reduced pressure and the

residue was purified by a quick column chromatography (SiO2, pentane:CH2Cl2 = 10:1). The green fraction

was concentrated under reduced pressure to yield 9H-fluorene-9-thione 7 (1.150 g, 5.85 mmol) as dark

green needles (note: the purity of the thioketone appeared to significantly influence the outcome of the

following step; occasionally a second purification by flash column chromatography was required). Under


181

nitrogen, a solution of 5 (780 mg, 2.51 mmol) in dry DMF (25 mL) was cooled to -50 °C and a solution of

bis(trifluoroacetoxy)iodobenzene (1.19 g, 2.75 mmol, 1.1 equiv) in dry DMF (10 mL) was added to the

stirred solution. The reaction mixture was stirred for 1 min while the color was turning from yellow to dark

pink, indicating the in situ formation of the diazo compound 6. A solution of 7 (723 mg, 3.76 mmol, 1.5

equiv) in dry DMF (8 mL) and dry of CH2Cl2 (3 mL) was added to the mixture, which showed the release

of nitrogen bubbles. The mixture was allowed to warm to rt and stirred for 16 h. The mixture was diluted

with EtOAc (50 mL), washed with sat. aq. NH4Cl (60 mL), the organic layer was separated and the aqueous

layer was extracted with EtOAc (3 x 40 mL). The organic phases were collected, washed with water

(100 mL), brine (100 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure and

the crude product containing mixture of episulfide 8 and overcrowded alkene 9 was triturated with hot

EtOH:toluene ≈ 8:1 to yield 9 (778 mg, 1.76 mmol, 70%) as a light brown powder. The remaining residue

consisting mainly of 8 was converted to 9 as follows (note: when an impure fraction of thioketone 7 was

used, the conversion appeared to stop dramatically at the episulfide intermediate 8): to a solution of 8 in

toluene (10 mL/g) was added tris(dimethylamino)phosphine (2 equiv) and the mixture heated at 150 °C for

2–3 d in a pressure tube until full conversion was reached (monitored by TLC, pentane:EtOAc = 25:1). The

cooled mixture was concentrated under reduced pressure and triturated with EtOH:toluene ≈ 8:1 to yield

additional 9 (167 mg, 0.376 mmol, additional 15%). In case of failed precipitation or when a large amount

of impurities were still present, the residue was further purified by column chromatography (SiO2,

pentane:EtOAc = 25:1) providing 9 in variable yields. The various fractions of product 9 were collected

(984 mg, 2.133 mmol, 85%). Notably, product 9 was occasionally found to be composed of two distinct

conformers. The major conformer was isolated and fully characterized, while the minor conformer was

oberved in an impure fraction (large amount of leftover HMPT) after column chromatography. 1H NMR

spectra:

8 (mix of conformers): 1H NMR (400 MHz, CDCl3, 60:40 mixture of two atropisomers) δ 7.71 (d, J =

7.4 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.50–7.32 (m, 3H), 7.31–7.15 (m, 4.5H), 7.03 (t, J = 7.3 Hz, 1H),

7.00–6.94 (m, 1H), 6.92–6.82 (m, 1.5H), 6.81–6.73 (m, 2H), 3.82 (s, 1.8H), 3.73 (s, 1.8H), 3.71–2.66 (two

overlapped s, 2.4H), 2.88 (s, 1H), 2.94–2.78 (m, 1.5H), 2.05–1.95 (m, 1.15H), 1.70–1.55 (m, 2H), 1.38–

1.22 (m, 1.5 H), 1.16 (d, J = 6.9 Hz, 2.0H), 1.07 (d, J = 7.1 Hz, 1.2 H), 1.02–0.90 (m, 1H); 13

C NMR

(75 MHz, CDCl3, 60:40 mixture of two atropisomers) δ 156.9, 156.2, 154.3, 146.8, 145.2, 143.8, 142.6,

141.8, 141.5, 141.1, 140.5, 140.5, 140.0, 137.4, 136.7, 135.4, 134.4, 133.9, 129.3, 128.9, 128.8, 128.7,

128.4, 128.4, 128.2, 128.1, 127.6, 127.3, 127.1, 126.3, 126.2, 126.0, 125.9, 125.7, 125.1, 124.7, 124.0,

123.6, 120.5, 120.5, 120.0, 119.9, 119.3, 119.2, 118.7, 110.2, 110.1, 56.3, 54.7, 53.6, 37.1, 30.6, 28.4, 22.7;

HRMS (ESI, m/z): calcd for C32H29O2S [M+H]+: 477.1883, found: 477.1881.

9 (major conformer): m.p. 172–173 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 3H), 7.63 (d, J

= 6.9 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.26–7.13 (m, 3H), 7.06 (d, J = 8.2 Hz,

1H), 7.00–6.89 (m, 2H), 6.81 (dd, J = 7.6, 1.4 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 6.34 (t, J = 7.2 Hz, 1H),

3.96 (app. sext, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 2.68–2.52 (m, 1H), 2.40–2.24 (m, 2H), 1.29–

1.21 (m, 1H) 1.25 (d, J = 6.8 Hz, 3H); 13

C NMR (50 MHz, CDCl3) δ 156.9, 156.35, 146.9, 140.6, 139.9,

139.4, 139.1, 138.8, 134.4, 134.0, 132.6, 128.3, 127.6, 127.1, 126.9, 126.8, 126.7, 125.0, 124.7, 124.6,

119.6, 119.2, 119.0, 111.9, 109.7, 56.7, 55.2, 44.8, 35.9, 32.5, 28.7, 20.7; HRMS (ESI, m/z): calcd for

C32H29O2 [M+H]+: 445.2162, found: 445.2153.

9 (minor conformer): 1H NMR (200 MHz, CDCl3) δ 7.70 (dd, J = 5.9, 3.0 Hz, 1H), 7.52–7.45 (m, 1H),

7.35 (dt, J = 7.5, 1.0 Hz, 1H), 7.21–7.11 (m, 3H), 7.01 (ddd, J = 6.9, 3.8, 1.6 Hz, 2H), 6.93 (d, J = 8.2 Hz,

1H), 6.86–6.73 (m, 3H), 6.49 (td, J = 7.4, 1.1 Hz, 1H), 6.30 (dd, J = 8.2, 1.1 Hz, 1H), 4.00 (p, J = 7.0 Hz,

1H), 3.71 (s, 3H), 3.24 (s, 3H), 2.47 (q, J = 2.1 Hz, 1H), 2.36–2.13 (m, 2H), 1.39 (d, J = 6.9 Hz, 3H), 1.16–

0.97 (m, 1H).

Chapter 5

182

(±)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-tetrahydronaphthalen-2-ol

((R*,P*,Ra/Sa*)-1)

Compound (R*,P*,Ra/Sa*)-1 was prepared from 9 by modification of a previously

reported procedure.105

A Schlenk tube is charged with 9 (690 mg, 1.55 mmol),

sealed with a rubber septum and evacuated and backfilled with nitrogen three

times. A solution of MeMgI (3M in Et2O, 2.60 mL, 7.76 mmol, 5 equiv) was

injected through the septum with a syringe. To ensure optimal contact between

the reagents, the slurry was sonicated for few seconds. Keeping overpressure of

nitrogen, the septum was pierced with a needle and the Schlenk tube was heated

up to 80 °C over 1 h to gently evaporate the ether. Subsequently the Schlenk tube was sealed and heated at

165 °C over 5 h. The mixture was allowed to cool down to rt and the reaction was quenched first with ice

and then sat. aq. NH4Cl (20 mL). After addition of CH2Cl2 (20 mL), the aqueous layer was extracted with

CH2Cl2 (3 x 20 mL). The organic phases were collected, washed with water (80 mL) and brine (80 mL),

dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was

purified by column chromatography (SiO2, gradient pentane:EtOAc = 6:1) to yield racemic (R*,P*,Ra/Sa*)-

1 (540 mg, 1.30 mmol, 84%, 60:40 mixture of two atropisomers as observed by 1H NMR spectroscopy

analysis of a solution in CDCl3) as a yellow foam. m.p. 167–168 °C; 1H NMR (300 MHz, CDCl3, 60:40

mix. of two atropisomers) δ 7.83–7.76 (m, 1H), 7.71 (d, J = 7.4 Hz, 0.4H), 7.63 (dd, J = 6.8, 1.7 Hz, 0.4H),

7.60–7.55 (m, 1H), 7.50 (d, J = 7.5 Hz, 0.6H), 7.35–7.28 (m, 1.2H), 7.28–7.18 (m, 32.2H), 7.18–7.09 (m,

2H), 7.03–6.82 (m, 2H), 6.75 (dt, J = 7.9, 1.9 Hz, 0.8H), 6.72–6.61 (m, 1H), 6.58 (d, J = 7.9 Hz, 0.4H),

6.53 (dd, J = 8.1, 1.3 Hz, 0.6H), 6.42 (td, J = 7.5, 1.2 Hz, 0.4H), 5.56 (br s, 0.6H), 4.82 (br s, 0.4H), 4.77

(br s, 0.6H), 4.58 (br s, 0.4H), 4.18–3.88 (m, 1H), 2.74–2.61 (m, 1H), 2.49–2.26 (m, 2H), 1.53 (d, J =

6.9 Hz, 1.8H), 1.31 (d, J = 6.8 Hz, 1.2H), 1.39–1.18 (m, 1H); 13

C NMR (75 MHz, CDCl3, 60:40 mix. of

two atropisomers) δ 155.0, 153.6, 153.3, 153.1, 152.6, 152.5, 145.2, 144.8, 140.7, 140.5, 139.8, 139.6,

138.7, 138.7, 138.5, 138.4, 138.4, 135.90, 134.9, 134.7, 133.4, 131.5, 130.6, 129.5, 129.4, 128.6, 127.5,

127.5, 127.4, 127.4, 127.1, 127.0, 126.9, 126.5, 125.5, 124.9, 124.7, 124.5, 123.3, 123.2, 121.4, 121.0,

120.4, 119.7, 119.7, 119.4, 119.3, 117.8, 117.6, 117.0, 116.5, 115.8, 35.5, 35.2, 32.3, 31.9, 29.0, 28.5, 21.9,

21.0; 1H NMR (400 MHz, toluene-d8, 67:33 mix. of two atropisomers) δ 7.78 (d, J = 7.8 Hz, 0.8H), 7.72–

7.68 (m, 0.4H), 7.44–7.38 (m, 0.8H), 7.31 (dd, J = 15.5, 7.4 Hz, 0.4H), 7.17 (dd, J = 7.5, 2.0 Hz, 0.8H),

7.14–6.93 (m, 7.4H), 6.90 (dd, J = 7.5, 1.7 Hz, 0.4H), 6.83–6.78 (m, 0.6H), 6.73 (t, J = 7.6 Hz, 0.6H), 6.61–

6.54 (m, 0.4H), 6.53–6.40 (m, 2H), 6.18 (t, J = 7.4 Hz, 0.4H), 6.13 (dd, J = 7.7, 1.6 Hz, 0.6H), 5.69 (br s,

0.6H), 4.73 (br s, 0.4H), 4.62 (br s, 0.6H), 4.31 (br s, 0.4H), 3.94 (app. sext, J = 7.2 Hz, 0.6H), 3.85 (app.

sext, J = 7.1 Hz, 0.4H), 3.35–3.25 (m, 0.4H), 2.39–2.26 (m, 1.2H), 2.24–2.13 (m, 0.8H), 2.03–1.91 (m,

0.4H), 1.33 (d, J = 6.9 Hz, 1.8H), 1.22 (d, J = 7.0 Hz, 1.2H), 1.13–0.96 (m, 1H); note: a total amount of ca.

7.4H is expected to be hidden underneath the residual solvent signals of toluene-d8; 13

C NMR (150 MHz,

toluene-d8, 67:33 mix. of two atropisomers) δ 153.4, 153.2, 152.9, 144.7, 140.9, 140.1, 139.9, 139.8,

138.77, 138.7, 138.5, 135.4, 135.3, 134.1, 134.0, 133.5, 131.6, 130.3, 129.1, 128.5, 128.4, 127.6, 127.6,

127.4, 127.4, 127.3, 127.3, 126.9, 126.9, 126.8, 126.8, 126.6, 126.5, 124.7, 124.7, 124.6, 124.3, 124.0,

123.4, 120.6, 120.2, 120.1, 119.8, 119.5, 119.3, 118.0, 117.3, 116.5, 115.8, 35.5, 35.2, 32.1, 31.8, 30.3,

29.0, 28.3, 21.6; note: multiple peaks are expected to be hidden underneath the residual solvent signals of

toluene-d8; HRMS (ESI, m/z): calcd for C30H25O2 [M+H]+: 417.1849, found: 417.1850. Separation of the

enantiomers was achieved by CSP-HPLC (Chiralpak AD-H, heptane:2-propanol = 85:15, flow rate =

0.5 mL/min, column temperature = 40 °C, Rt: 12.3 min for (S,M,Ra/Sa)-1, 18.0 min for (R,P,Sa/Ra)-1.


183

Resolution of 8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-tetrahydronaphthalen-

2-ol ((+)-(R,P,Sa/Ra)-1 and (−)-(S,M,Ra/Sa)-1))

Note: the batch of EtOAc (analytical grade) used in the following

step was purified beforehand from traces of acids and bases by

flushing it through a column packed with neutral alumina

(bottom), acidic-active alumina (middle), basic-active alumina

(top). During this work it was observed that use of strong

inorganic bases (eg. NaOH, KOH) caused the decomposition of 1

into an unidentified red impurity with loss of the overcrowded

alkene moiety. Notably the decomposition was also occurring in

minor extent when a non-purified batch of EtOAc was used.

To a solution of (R*,P*,Sa/Ra*)-1 (380 mg, 0.91 mmol) in EtOAc (10 mL) was added (8S,9R)-(−)-N-

benzylcinchonidinium chloride 10 (176 mg, 0.46 mmol, 0.5 equiv).106–108

The reaction mixture was stirred

at rt overnight, affording a slurry of a white precipitate in a light yellow solution. The slurry was filtered on

a P4 glass fritted funnel under vacuum and the precipitate was washed three times with cold EtOAc. The

solution was evaporated under reduced pressure to yield an enantiomerically enriched mixture of

(R,P,Sa/Ra)-1 (230 mg, 55 mmol, 60%, 54% ee) as a yellow foam. The white solid was dissolved in CH2Cl2

(40 mL) and added to aq. 1M HCl (40 mL) and stirred vigorously over 1 h. The organic phase was

separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic phases were

collected, washed with NaHCO3 aq. (100 mL) and brine (100 mL), dried over Na2SO4, filtered and the

solvent evaporated under reduced pressure. The yellow residue was stripped over CHCl3 few times to yield

an enantiomerically enriched mixture of (S,M,Ra/Sa)-1 (150 mg, 36 mmol, 40%, 94% ee) as a yellow foam.

The procedure was repeated on an enantioenriched fraction of (S,M,Ra/Sa)-1 (94% ee, 290 mg, 70 mmol)

with 10 (290 mg, 70 mmol, 1.0 equiv) in EtOAc (10 mL) to yield pure (−)-(S,M,Ra/Sa)-1 (230 mg,

55 mmol, 79%, >99% ee) from the solid fraction as previously described.

The procedure was repeated on an enantioenriched fraction of (R,P,Sa/Ra)-1 (54% ee, 1.02 g, 2.46 mmol)

with 10 (310 mg, 74 mmol, 0.3 equiv) in EtOAc (10 mL) to yield (R,P,Sa/Ra)-1 (800 mg, 1.92 mmol, 78%,

81% ee) from the solution as previously described. After removal of the volatiles under reduced pressure,

the residue was recrystallized from EtOH:water ~1:1 to yield highly enriched (R,P,Sa/Ra)-1 (150 mg,

0.36 mmol, 15%, 96% ee) as a light brown powder. The mother liquor was recovered, purified by flash

column chromatography (SiO2, pentane:EtOAc = 6:1) if minor impurities were present, combined with

other scalemic batches and resubmitted to further resolution.

The data were identical in all respects to those previously reported for (R*,P*,Sa/Ra*)-1. [ ] +27.60 (c

0.544, MeOH) for (R,P,Sa/Ra)-1 (96% ee).

During an attempt to purify (R,P,Sa/Ra)-1 (80% ee) from minor impurities by flash column chromatography

(SiO2, pentane:EtOAc = 20:1) few particularly concentrated fractions were left to evaporate slowly over

night. Yellow monocrystals of enantiomerically and conformationally pure (R,P,Sa)-1 were obtained and

analyzed by X-ray crystallography (see X-ray crystallography section for further details), which allowed to

assign the relative and absolute configuration of the stereogenic center.

Chapter 5

184

Final recrystallization from EtOH:water ~1:1: (+)-(R,P,Sa/Ra)-1, 96% ee

2nd

resolution cycle, precipitate: (−)-(S,M,Ra/Sa)-1, >99% ee

5.5.3 X-ray Crystallography

A single crystal of compound (R,P,Sa)-1 was mounted on top of a cryoloop and transferred into the cold

nitrogen stream (100 K) of a Bruker-AXS D8 Venture diffractometer. A high-brilliance Cu IμS microfocus

source was used (Cu Kα radiation wavelength = 1.54178 Å). The collection strategy was chosen such that

high data multiplicity (average 9.4 for data up to 0.80 Å resolution) was achieved in order to be able to


185

determine the absolute configuration in the absence of atoms that show significant anomalous scattering.

Data collection and reduction was done using the Bruker software suite APEX2.109

The final unit cell was

obtained from the xyz centroids of 9682 reflections after integration. A multiscan absorption correction was

applied, based on the intensities of symmetry-related reflections measured at different angular settings

(SADABS).109

The structures were solved by direct methods using SHELXT, 63

and refinement of the

structure was performed using SHLELXL.64

The hydrogen atoms were generated by geometrical

considerations, constrained to idealized geometries and allowed to ride on their carrier atoms with an

isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms.

Refinement of the Flack x parameter converged at 0.00(7) for the enantiomer with R stereochemistry at

C(15); the Bijvoet-Pair analysis65

implemented in PLATON (based on Bayesian statistics) is consistent

with this being the correct enantiomer (P2(true) = 1.000; P3(true) = 1.000; Hooft y = -0.01(7) based on

1927 Friedel pairs). Crystal data and details on data collection and refinement are presented in Table 5.5.

Ball-and-stick models (front view and top view, see main text, Figure 5.3) were obtained from the analysis

of the crystallographic data with Mercury v. 3.7.

Table 5.5. Crystallographic data for (R,P,Sa)-1.

5.5.4 1H NMR spectroscopy coalescence experiments.

The sample was prepared by dissolving stable isomers (R,P,Sa/Ra)-1 (~5.0 mg) in toluene-d8 (0.7 mL) in a

Schlenk tube under argon. The sample was freeze-thawed three times to remove any traces of oxygen and

transferred into an NMR tube. 1H NMR spectra were collected at with 300 MHz spectrometer at 50, 55, 60,

65, 70, 75, 80, 85, 90, 95, and 100 ºC. No clear coalescence of the diagnostic peaks was observed at the

tested temperature range.

5.5.5 Exchange spectroscopy measurements (EXSY)

The sample was prepared by dissolving stable isomers (R,P,Sa/Ra)-1 (~10.0 mg) in toluene-d8 (0.7 mL) in a

Schlenk tube under argon. The sample was freeze-thawed three times to remove any traces of oxygen and

transferred into an NMR tube. One-dimensional phase-sensitive 1H-

1H nuclear Overhauser enhancement

spectra (1D-NOESY)72

for NMR exchange experiments were collected at 500 MHz by exciting the sample

with an impulse with frequency range corresponding to the absorption at δ 7.78 ppm and using the

following acquisition parameters: π/2 pulse width, 8.33 µs; spectral width, 6.000 Hz; data size, 32 K;

recycling delay, 4 s; number of transients, 32; acquisition time, 2.048 s; steady-state, 8; scans, 64. The

measurements were conducted at 39.17, 44.85, 49.30, 54.43, and 60.86 ºC (respectively, 312.32, 318.00,

chem formula C30 H24 O2 temp (K) 100(2)

Mr 416.49 range (deg) 4.083 – 74.690

cryst syst orthorhombic data collected (h,k,l) -9:11, -19:19, -19:19

color, habit yellow, block no. of rflns collected 36326

size (mm) 0.20 x 0.18 x 0.14 no. of indpndt reflns 4475

space group P2(1)2(1)2(1) observed reflns 4304 (Fo 2 (Fo))

a (Å) 9.3230(4) R(F) (%) 2.99

b (Å) 15.2792(6) wR(F2) (%) 7.28

c (Å) 15.3454(6) GooF 1.094

V (Å3) 2185.92(15) Weighting a,b 0.0369, 0.4027

Z 4 params refined 298

calc, g.cm-3

1.266 Flack x 0.00(7)

µ(Cu K ), cm-1

0.608 restraints 0

F(000) 880 min, max resid dens -0.177, 0.135

Chapter 5

186

322.45, 327.58, 334.01 K) consisting of an arrayed cluster of mixing times (tm= 0.10, 0.20, 0.30, 0.40, 0.50,

0.65, 0.80, 0.95, 1.10, 1.30, 1.50, 1.70, and 2.00 s) per temperature.69,110

5.5.6 Irradiation experiments: characterization and monitoring by UV-vis and CD spectroscopy,

determination of PSS mixtures ratios by CSP-HPLC

The irradiation experiments were performed as follows (for UV-vis absorption and CD spectra, see main

text, Figure 5.13). A solution of stable isomers (R,P,Sa/Ra)-1 (96% ee, toluene, 5.8·10-5

M) was transferred

in a fluorescence quartz cuvette with a magnetic stirrer and degassed with argon under stirring for 10 min.

The forward and backward irradiation process from the stable isomer towards the metastable isomer was

monitored by UV-vis absorption spectroscopy in a time-course measurement (wavelength range 300–

650 nm, scan periods of 20 s). After starting the acquisition, the sample was irradiated under stirring with

the proper LED source perpendicularly to the analysis path of the spectrophotometer (5 min at 365 nm,

10 min at 420 nm). To ensure that the PSS was reached, irradiations were continued until no further

changes in the absorption spectra were observed; five cycles of forward and backward irradiation were

performed sequentially on the same sample. A gradual decrease of the absorbance over multiple irradiation

cycles was observed, suggesting switching fatigue suffered by 1 (Figure 5.14).

Figure 5.14. Irradiation cycles of (R)-1 (toluene, ~6.0·10−5

M) towards opposite PSS mixtures (red:

365 nm, 4 min; blue: 420 nm, 15 min).

The same experiment was subsequently performed on a solution of (R)-1 (toluene, ~4.0·10−5

M) containing

a substoichiometric amount of TEMPO (~10−5

M), which resulted in no evidence of degradation even after

six irradiation cycles (see Figure 5.13). CD spectra were recorded for the starting solution of stable isomers

(R,P,Sa/Ra)-1 (96% ee, toluene, 5.8·10-5

M) and after reaching the PSS at 365 nm and 420 nm (mixture of

stable isomers (R,P,Sa/Ra)-1 and metastable isomers (R,M,Ra/Sa)-1; for ratios vide infra, first irradiation

cycle).

Chiral HPLC analysis of each irradiation stages of (R,P,Sa/Ra)-1 afforded the composition of each PSS

mixture (365 nm and 420 nm, first irradiation cycles) in toluene. Quantitative analysis was achieved by

setting the PDA detector of the HPCL at the isosbestic point λ = 368 nm as previously determined by the

UV-vis abs. analysis. Analysis was performed on CSP-HPLC: Chiralpak AD-H, heptane:2-propanol =

85:15, flow rate = 0.5 mL/min, column temperature = 40 °C, Rt: 15.5 min for metastable isomers

(R,M,Ra/Sa)-1 (broad peak spread over 1-3 min, depending on sample concentration), 18.4 min for stable

isomers (R,P,Sa/Ra)-1. Similarly, analysis of solutions of (S,M,Ra/Sa)-1 was performed on CSP-HPLC with

identical conditions: Chiralpak AD-H, heptane:2-propanol = 85:15, flow rate = 0.5 mL/min, column

temperature = 40 °C, Rt: 12.7 min for stable isomers (S,M,Ra/Sa)-1, 28 min for metastable isomers

(S,P,Sa/Ra)-1 (very broad peak spread over 5-10 min, depending on sample concentration). HPLC analysis

of the irradiated mixture displayed the appearance of a new eluted band having a PDA profile consistent


187

with the data obtained by UV-vis abs spectroscopy. Notably, the profile of new eluted band is symmetric

and very large, stretched over the span of ca. 10 min during the analytical HPLC run. Minor decomposition

suggested by emerging unidentified peaks was observed by HPLC analysis after irradiation of the samples

for prolonged time both at 365 and 420 nm.

Note: due to the low barrier for rotation of the biaryl core, no separation of the atropisomers was observed

by HPLC analysis. Each pair of atropisomers (e.g. (R,P,Sa)-1 and (R,P,Ra)-1), is eluted as a single

symmetrical peak in the chromatogram. Attempts to lower the temperature of the column (down to 0 °C) in

order to achieve Dynamic HPLC76–78,111,112

and allowing the investigation of possible stereomutation

processes did not lead to any change in the shape of the chromatograms. See EXSY experiments for

determination of energy barrier of biary inversion.

Stable isomers (R,P,Sa/Ra)-1, 96% ee

PSS365 mixture of stable isomers (R,P,Sa/Ra)-1 : metastable isomers (R,M,Ra/Sa)-1 = 17 : 83

PSS420 mixture of stable isomers (R,P,Sa/Ra)-1 : metastable isomers (R,M,Ra/Sa)-1 = 50 : 50

Chapter 5

188

5.5.7 Irradiation experiments: monitoring of isomerization, characterization of metastable isomers

(R,M,Ra/Sa)-1 by 1H NMR

(R,P,Sa/Ra)-1 (~5.0 mg) was dissolved in toluene-d8 (0.7 mL). The sample was placed in an NMR tube and

irradiated (365 nm) at a distance of 3 cm from the center of the lamp for 30 min, with periodic mixing of

the solution to facilitate diffusion. 1H NMR spectra of the sample were taken before, during and after

irradiation at rt. The irradiation was not continued after 30 min in order to avoid decomposition of the

sample and emergence of secondary peaks. The relative integration of the absorptions peaks of the two

isomers revealed a photostationary state ratio in toluene-d8 at 365 nm of stable isomers (R,P,Sa/Ra)-1 :

metastable isomers (R,M,Ra/Sa)-1 = 35:65. 1H and COSY NMR spectra of PSS365 mixtures are displayed in

Figure 5.15. For stacked 1H NMR spectra of the solution before and after irradiation with assignment of

distinctive absorptions, see Figure 5.12. For corresponding UV-vis and CD spectra, see Figure 5.13. See

following section for characterization of isolated metastable state.


189

Figure 5.15. 1H NMR spectra (toluene-d8) of stable isomers (R,P,Sa/Ra)-1 after 30 min of irradiation with

365 nm UV light, affording a mixture in toluene-d8 of stable isomers (R,P,Sa/Ra)-1 : metastable isomers

(R,M,Ra/Sa)-1 = 35 : 65 (note: overall summed quantities of atropisomers mixtures for each state).

5.5.8 Isolation of metastable isomers (R,M,Ra/Sa)-1 by preparative HPLC and characterization by

NMR spectroscopy.

A Schlenk tube equipped with a stirring bar was charged with stable isomers (R,P,Sa/Ra)-1 (21 mg,

0.05 mmol). The Schlenk tube was connected to a vacuum/nitrogen line and evacuated and backfilled three

times. Dry Et2O (15 mL) was added and the solution was purged with Argon under stirring for 10 min at -

20°C. The solution was irradiated with 365 nm light to PSS over 30 min under stirring at rt. A jet of air on

the outer surface of the Schlenk tube was used to avoid heating from the UV-light source during the

irradiation (a yellow precipitate was otherwise observed). The solvent was evaporated under reduced

pressure and the residue was re-dissolved in heptane:2-propanol = 85:15 (1.5 mL). Separation of the

metastable isomers (~4 mg) was achieved by CSP-HPLC: Chiralpak AD-H, heptane:2-propanol = 90:10,

flow rate = 0.5 mL/min, column temperature = 40 °C, injection volume per run = 100 µL, Rt: 21.3 min for

metastable isomers (R,M,Ra/Sa)-1, 27.7 min for stable isomers (R,P,Sa/Ra)-1.

Stable isomers (R,P,Ra/Sa)-1: 1

H NMR (400 MHz, toluene-d8, 67:33 mix. of two atropoisomers) δ 7.78 (d,

J = 7.8 Hz, 0.8H), 7.72–7.68 (m, 0.4H), 7.44–7.38 (m, 0.8H), 7.31 (dd, J = 15.5, 7.4 Hz, 0.4H), 7.17 (dd, J

= 7.5, 2.0 Hz, 0.8H), 7.14–6.93 (m, 7.4H), 6.90 (dd, J = 7.5, 1.7 Hz, 0.4H), 6.83–6.78 (m, 0.6H), 6.73 (t, J

= 7.6 Hz, 0.6H), 6.61–6.54 (m, 0.4H), 6.53–6.40 (m, 2H), 6.18 (t, J = 7.4 Hz, 0.4H), 6.13 (dd, J = 7.7,

1.6 Hz,0.6H), 5.69 (br s, 0.6H), 4.73 (br s, 0.4H), 4.62 (br s, 0.6H), 4.31 (br s, 0.4H), 3.94 (app. sext, J =

7.2 Hz, 0.6H), 3.85 (app. sext, J = 7.1 Hz, 0.4H), 3.35–3.25 (m, 0.4H), 2.39–2.26 (m, 1.2H), 2.24–2.13 (m,

0.8H), 2.03–1.91 (m, 0.4H), 1.33 (d, J = 6.9 Hz, 1.8H), 1.22 (d, J = 7.0 Hz, 1.2H), 1.13–0.96 (m, 1H); note:

a total amount of ca. 7.4H is expected to be hidden underneath the solvent signals of toluene-d8.

Metastable isomers (R,M,Ra/Sa)-1: 1H NMR (400 MHz, toluene-d8, 55:45 mixture of two atropisomers) δ

7.69 (d, J = 7.8 Hz, 1.3H), 7.54 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.6 Hz, 4H), 7.16–7.14 (m, 2H), 7.05–6.93

(m, 7H), 6.83 (t, 1.4H), 6.72 (dd, J = 7.3, 2.0 Hz, 0.8H), 6.63 (t, 0.9H), 6.57–6.43 (m, 4.5H), 6.37–6.32 (m,

2H), 6.25 (t, J = 7.5, 1.2 Hz, 1.3H), 5.13 (s, 1H), 4.33 (s, 1H), 3.82 (p, J = 6.7 Hz, 1H), 3.42 (s, 0.8H), 2.73–

Chapter 5

190

2.59 (m, 2.3H), 2.48–2.31 (m, 2.9H), 2.27 (d, J = 8.9 Hz, 0.91H), 1.66–1.58 (m, 3H), 1.49 –1.34 (m, 4H),

1.29 (d, J = 6.7, 3H), 1.29 (d, J = 6.7, 4H), 1.06–0.91 (m, 4H); note: due to the presence of two

atropisomers in an apparent ~55:45 ratio and presence of several overlapped absorption peaks, the

integrals of the signals corresponding to the absorption peaks of the products do not indicated the absolute

values but merely the experimental relative ratio; 13

C NMR (100 MHz, toluene-d8, 55:45 mixture of two

atropisomers) δ 156.3, 156.0, 155.1, 155.0, 148.7, 146.3, 144.2, 143.1, 142.6, 142.2, 142.1, 141.7, 141.1,

136.7, 136.5, 132.5, 129.6, 129.4, 129.3, 129.2, 129.1, 128.9, 128.9, 128.1, 127.9, 127.9, 126.6, 126.0,

126.0, 123.9, 123.8, 122.9, 122.5, 122.1, 121.6, 121.5, 121.4, 120.8, 119.9, 118.3, 36.7, 35.0, 34.5, 34.5,

32.7, 29.9, 29.6; note: due to the limited amount of isolated compound, the intensity of the signals

corresponding to the product peaks were affected by the strong intensity of the absorption peaks of the

solvent residue of toluene-d8 and multiple unidentified peaks of the product are likely to be hidden

underneath the solvent peaks. Analysis was performed on CSP-HPLC: Chiralpak AD-H, heptane:2-

propanol = 85:15, flow rate = 0.5 mL/min, column temperature = 40 °C, Rt: 15.5 min for metastable

isomers (R,M,Ra/Sa)-1.

5.5.9 General procedures for enantioselective additions of dialkylzinc to aldehydes

General procedure for the catalyzed addition of dialkylzinc to aldehydes with stable isomers

(R,P,Sa/Ra)-1 (main manuscript, Table 5.1, odd number entries 1-13)

A Schlenk tube equipped with a stirring bar was charged with (R,P,Sa/Ra)-1 (5.21 mg, 0.013 mmol, 0.1

equiv). The Schlenk tube was connected to a vacuum/nitrogen line, evacuated and backfilled three times.

Dry toluene (0.5 mL) was added and the solution was stirred at 0 °C for 5 min. A solution of dialkylzinc

(Et2Zn, 1.0 M in hexane; i-Pr2Zn, 1.0 M in toluene; 0.375 mL, 0.375 mmol, 3 equiv) was added dropwise at

this temperature and the solution was stirred over 10 min. The selected aldehyde 11 (0.125 mmol, 1 equiv)

was added dropwise. The reaction mixture was stirred at 0 °C for 7 d. The progress of the reaction was

monitored by GC-MS analysis by withdrawing aliquots and quenching in an Et2O:MeOH = 3:1 solution.

Aq. 1M HCl (3 mL) was added at 0 °C and the aqueous layer was extracted with Et2O (3 x 3 mL). The

combined organic layer was washed with brine, dried over anhydrous MgSO4 and filtered. After removal of

the solvent, the crude mixture was analyzed by 1H NMR spectroscopy to measure conversion and

selectivity (1,2-addition vs. reduction products). The residue was then purified by quick column

chromatography (SiO2, pentane:Et2O = 10:1 to 5:1) to yield the secondary alcohols 12 as colorless liquids.

The mixture was further eluted (pentane:Et2O = 2:1) to recover 1. The ee values of the secondary alcohols

were determined by Chiral HPLC or Chiral GC analysis. The absolute configuration of major enantiomer of

the alcohols 12 was assigned as (R) by comparison of the sign of the optical rotation with reported

data.103,113,114

General procedure for the catalyzed addition of dialkylzinc to aldehydes with irradiated mixture of

(R,P,Sa/Ra)-1 (Table 5.2, even number entries 2-14)

A Schlenk tube equipped with a stirring bar was charged with (R,P,Sa/Ra)-1 (5.21 mg, 0.013 mmol, 0.1

equiv),connected to a vacuum/nitrogen line, evacuated and backfilled three times. Dry Et2O (15 mL) was

added and the solution was purged with nitrogen under stirring for 10 min at -20°C. The solution was

irradiated with 365 nm UV-light to PSS over 30 min under stirring at rt (PSS ratio was measured by HPLC

analysis after irradiation). A jet of air on the outer surface of the Schlenk tube was used to avoid heating

from the UV-light source during the irradiation. The ether was evaporated under reduced pressure and the

residue was re-dissolved in dry toluene (0.5 mL). The solution was stirred at 0 °C for 5 min. The procedure

follows with addition of dialkylzinc and aldehyde, stirring over 7 d, work up, purification and analysis

according to the methodology described above. The absolute configuration of major enantiomer of the

alcohols 12 was assigned as (S) by comparison of the sign of the optical rotation with reported data.103,113,114


191

Procedure for the addition of diethylzinc to benzaldehyde without (R,P,Ra/Sa)-1 (entry 15, Table 5.1).

The Schlenk tube was connected to a vacuum/nitrogen line, then evacuated and backfilled three times. Dry

toluene (0.5 mL) and a solution of diethylzinc (1.0 M in hexanes, 0.375 mL, 0.375 mmol, 3 equiv) were

added dropwise at 0 °C. After stirring for 5 min, benzaldehyde 11a (13 mg, 0.125 mmol, 13 µL, 1 equiv)

was added dropwise to the solution. The procedure follows with work up, purification and analysis

according to the methodology described above. The isolated yield was not determined.

General procedure for preparation of racemic mixtures of secondary alcohols for Chiral HPLC and

GC analysis

The Schlenk tube was connected to a vacuum/nitrogen line, evacuated and backfilled three times and

charged with dry Et2O (2 mL) and aldehyde 11 (0.5 mmol, 1 equiv). The solution was cooled to 0 °C. A

solution of ethyl magnesium bromide (3.0 M in Et2O, 0.22 mL, 0.65 mmol, 1.3 equiv) was added dropwise

and the reaction mixture was stirred for 1 h. Aq. 1M HCl (3 mL) was added and the aqueous layer was

extracted with Et2O (3 x 3 mL). The combined organic layer was washed with brine, dried over anhydrous

MgSO4 and filtered. After removal of the solvent, the residue was then purified by a quick column

chromatography (SiO2, pentane:Et2O = 10:1 to 5:1) to yield the secondary alcohols 12 as colorless liquids.

Catalytic tests with tetrabutylammonium bromide and related comments

Song and co-workers demonstrated the significant synergistic effect of achiral quaternary ammonium salts

on chiral phosphoramide catalyzed asymmetric additions of diethylzinc to aldehydes, allowing to maintain

high catalytic efficiency in the presence of 10 mol% of Bu4NBr and only 0.5 mol% of chiral

phosphoramide.103

In an attempt to improve catalytic activity, screening of variable loading amount of

stable isomers (R,P,Sa/Ra)-1 (1, 3 and 10 mol%) in presence of 10 mol% of Bu4NBr resulted in a dramatic

increase of the reaction rate and selectivity, with full conversion reached within 16 h (Table 5.6). However,

the enantioselectivity was completely lost. By comparison with the reaction performed in the presence of

only the ammonium salt (entry 15), it clearly shows how this additive could be responsible for a competing

fast background reaction with loss of control from the chiral ligand (R,P,Sa/Ra)-1.

Table 5.6. Catalysis test for synergistic effect of achiral quaternary ammonium salts with (R)-1 in

enantioselective addition of diethylzinc to benzaldehyde.

Entrya

Loading of (R)-1

(mol%) Conv. of 11a (%)

b Yield of 12 (%)

c ee of 12 (%)

c 12:13

b

1e 1 >95 N.D. <5 (±)-12a >98:2

2e 3 >95 N.D. <5 (±)-12a >98:2

3e 10 >95 N.D. <5 (±)-12a >98:2

4e 0 >95 N.D. N.A. >98:2

General reaction conditions: (R,P,Sa/Ra)-1 (loading reported in table) and NBu4Br (4.03 mg, 0.013 mmol)

in 0.5 mL of dry toluene cooled at 0 °C; 0.375 mmol of R2Zn (Et2Zn, 1.0 M sol. in hexane; iPr2Zn, 1.0 M

sol. in toluene) added dropwise and stirred over 10 min; 0.125 mmol of 11 added to mixture. Reaction

mixture stirred for 7 days at 0 °C. Conversion monitored by GC-MS analysis. b Determined by GC-MS and

1H NMR analysis of crude after quenching.

c Isolated yield.

e Full conversion reached after 16 h.

Abbreviations: N.A., Not Applicable; N.D., Not Determined.

Chapter 5

192

General procedure for the catalyzed addition of diethylzinc to benzaldehyde with (R,P,Sa/Ra)-1 and

tetrabutylammonium bromide (entries 16-18, Table 5.4)

A Schlenk tube equipped with a stirring bar was charged with stable isomers (R,P,Sa/Ra)-1 (catalyst loading

ranging from 0.01 eq to 0.1 eq: a) 0.52 mg, 0.001 mmol, 0.01 eq; b) 1.56 mg, 0.0038 mmol, 0.03 eq; c)

5.21 mg, 0.013 mmol, 0.1 equiv) and tetrabutylammonium bromide (4.03 mg, 0.013 mmol, 0.1 equiv). The

Schlenk tube was connected to a vacuum/nitrogen line, evacuated and backfilled three times. Dry toluene

(0.5 mL) was added and the solution was stirred at 0 °C for 5 min. The procedure follows with addition of

dialkylzinc and aldehyde, stirring over 16 h, work up, purification and analysis according to the

methodology described above. Racemic product was obtained in all cases.

Catalyst recovery and analysis after catalytic reaction

After isolation of the secondary alcohols by column chromatography, the residue was further eluted

(pentane:Et2O = 2:1) to recover the catalyst (R)-1. Under the reaction conditions no decomposition,

racemization or significant thermal relaxation of the recovered catalyst (90% average catalyst recovery)

was observed, as determined by 1H NMR and chiral HPLC analysis.

5.5.10 Characterization data for compounds 12a-12f

1-Phenylpropanol (12a, entries 1-2 in Table 5.4)

Reaction conducted with non-irradiated (R)-1 (entry 1 in Table 5.4): 12a:13a = 93:7,

86% yield, 68% ee (R).

Reaction conducted with irradiated mixture (365 nm) of (R)-1 (entry 2 in Table 5.4):

12a:13a = 93:7, 87% yield, 45% ee (S).

Colorless oil. The ee value was determined by CSP-HPLC analysis: Chiralcel OD-H, heptane:2-propanol =

90:10, flow rate = 0.5 mL/min, column temperature = 40 °C, Rt: 10.7 min for (R), 11.2 min for (S). [ ] =

+14.8 (c 1.00, CHCl3) for 68% ee (R) [Lit.103

[ ] = +20.3 (c 1.00, CHCl3) for 93% ee (R)].

1H NMR

(400 MHz, CDCl3) δ 7.46–7.22 (m, 1H), 4.63 (t, J = 6.6 Hz, 0H), 1.96–1.68 (m, 1H), 0.95 (t, J = 7.4 Hz,

1H); 13

C NMR (75 MHz, CDCl3) δ 144.5, 128.3, 127.4, 125.9, 75.9, 31.8, 10.1; HRMS (ESI, m/z): calcd

for C9H11 [M-H2O]+: 119.0855, found: 119.0852.

1-(4-Chlorophenyl)propanol (12b)

Reaction conducted with non-irradiated (R)-1 (entry 3 in Table 5.4): 12b:13b = 81:19,

80% yield, 35% ee (R).


12b:13b = 81:19, 80% yield, 24% ee (S).

Colorless oil. The ee value was determined by Chiral GC: CP-Chirasil-Dex-CB, 25m x 0.25mm, He-flow

1.0 mL/min, column temperature: 40 °C, gradient 10 °C/min to 140 °C, hold 140 °C, Rt: 26.3 min for (R),

28.1 min for (S). [ ] = +16.8 (c 1.00, CHCl3) for 26% ee (R) [Lit.

113 [ ]

= +22.0 (c 0.52, CHCl3) for

68% ee (R)]. 1H NMR (400 MHz, CDCl3) δ 7.40–7.19 (m, 1H), 4.58 (t, J = 6.6 Hz, 0H), 1.83–1.65 (m, 0H),

0.90 (t, J = 7.4 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 143.0, 133.1, 128.5, 127.3, 127.3, 75.3, 31.9, 10.0;

HRMS (ESI, m/z): calcd for C9H10Cl [M-H2O]+: 153.0466, found: 153.0466.

1-p-Tolylpropanol (12c)

Reaction conducted with non-irradiated (R)-1 (entry 5 in Table 5.4): 12c:13c = 89:11,

87% yield, 40% ee (R).


12c:13c = 88:12, 86% yield, 42% ee (S).


193

Colorless oil. The ee value was determined by CSP-HPLC analysis: Chiralcel OB-H, heptane:2-propanol =

98:2, flow rate = 0.5 mL/min, column temperature = 40 °C, Rt: 18.6 min for (S), 22.8 min for (R). [ ] =

+14.5 (c 1.00, CHCl3) for 40% ee (R) [Lit.114

[ ] = +37.2 (c 1.00, CHCl3) for 85% ee (R)].

1H NMR

(400 MHz, CDCl3) δ 7.23 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 4.56 (t, J = 6.6 Hz, 1H), 2.35 (s,

3H), 1.90–1.62 (m, 3H), 0.91 (t, J = 7.4 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 141.6, 137.1, 129.1,

125.9, 75.9, 31.8, 21.1, 10.2; HRMS (ESI, m/z): calcd for C10H13 [M-H2O]+: 133.1012, found: 133.1013.

1-(4-Methoxyphenyl)propanol (12d)

Reaction conducted with non-irradiated (R)-1 (entry 7 in Table 5.4): 12d:13d =

62:38, 37% yield, 40% ee (R).


12d:13d = 97:3, 76% yield, 55% ee (S).



+30.8 (c 1.00, CHCl3) for 40% ee (R) [Lit.113

[ ] = +22.7 (c 0.59, CHCl3) for 50% ee (R)].

1H NMR

(300 MHz, CDCl3) δ 7.39–7.19 (m, 3H), 6.97 (t, 1H), 6.89 (d, J = 8.2 Hz, 1H), 4.79 (t, J = 6.7 Hz, 1H),

3.86 (s, 3H), 1.91–1.75 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 156.6, 132.3,

128.2, 127.1, 120.7, 110.5, 72.5, 55.3, 55.2, 30.12, 10.5; HRMS (ESI, m/z): calcd for C10H13O [M-H2O]+:

149.0961, found: 149.0958.

1-o-Tolylpropanol (12e)

Reaction conducted with non-irradiated (R)-1 (entry 9 in Table 5.4): 12e:13e = 63:37, 58%

yield, 48% ee (R).


12d:13d = 85:15, 79% yield, 50% ee (S).

Colorless oil. The ee value was determined by CSP-HPLC analysis: Chiralpak AD-H, heptane:2-propanol =


+51.9 (c 1.00, CHCl3) for 48% ee (R) [Lit.113

[ ] = +40.3 (c 0.51, CHCl3) for 73% ee (R)].

1H NMR

(300 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 1H), 7.25–7.10 (m, 3H), 4.87 (t, J = 6.4 Hz, 1H), 2.35 (s, 3H),

1.87–1.65 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 156.6, 132.3, 128.2, 127.1,

120.7, 110.5, 72.5, 55.2, 30.1, 10.5; HRMS (ESI, m/z): calcd for C10H13 [M-H2O]+: 133.1012, found:

133.1009.

1-(2-Methoxyphenyl)propanol (12f)

Reaction conducted with non-irradiated (R)-1 (entry 11 in Table 5.4): 12f:13f = 89:11, 81%

yield, 46% ee (R).


12f:13f = 83:17, 72% yield, 31% ee (S).

Colorless oil. The ee value was determined by CSP-HPLC analysis: Chiralpak AD-H, heptane:2-propanol =


+18.1 (c 1.00, CHCl3) for 46% ee (R) [Lit.113

[ ] = +13.2 (c 0.50, CHCl3) for 67% ee (R)].

1H NMR

(300 MHz, CDCl3) δ 7.36–7.17 (m, 3H), 6.96 (t, 1H), 6.89 (d, J = 8.2 Hz, 1H), 4.79 (t, J = 6.7 Hz, 1H),

3.85 (s, 3H), 1.88–1.76 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 142.7, 134.6,

130.3, 127.1, 126.2, 125.2, 72.1, 30.9, 19.1, 10.4.; HRMS (ESI, m/z): calcd for C10H13O [M-H2O]+:

149.0961, found: 149.0960.

Chapter 5

194

2-Methyl-1-phenylpropan-1-ol (12g)

Reaction conducted with non-irradiated (R)-1 (entry 13 in Table 5.4): 12g:13g = 41:59,

40% yield, racemic mixture.


12g:13g = 58:42, 57% yield, racemic mixture.


98:2, flow rate = 0.5 mL/min, column temperature = 40 °C, Rt: 25.1 min for (1st en.), 26.7 min for (2

nd en.).

1H NMR (300 MHz, CDCl3) δ 7.42–7.22 (m, 5H), 4.37 (d, J = 6.9 Hz, 1H), 1.97 (h, J = 6.8 Hz, 1H), 1.01

(d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H). 13

C NMR (75 MHz, CDCl3) δ 143.6, 128.2, 127.4, 126.5,

35.3, 19.0, 18.2; HRMS (ESI, m/z): calcd for C10H13 [M-H2O]+: 133.1012, found: 133.1011.

5.6 References

(1) Eliel, E. L.; Wilen, S. H. Stereochemistry of organic compounds; Wiley: New York, 1994.


(3) Blackmond, D. G. Cold Spring Harbor perspectives in biology. Cold Spring Harbor Laboratory Press

May 2010, p a002147.



(5) Timsit, Y.; Youri. Int. J. Mol. Sci. 2013, 14, 8252–8270.

(6) Boyer, P. D. Nature 1999, 402, 247–249.

(7) Murata, S.; Yashiroda, H.; Tanaka, K. Nat. Rev. Mol. Cell Biol. 2009, 10, 104–115.

(8) Ramakrishnan, V. Cell 2002, 108, 557–572.

(9) Lodish, H.; Berk, A.; Zipursky, S. L.; Matsudaira, P.; Baltimore, D.; Darnell, J. In Molecular Cell

Biology. 4th edition, Section 18.3; W. H. Freeman: New York, 2000.

(10) Berg, J.; Tymoczko, J.; Stryer, L. In Biochemistry. 5th edition, Section 34.3; W H Freeman: New York,

2002.

(11) Berg, H. C.; Anderson, R. A. Nature 1973, 245, 380–382.

(12) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew.

Chemie Int. Ed. 2005, 44, 5384–5427.

(13) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2010, 111, 563–639.

(14) Rickhaus, M.; Mayor, M.; Juríček, M. Chem. Soc. Rev. 2016, 45, 1542–1556.

(15) Bolm, C.; Muñiz, K. Chem. Soc. Rev. 1999, 28, 51–59.

(16) Sokolov, V. I. Chirality and Optical Activity in Organometallic Compounds; Gordon and Breach Science

Publishers: New York, 1990.

(17) Mislow, K. Introduction to Stereochemistry; Dover Publications: Dover, 2003.

(18) Wells, N. C. Jounal Nat. Prod. 2012, 5, 1729–1732.

(19) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem. Int. Ed. 1966, 5, 385–415.

(20) Prelog, V.; Helmchen, G. Angew. Chemie, Int. Ed. 1982, 21, 567–583.

(21) Oki, M. Top. Stereochem. 1983, 14, 1−81.

(22) Leroux, F. Chem. Bio. Chem. 2004, 5, 644–649.

(23) Collins, B. S. L.; Kistemaker, J. C. M.; Otten, E.; Feringa, B. L. Nat. Chem. 2016, 8, 860–866.

(24) LaPlante, S. R.; D. Fader, L.; Fandrick, K. R.; Fandrick, D. R.; Hucke, O.; Kemper, R.; Miller, S. P. F.;

Edwards, P. J. J. Med. Chem. 2011, 54, 7005–7022.

(25) Bandara, H. M. D.; Burdette, S. C. Chem. Soc. Rev. 2012, 41, 1809–1825.

(26) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789–1816.


10206.

(28) Irie, M.; Fukaminato, T.; Matsuda, K.; Kobatake, S. Chem. Rev. 2014, 114, 12174–12277.

(29) Canary, J. W. Chem. Soc. Rev. 2009, 38, 747–756.

(30) Kelly, T. R.; De Silva, H.; Silva, R. A. Nature 1999, 401, 150–152.



(33) Fletcher, S. P.; Dumur, F.; Pollard, M. M.; Feringa, B. L. Science 2005, 310, 80–82.

(34) Lin, Y.; Dahl, B. J.; Branchaud, B. P. Tetrahedron Lett. 2005, 46, 8359–8362.

(35) Dahl, B. J.; Branchaud*, B. P. Org. Lett. 2006, 8, 5841–5844.

(36) Anyika, M.; Gholami, H.; Ashtekar, K. D.; Acho, R.; Borhan, B. J. Am. Chem. Soc. 2014, 136, 550–553.

(37) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44, 3418–3430.


195

(38) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J. Chem. Rev. 2015, 115, 11239–11300.

(39) Berlman, I. Handbook of florescence spectra of Aromatic Molecules, 2nd ed.; Elsevier Science:

Burlington, 2012.

(40) Effenberger, F.; Agster, W.; Fischer, P.; Jogun, K. H.; Stezowski, J. J.; Daltrozzo, E.; Nelb, G. K.;

Germany, W. J. Org. Chem. 1983, 48, 4649–4658.

(41) Cheng, L. T.; Tam, W.; Marder, S. R.; Stiegman, A. E.; Rikken, G.; Spangler, C. W. J. Phys. Chem. 1991,

95, 10643–10652.

(42) Llarena, I.; Benniston, A. C.; Izzet, G.; Rewinska, D. B.; Harrington, R. W.; Clegg, W. Tetrahedron Lett.

2006, 47, 9135–9138.

(43) Carlson, E. J.; Riel, A. M. S.; Dahl, B. J. Tetrahedron Lett. 2012, 53, 6245–6249.

(44) Benniston, A. C.; Harriman, A.; Patel, P. V.; Sams, C. A. European J. Org. Chem. 2005, 2005, 4680–

4686.

(45) Reichert, S.; Breit, B. Org. Lett. 2007, 9, 899–902.

(46) de Jong, J. J. D.; van Rijn, P.; Tiemersma-Wegeman, T. D.; Lucas, L. N.; Browne, W. R.; Kellogg, R. M.;

Uchida, K.; van Esch, J. H.; Feringa, B. L. Tetrahedron 2008, 64, 8324–8335.

(47) Thomas, R.; Tamaoki, N. Org. Biomol. Chem. 2011, 9, 5389–5393.

(48) Chen, C.-T.; Chen, C.-H.; Ong, T.-G. J. Am. Chem. Soc. 2013, 135, 5294–5297.







124, 5037–5051.

(55) Klok, M.; Walko, M.; Geertsema, E. M.; Ruangsupapichat, N.; Kistemaker, J. C. M.; Meetsma, A.;

Feringa, B. L. Chemistry 2008, 14, 11183–11193.

(56) Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 5127–5135.


2016, 22, 13478–13487.

(58) Štacko, P.; Kistemaker, J. C. M.; van Leeuwen, T.; Chang, M.-C.; Otten, E.; Feringa, B. L. Science, 2017,

356, 964–968.

(59) Sahnoun, R.; Koseki, S.; Fujimura, Y. J. Phys. Chem. A 2006, 110, 2440–2447.

(60) Cabrera, E. V.; Sanchez, J. L.; Banerjee, A. K. Org. Prep. Proced. Int. 2011, 43, 364–367.

(61) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696.

(62) van Leeuwen, T.; Gan, J.; Kistemaker, J. C. M.; Pizzolato, S. F.; Chang, M.-C.; Feringa, B. L. Chem. Eur.

J. 2016, 22, 7054–7058.

(63) Sheldrick, G. M. Acta Crystallogr. Sect. A, Found. Adv. 2015, 71, 3–8.

(64) Sheldrick, G. M. Acta Crystallogr. A. 2008, 64, 112–122.

(65) Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2010, 43, 665–668.

(66) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2007, 72, 10045–10050.

(67) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Anderson, J. E. J. Org. Chem. 2006, 71, 5474–5481.

(68) Casarini, D.; Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Rosini, C. J. Org. Chem. 2007, 72, 7667–7676.

(69) Orrell, K. G.; Šik, V.; Stephenson, D. Prog. Nucl. Magn. Reson. Spectrosc. 1990, 22, 141–208.

(70) Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy; Academic Press: New York, 1969.

(71) Shoemaker, Rick; Sandstöm, J. Determining the Energy of Activation Parameters from Dynamic NMR

Experiments http://chemnmr.colorado.edu/manuals/DNMR_Calculations.pdf.

(72) Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry; Newnes, 2008; Vol. 19.

(73) NMR of dynamic processes http://chem.ch.huji.ac.il/nmr/techniques/other/dynamic/dynamic.html.

(74) It should be emphasized that compared with compound 1, the methoxy-protected precursor 9 could be

obtained and isolated as variable mixtures of non-equilibrating atropisomers (see Experimental section

for details). Notably no isomerization or coalescence of the NMR absorptions was observed even at

temperatures up to 100 °C .

(75) Ceccacci, F.; Mancini, G.; Mencarelli, P.; Villani, C. Tetrahedron: Asymmetry 2003, 14, 3117–3122.

(76) Trapp, O.; Trapp, G.; Schurig, V. J. Biochem. Biophys. Methods 2002, 54, 301–313.

(77) Cabrera, K.; Jung, M.; Fluck, M.; Schurig, V. J. Chromatogr. A 1996, 731, 315–321.

(78) Andreani, R.; Bombelli, C.; Borocci, S.; Lah, J.; Mancini, G.; Mencarelli, P.; Vesnaver, G.; Villani, C.

Tetrahedron: Asymmetry 2004, 15, 987–994.

(79) Jeener, J.; Meier, B. H.; Bachmann, P.; Ernst, R. R. J. Chem. Phys. 1979, 71, 4546–4553.

(80) Bodenhausen, G.; Ernst. R. R., E. R. J. Am. Chem. Soc. 1982, 104, 1304–1309.

(81) Kistemaker, J. C. M. PhD thesis, Autonomy and Chirality in Molecular Motors, University of Groningen,

Chapter 5

196

2017.

(82) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.

Chem. Soc. 2001, 123, 2466–2467.

(83) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539–1542.

(84) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;

Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169–2178.

(85) Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K. Org. Lett. 2002, 4, 4349–4352.

(86) Noyori, R. Asymmetric catalysis in organic synthesis; Wiley: Chichester, 1994.

(87) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.

(88) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856.

(89) Noyori, R.; Kitamura, M. Angew. Chemi. Int. Ed. 1991, 30, 49–69.

(90) Hirose, T.; Kodama, K. In Comprehensive Organic Synthesis II; 2014; pp 204–266.

(91) Schmidt, B.; Seebach, D. Angew. Chemi. Int. Ed. 1991, 30, 99–101.

(92) Song, T.; Zheng, L.-S.; Ye, F.; Deng, W.-H.; Wei, Y.-L.; Jiang, K.-Z.; Xu, L.-W. Adv. Synth. Catal. 2014,

356, 1708–1718.

(93) Dean, M. A.; Hitchcock, S. R. Tetrahedron: Asymmetry 2008, 19, 2563–2567.

(94) Shibata, T.; Tarumi, H.; Kawasaki, T.; Soai, K. Tetrahedron Asymmetry 2012, 23, 1023–1027.

(95) Hirose, T.; Sugawara, K.; Kodama, K. J. Org. Chem. 2011, 76, 5413–5428.

(96) Yue, H.; Huang, H.; Bian, G.; Zong, H.; Li, F.; Song, L. Tetrahedron: Asymmetry 2014, 25, 170–180.

(97) Mao, J.; Wan, B.; Zhang, Z.; Wang, R.; Wu, F.; Lu, S. J. Mol. Catal. A Chem. 2005, 225, 33–37.

(98) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929–

6941.

(99) Erdik, E. In Organozinc Reagents in Organic Synthesis; CRC Press: Boca Raton, FL, 1996; pp 215–216.

(100) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473–7484.

(101) The same reaction catalyzed by (P)-3,3‘-diphenyl BINOL was reported to yield the product in 44% ee

(see Ref. 95).

(102) It should be noted that the quality of the commercial diethylzinc solution had a large impact on the results

of the catalytic reactions, affording lower yields and selectivities as degradation of the reagent

progressed.

(103) Zong, H.; Huang, H.; Bian, G.; Song, L. Tetrahedron Lett. 2013, 54, 2722–2725.

(104) Poon, P. S.; Banerjee, A. K. J. Chem. Res. 2009, 2009, 737–738.

(105) Ohigashi, H.; Koshimizu, K. Agric. Biol. Chem. 1976, 40, 2283–2287.

(106) Tanaka, K.; Okada, T.; Toda, F. Angew. Chemie Int. Ed. 1993, 32, 1147–1148.

(107) Toda, F.; Tanaka, K.; Stein, Z.; Goldberg, I. J. Org. Chem 1994, 59, 5748–5751.

(108) Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7991–7994.

(109) Bruker, (2012). APEX2 (v2012.4-3), SAINT (Version 8.18C) and SADABS (Version 2012/1). Bruker AXS

Inc., Madison, Wisconsin, USA.

(110) Willem, R. Prog. Nucl. Magn. Reson. Spectrosc. 1988, 20, 1–94.

(111) Ceccacci, F.; Mancini, G.; Mencarelli, P.; Villani, C. Tetrahedron: Asymmetry 2003, 14, 3117–3122.

(112) Carradoria, S.; Cirilli, R.; Dei Cicchia, S.; Ferretti, R.; Menta, S.; Pierinia, M.; Secci, D. J. Chromatogr. A

2012, 1269, 168–177.

(113) Ueda, Y.; Yagishita, F.; Ishikawa, H.; Kaji, Y.; Baba, N.; Kasashima, Y.; Mino, T.; Sakamoto, M.

Tetrahedron 2015, 71, 6254–6258.

(114) Yoshida, K.; Toyoshima, T.; Akashi, N.; Imamoto, T.; Yanagisawa, A. Chem. Commun. 2009, No. 20,

2923.

Chapter 6 Chapter 5

Phosphoramidite-Molecular Switches as

Photoresponsive Ligands Displaying Multifold

Transfer of Chirality in Dynamic Enantioselective

Metal Catalysis

Transfer and amplification of chirality in biological and artificial systems is a fundamental process that

allows dynamic control of structure and functions. Only few responsive systems harness the dynamic

transfer of chirality and can act as photoswitchable chiral inductors. In this chapter we demonstrate that

photoresponsive phosphoramidite ligands based on a chiral light-driven biaryl-substituted molecular

switch can be used to alter the activity and invert the stereoselectivity of a copper-catalyzed asymmetric

conjugate addition. The phosphoramidites were obtained as pairs of diastereoisomers, each displaying a

distinctive catalytic activity and opposite stereoselectivity as results of photo-triggered matched-

mismatched chiral interactions among the multiple stereochemical elements featured by the ligand. The

result is an elegant balance of two competing catalysts, of which the complementary catalytic performance

is tunable via internal dynamic transfer of chirality upon alkene photoisomerization.

This chapter will be published as: S. F. Pizzolato, P. Štacko, J. C. M. Kistemaker, T. van Leeuwen, Prof. B.

L. Feringa, manuscript in preparation.

The computational studies here reported were performed by J. C. M. K. and T. v. L. For more details, see


Chapter 6

198

6.1 Introduction

The precision and efficiency with which nature controls the interplay and metabolic function of chiral

biological structures has spurred and inspired the development of artificial switchable systems capable of

displaying dynamic chirality upon external triggering.1–3

The exquisite selectivity realized by enzymes

relies among others on the dynamic conformational properties produced by molecular folding to

communicate structural information over large distances to the active site.4 In contrast, synthetic catalysts

generally depend on static, proximal structural information for selectivity.5 Notably, examples of chirality-

responsive helical polymers for control of catalytic functions have been disclosed.6 The quest for

biomimetic molecules that exploit a chiral, folded secondary structure in asymmetric catalysis remains as a

highly challenging objective in the search for function in artificial systems.7–9

Achieving this objective

would minimally require the amplification and relay of local stereochemistry to the reactive/catalytic site

via an intervening secondary structure. In recent years, the development of stimuli-responsive catalysts has

attracted considerable attention and important efforts have been devoted to ON–OFF switching of catalytic

activity.10–12

Remarkable reversal of enantioselectivity in asymmetric catalysis has been achieved using

solvent responsive helical polymers,13

light-triggered organocatalysts14,15

and redox sensitive metal

complexes.16

However, a highly desirable feature of an ideal responsive stereoselective catalyst is the

ability to readily modify the chiral configuration of its active form in a non-invasive manner. In the case of

homogenous catalysts based on metal complexes, some of the previously described systems rely on the

isomerization of photoresponsive coordination ligands before the addition of the metal source.17,18

Such an

approach is exploited because the formation of the active catalyst might impede the efficient

reconfiguration, either due to slow metal-ligand dissociation processes in multi-dentate complexes19

or

quenching of the photo-generated excited state via internal energy transfer influenced by the metal center.20

Moreover, the use of multi-dentate responsive ligands characterized by a large variation in geometry and

distance of coordination sites between the interchangeable states, may lead to the reconfiguration among

mono- and oligomeric structures with divergent catalytic performances.17,18

On the other hand, the optimal

stereoselective metal-based catalyst should feature a limited number (ideally two) of isomers, e.g.

enantiomeric or pseudoenantiomeric active forms. The latter should also be interchangeable in their

coordinated states, providing access to chiral catalysts that could perform multiple enantioselective

transformation in a sequential manner without the need of an intermediate metal-decomplexation step.

Although it is difficult to switch the chirality of conventional ligands, artificial light-driven molecular

motors and switches provide a unique platform to achieve this goal.21–23

Unidirectional rotary molecular

motors based on overcrowded alkenes (Scheme 6.1a) can intrinsically act as multistage chiral switches as

we have recently shown in the design of three-stage organocatalysts14,15

and phosphine ligands for metal

catalysts.18

The photochemical and thermal isomerizations resulting in unidirectional rotation around the

central overcrowded alkene bond provide stepwise control over the helicity of the bifunctional catalyst or

bidentate ligand and spatial distance between these two interacting sites (Scheme 6.1b). As the

photochemically-generated isomer [e.g. (P,P)-Z] and subsequent thermally-triggered isomer [e.g. (M,M)-Z]

are pseudo enantiomers, chiral products with opposite absolute configuration are obtained when these

isomers are used in a catalytic asymmetric transformation (Scheme 6.1). However, the thermally induced

process of helix inversion between the pseudoenantiomeric (P,P)-Z and (M,M)-Z forms is not per se

reversible. Indeed, starting from the (M,M)-Z isomer, three consequent isomerization (light-heat-light) are

required to recover the initial (P,P)-Z isomer.24

Hence, fully reversible switching the handedness of chiral

inductors remains highly challenging so far. Addressing this, we anticipated that light might allow non-

invasive and dynamic control of multistage ligand chirality, introducing simple yet efficient designs of

programmable coordination complexes.25

Fascinating prospects in the control of functions would arise from

such a strategy (note that dynamic chiral metal complexes were recently used in chiral recognition,26,27

transmission of chirality,28

chiral amplification29

and asymmetric catalysis16–18

). The design used to date is

based on first generation molecular motors (Scheme 6.1a),24

of which core is composed of two identical

halves each bearing one functional group of the catalytic pair (Scheme 6.1b). However, bridging the two

Phosphoramidite-Molecular Switches as Photoresponsive Ligands Displaying Multifold Transfer of

Chirality in Dynamic Enantioselective Metal Catalysis

199

halves to construct a cyclic ligand structure would impede the characteristic isomerization cycle. Herein,

we report molecular-switch-phosphoramidite30

hybrid structures based on second generation molecular

motors (see Scheme 6.2b)31

in which, for the first time, the two-stage switching process of chirality via

multifold coupled chirality transfer within monodentate tricyclic ligands can be driven by light in a fully

reversible manner. As proof of concept, application in external modulation of catalytic activity and

stereoselectivity of a copper-catalyzed asymmetric conjugate addition32

is demonstrated.

Scheme 6.1. Schematic representation of chiral photoresponsive bi-functional catalyst based on molecular

motors. a) Example of molecular motors of first (top) and second (bottom) generation. b) Schematic

representation of unidirectional four-step rotary cycle of bi-functionalized molecular motor, comprising two

photochemical E-Z isomerizations (PEZI) and two thermal helix inversions (THI).


6.2.1 Design

In Chapter 5 we reported a photoresponsive molecular switch 1 featuring a versatile 2,2‘-biphenol motif in

which chirality is transferred across three stereochemical elements (Scheme 6.2a). The isomer (S,M=,Ma)-1

is selectively obtained from synthesis being the global minimum due to the thermodynamically more

favored pseudoaxial orientation adopted by the methyl group at the stereogenic center. The photochemical

E-Z isomerization (PEZI) of the helical-shaped central alkene bond towards the isomer (S,P=,Pa)-1 less

thermodynamically favored pseudequatorial orientation adopted by the methyl substituent allows via

coupled motion the reversible control of the helical and axial chirality of the biaryl motif. In our previous

study, we demonstrated that the specific switch core of 1 (6-membered ring upper half, 5-membered ring

lower half)33

displayed high photostationary states (PSS) in the reversible photoisomerization process. In

addition, it is characterized by an unprecedented thermal bi-stability,34

which increases its usefulness as

dynamic chiral inductor in applications where thermal stability is desired.

Compared with previously reported molecular motor based systems, the reduction from four (Scheme 6.1)

to two isomerization stages (Scheme 6.2a) featured by such a biaryl-functionalized design provides a

simpler, reusable and more efficient dynamic responsive core.14,15,18,35–37

Moreover, the disubstituted biaryl

motif could also operate as a flexible chiral selector if merged into a bridged tricyclic structure. Hence, we

envisioned that upon cyclization, tricyclic biaryl structures and bidentate metallacyclic complexes could be

Chapter 6

200

constructed and isomerized without disrupting the bridged biaryl unit or affecting its flexibility, nor

obstructing the motion of the photoswitchable alkene unit.

Scheme 6.2. Design of chiral photoresponsive phosphoramidite ligands. a) Chiral 2,2‘-biphenol-substituted

switch 1 described in Chapter 5. b) Front structural view of photoswitchable phosphoramidite-2,2‘-

biphenyl-substituted overcrowded alkene-derivative L with axial helicity and chirality (black) of the 2,2‘-

biphenyl core coupled to helicity (blue) and point chirality (red) of the molecular switch scaffold. Point

chirality on phosphorus (green) is not reversed. Descriptors are based on the structure of compound (S,SP)-

L (for explanation of the chiral descriptors, vide infra). d) Schematic top-down view after metal-L

complexation: two metal-ligand complexes with opposite alkene and biaryl coupled helicity (M or P) can

be selectively addressed by irradiation with UV-light: (S,SP,M=,Ma)-L and (S,SP,P=,Pa)-L. The descriptor

for the biaryl axial chirality Ra/Sa is inextricably dictated by the helicity of the alkene and of the bridged

biaryl structure (hence omitted in the rest of the manuscript for simplicity). The descriptor for the chirality

of phosphorus in the complex matches that of the free ligand; naturally complexation of a metal with higher

priority than oxygen would invert the absolute stereodescriptor.

Phosphoramidites38–40

have emerged as a highly versatile and readily accessible class of chiral ligands,

showing exceptional levels of stereocontrol in homogeneous catalysis.30,32

In this context, we decided to

explore the application of 1 as the chiral biaryl module in photoresponsive chiral phosphoramidite ligands

for metal-catalyzed transformations (Scheme 6.2b). The system described herein features five

stereochemical elements: i) the first element is the fixed stereogenic carbon center (R or S) of the switch



201

(highlighted in red); ii) the second element is the helicity of the overcrowded alkene (blue), which can be

inverted upon photoisomerization between right-handed (P=) or left-handed (M=); the third and fourth

elements are, respectively, iii) the helical geometry (Pa or Ma) and iv) axial chirality (Ra or Sa) of the biaryl

unit (black), which is dictated by the helicity of the alkene (vide infra) due to steric interaction and can be

assigned according to the CIP rules;41,42

v) the fifth element is the fixed stereogenic phosphorus center (RP

or SP) of the phosphoramidite motif (green) as dictated upon synthesis (vide infra). The barrier for

phosphine pyramidal inversion is high enough to prevent inversion occurring appreciably at room

temperature.43,44

When coordinated to transition metal centers, enhanced configuration stability can be

expected.45

Moreover, BINOL-based phosphoramidite ligands with asymmetric substitution pattern on the

binaphthyl unit have been previously reported to be obtainable as stable and separable diastereoisomers at

room temperature, which also displayed distinctive catalytic activity and selectivity.46

Similar to the previously described coupled transfer of dynamic chirality displayed by 1, the true helicity

(and consequently the axial chirality) of the biaryl is inextricably connected to the helicity of the

overcrowded alkene chromophore, and is identical to it in each of the isomers. Therefore, three

stereodescriptors (R/S,RP/SP,P/M) will be sufficient for the assignment of any expected isomer reported in

this work. So for isomer (S,SP,M)-L: S = fixed configuration at C-stereogenic center, SP = fixed

configuration at P-stereogenic center, P = dynamic helicity of alkene chromophore and biaryl moiety. The

doubly expressed P-stereodescriptor (RP/SP) throughout the text denotes a mixture of diastereoisomers with

identical absolute stereochemistry at the C-stereocenter and configurational helicity of the switch module

but opposite absolute stereochemistry at the P-stereocenter [e.g. (S,SP/RP,M)-L means a mixture of

(S,SP,M)-L and (S,RP,M)-L]. When not expressed otherwise, L indicates the thermodynamic mixture of

diastereoisomers as obtained from synthesis without subsequent separation. For simplicity, we kept the

descriptor for the chirality at phosphorus of the metal complex matching that of the free ligand – naturally

complexation of a metal with higher priority than oxygen would invert the absolute stereodescriptor.

Scheme 6.2c illustrates the delicate interplay of dynamic stereochemical elements of monodentate ligand

(S,SP)-L after metal complexation and the light-triggered switching process between the two proposed

diasteroisomeric species.47

We envisioned a large variation of axial chiral induction and net steric hindrance

provided around the coordinated metal center upon photochemical isomerization of the responsive ligand.

6.2.2 Synthesis

Biphenol switch (S)-1 was prepared from 8-bromo-7-methoxytetralone and 2-methoxyphenyl boronic acid

via Suzuki cross coupling, subsequent Barton-Kellogg coupling of the corresponding hydrazone derivative

with thiofluorenone, followed by chiral resolution of the deprotected biphenol intermediate with cinchona

ammonium salt, according to synthetic methodology recently described by van Leeuwen.48

The synthesis of

molecular switch-based ligands L1-5 is presented in Scheme 6.3. Starting from pure (S,M=,Ma)-1, ligands L

were obtained regarding their switch module only as (S,M=,Ma)-isomers (or (R,P=,Pa)-isomers in case of L3,

starting from (R,P=,Pa)-1), i.e. without loss of their helical purity. However, it should be noted that the

chiral switch structure features a C1-symmetry, as opposed to the C2-symmetry of BINOL-based

phosphoramidite ligands. As a consequence, ligands L1-5 were obtained as pairs of diastereoisomers due to

the P-stereogenic center generated upon derivatization of 1, of which the distinctive relative ratio [dr, for

instance (S,SP)-L:(S,RP)-L] is influenced by the steric requirements of the specific amine substituent.46,49,50

N,N-dimethyl-substituted ligand L1 [(S,SP)-L1:(S,RP)-L1 = 56:44, 80% yield] was obtained from (S)-1

upon reaction with tris(dimethylamino)phosphine. Ligands L2-5 were obtained from either (S)-1 (99% ee)

or (R)-1 (96% ee) via reaction with phosphorus trichloride followed by coupling with the correspondent

secondary amine. Ligand L2 features the achiral N,N-diisopropylamine substituent, which upon comparison

with L1 would allow investigating the influence of more sterically hindered phosphoramidite functionality

on the catalytic performance. Isomer separation was achieved via column chromatography of the

thermodynamic mixture of diastereoisomers of L2 obtained from synthesis [(S,SP)-L2:(S,RP)-L2 = 86:14,

62% yield], providing almost pure major diastereoisomer (S,SP)-L2 [(S,SP)-L2:(S,RP)-L2 = 98:2] and an

Chapter 6

202

additional fraction with lower dr [(S,SP)-L2:(S,RP)-L2 = 60:40]. An important property of phosphoramidite

ligands is that different combinations of chiral diol and chiral amine allow tuning of the

stereodiscrimination for the envisaged catalytic system.30

These features also result in matched/mismatched

effects of the different diastereoisomers, of which distinct stereodiscrimination is exploitable to optimize

the enantioselectivity in asymmetric reactions. Ligands L3 [(R,RP)-L3:(R,SP)-L3 = 95:5, 52% yield] and L4

[(S,SP)-L4:(S,RP)-L4 = 92:8, 40% yield] were synthesized from (R)-1 and (S)-1, respectively, in

combination with the chiral bis((R)-1-phenylethyl)amine.51

The latter is an established motif in various

phosphoramidite ligands, first and foremost its BINOL-derivative which achieved remarkable results in

many metal-catalyzed asymmetric transformations.30,32

It should be noted that in ligands L3 and L4 the

number of stereochemical elements is raized up to seven [two additional fixed chiral centers (R1

N,R2

N) in

the amine unit]. Lastly, ligand L5 [(S,SP)-L5:(S,RP)-L5 = 60:40, 55% yield] was synthesized from (S)-1 and

tetrahydroquinoline (THQuin), which compared with L2 could provide insights on the influence of a non-

symmetric achiral amine functionality on the catalytic performance. All molecular switches-based ligands

L1-5 were characterized by 1H,

13C and

31P NMR, UV-vis absorption and CD spectroscopy (see

Experimental section for further details).

Scheme 6.3. Reagents and conditions for the synthesis of ligands L1-5. a) L1: P(NMe2)3, NH4Cl, benzene,

reflux, 16 h, 91:9 dr after recrystallization from Et2O-pentane. b) L2: PCl3, i-Pr2NH, NEt3, THF, then (S)-1,

0 °C to rt, 16 h, major diastereoisomer (S,SP):(S,RP) = 98:2 isolated by column chromatography. c) L3:

PCl3, (R)-[PhCH(CH3)]2NH, NEt3, THF, then (R)-1, 0 °C to rt, 16 h. d) L4: PCl3, (R)-[PhCH(CH3)]2NH,

NEt3, THF, then (S)-1, 0 °C to rt, 16 h. e) L5: PCl3, tetrahydroquinoline (THQuin), NEt3, toluene, 80 °C,

then (S)-1, THF, -78 °C to rt, 16 h. Ligands were obtained maintaining the helicity present in the starting

biphenol 1. For all ligands L1-L5 only the major diastereoisomer is shown with a diastereoisomeric ratio as

obtained from synthesis before isomer separation indicated below the structure. Structural view of

diastereoisomers L with opposite point chirality on phosphorus reported in the box. Isolated yield (%) of

diastereoisomeric mixture.


With the switchable ligands in hand, their photochemical and thermal isomerization properties were

investigated. The reversible photochemical isomerization process of pure major diastereoisomer (S,SP,M)-

L2 in dichloromethane was monitored by UV-vis absorption, CD and 1H/

31P NMR spectroscopy (Figures

6.1 and 6.2, see Experimental section for L1-3-4-L5). The forward photoisomerization step was achieved

by irradiation at 365 nm, which resulted in a significant decrease in the intensity of the absorption band at

340 nm and the appearance of a new absorption band at 380 nm with clear isosbestic points (Figure 6.1b).



203

This red shift is indicative of the formation of the diastereoisomer (S,SP,M)-L2.33

1H and

31P NMR studies

in CD2Cl2 also confirmed this structure as is evident from the downfield chemical shift of all the aliphatic

ring protons in 1H NMR and the shift of the phosphorus resonances in

31P NMR from 150.3 ppm to 145.4

ppm (Figure 6.2a-c). After reaching the photostationary state at 365 nm (PSS365), a ratio of (S,SP,M)-

L2:(S,SP,P)-L2 = 26:74 was established by 1H and

31P NMR spectroscopy (Figure 6.2c). The observed

changes in the CD spectrum also support that the M to P helix inversion occurs during this step (new band

at 410 nm, Figure 6.1c). The subsequent backward photoisomerization step was performed by irradiation at

420 nm of the previous PSS365 mixture, which largely regenerated the initial (S,SP,M)-L2. After reaching

the PSS420, a ratio of (S,SP,M)-L2:(S,SP,P)-L2 = 87:13 was established (Figure 6.2d). The excellent

reversibility and high PSS ratios are highly beneficial in applications of catalytic asymmetric reactions and

dynamic control of chiral space. Complete photochemical isomerization study was also performed on

ligands L1-3-4-L5 with similar results (see Experimental section for further details). Notably, photo-

switching was successfully performed both with the free ligands and as the copper complexes (see Catalysis

tests, vide infra) without a significant difference in stability or selectivity.

Figure 6.1. Photochemical isomerization study of (S,SP,M)-L2 by UV-vis absorption and CD spectroscopy.

a) Photochemical E-Z isomerization of (S,SP,M)-L2 to (S,SP,P)-L2. b) UV-vis absorption spectral changes

of the switching process of L2 (CH2Cl2, 5.5·10−5

M). Starting isomer (S,SP,M)-L2 (black). Irradiation at

365 nm towards (S,SP,P)-L2 afforded a PSS365 mixture (red). Irradiation at 420 nm of the previous PSS365

mixture resulted in reversed E-Z isomerization affording a new PSS420 mixture (blue). Insert displays

irradiation cycles between the two PSS mixtures. c) Corresponding experimental CD spectral changes of

previous sample.

Chapter 6

204

Figure 6.2. Photochemical isomerization study of (S,SP,M)-L2 by 1H NMR and

31P NMR spectroscopy. a)

Photochemical E-Z isomerization of (S,SP,M)-L2 to (S,SP,P)-L2 with labelled H and P atoms. d) 1H/

31P

NMR spectra of L2 [(S,SP):(S,RP)= 98:2, 4.0 mg in 0.65 mL of CD2Cl2], 25 °C). e) 1H/

31P NMR spectra of

PSS365 mixture [(S,SP,M)-L2:(S,SP,P)-L2 = 26:74]. d) 1H/

31P NMR spectra of PSS420 mixture [(S,SP,M)-

L2:(S,SP,P)-L2 = 87:13]. Residual solvent peak region (5.80–4.80 ppm) cut for clarity. Complete

resonances assignment by 1D/2D-NMR techniques reported in following section.



205

6.2.4 Assignment of 1H NMR absorptions of (M) and (P) isomers of L2 via 1D-2D NMR techniques

Full assignment of the 1H NMR absorptions of major diastereoisomer (S,SP,M)-L2 (98:2 dr) was achieved

by comparing the 1H NMR (Figure 6.3), gCOSY (Figure 6.4) and NOESY (Figure 6.5) spectra here

reported with the calculated NMR spectra (reported in Experimental section). Structure optimization of

diastereoisomers (S,SP,M)-L2 and (S,RP,M)-L2 was executed with DFT (b3lyp/6-31g(d,p)) in gas-phase

(see Experimental section for further details on calculation study and comparison between experimental and

calculated spectra). Insert with corresponding magnification of the aromatic protons range is reported in

each spectrum. Individual absorptions assignments are indicated by single letters in the 1H-NMR spectrum,

while cross-peaks are indicated by double letters in the gCOSY and NOESY spectra. In the current sample

of (S,SP,M)-L2, coupling through space via NOE effect was observed via cross-peaks between protons A-L,

A-T, B-T and U-I. Notably, no coupling through space via NOE effect was observed via cross-peak

between protons U-H. This experimental evidence supports the proposed stereochemical assignment to be

diastereoisomer (S,SP,M)-L2, in which the diisopropylamine substituent is syn with the stereogenic center

of the upper half (rotor). The X-ray structure of the opposite diastereoisomer (S,RP,M)-L2 (see Figure 6.7),

which possesses opposite chirality on the phosphorus atom, clearly shows the close proximity of the

diisopropylamine substituent with the protons M and N located in the fluorenyl lower half (stator). Indeed,

no coupling through space would be expected between protons U-H for the latter diastereoisomer (S,RP,M)-

L2. Likewise, no U-H cross-peak would be expected for the photo-generated isomer (S,SP,P)-L2, due to the

inverted axial chirality of the biaryl unit which results in an increased distance between protons U and H if

compared with starting compound (S,SP,M)-L2.

Figure 6.3. 1H NMR (400 MHz, CD2Cl2) of (S,SP,M)-L2 with expansion of aromatic region; residual

solvent peak range (5.40–5.25 ppm) cut for clarity.

Chapter 6

206

Figure 6.4. gCOSY (400 MHz, CD2Cl2) of (S,SP,M)-L2 with expansion of aromatic region.



207

Figure 6.5. NOESY (400 MHz, CD2Cl2) of (S,SP,M)-L2 with expansion of aromatic region.

Chapter 6

208

The NMR analysis and assignment of the absorption peak was also performed on the photo-generated

isomer (S,SP,P)-L2 (Figures 6.6 and 6.7). The starting sample was diluted in CH2Cl2 (20 mL), purged with

nitrogen for 5 min and irradiated at 365 nm until PSS was reached ((S,SP,M)-L2:(S,SP,P)-L2 = 26:74) (see

Experimental section for details). The suboptimal quality of the NMR spectrum and inherent incomplete

conversion at the PSS365 did not allow recording a clear NOESY spectrum. Indeed, a complex spectrum

with no significant cross-peak was obtained (not reported).

Figure 6.6. 1H NMR (400 MHz, CD2Cl2) of PSS365 mixture, absorptions highlighted for (S,SP,P)-L2;

residual solvent peak range (5.40–5.25 ppm) cut for clarity.



209

Figure 6.7. gCOSY (400 MHz, CD2Cl2) of (S,SP,P)-L2.

6.2.5 X-ray crystallography

Single crystals of L1 obtained upon crystallization from pentane/Et2O of the thermodynamic mixture of

diastereoisomers (S,SP)-L1:(S,RP)-L1 = 56:44 as obtained from synthesis were analyzed by X-ray

crystallography (Figure 6.1g, see Experimental section for further details). The reconstructed unit cell of the

lattice was shown to contain only the minor diastereoisomer (R,P,Sa)-1, which may be characterized by a

lower solubility in the crystallization solvent. The experimental data confirmed the proposed model of

coupled helical-to-axial transfer of helicity, demonstrating the most favored conformation of the lower aryl

substituent to be parallel to the fluorenyl lower half of the switch core (synclinal) in the crystal lattice. The

resolved structure also allows assessing the close proximity of the amine substituent to the fluorenyl group.

Such structural restraint generates the distinctive diastereoisomeric ratio observed for the ligands, for which

more sterically demanding amine substituents lead to higher dr. Lastly, the dihedral angle over the biaryl

motif determined from the X-ray structure in the solid state was found to be 46.03°.

Chapter 6

210

Figure 6.7. Schematic representation and X-Ray structure of (S,RP,M)-L1. Left: side view; right: top-down

view through biaryl bond. Ellipsoids set at 50% probability. Torsional angle of biaryl unit: 46.03°.


Having confirmed the structures and two-stage photo-switching process of phosphoramidites L1-5, we

investigated their performance as chiral switchable ligands in asymmetric catalysis. We selected copper(I)-

catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one (2) (Scheme 6.4a and Table 6.1), a well-

established model reaction to determine the enantiodiscrimination abilities of chiral ligands.32

The reaction

was carried out with 2 mol% of CuTC, 2 mol% of L in Et2O at -30 °C, either by using the copper-ligand

mixture as such [comprising of a single helicity, dr ratio reported in 3rd

column of Table 6.1] or after

irradiation at 365 nm [mixture of (M)- and (P)-isomers, determined by HPLC analysis, see 4th column of

Table 6.1]. Notably, the presence of the copper salt did not affect the switching properties of

photoresponsive ligands L. After addition of decane as internal standard, 1.2 equiv of Et2Zn (solution in

Et2O) and 0.25 mmol of 2-cyclohexen-1-one, the conversion was monitored over time by GC-MS analysis,

while enantiomeric excess was determine by chiral GC analysis of isolated product 2-ethylcyclohexan-1-

one (3). To our delight, the reaction proceeds with high chemoselectivity affording high conversion towards

product 3. Notably, upon comparison of the results of reactions conducted with almost pure (S,SP,M)-L2

using, respectively, the non-irradiated catalyst (see 3rd

-4th

columns in Table 6.1) and the catalyst mixture

after irradiation (see 5th-7

th columns), a large variation in enantioselectivity in favor of only (S)-3 was

observed (from 5% to 69% ee, respectively, entry 2). When a mixture of L2 with gradually lower

(S,SP):(S,RP) dr was used, an increasing preference for (R)-3 was observed in the reactions conducted with

non-irradiated catalyst (26% and 49%, entries 3-4). In addition, a decreasing enantioselectivity for (S)-3

was obtained in the reactions conducted with the irradiated catalyst mixture upon lowering the dr of the

ligand (from 69% to 66% and 55%, entries 2-3-4). As general trend, when using mixtures of ligands with a

low (S,SP):(S,RP) dr (namely L1, L2, and L5, entries 1-3-4-7) comparison of reactions conducted,

respectively, with a non-irradiated catalyst mixture, and the catalyst mixture after irradiation, displayed a

net reversal of stereoselectivity, yielding 3 with stereochemistry of opposite configuration. On the other

hand, when a mixture of ligands with a distinctively high dr was used (namely (S,SP,M)-L2, L3, and L4,

entries 2-5-6), a large variation in enantioselectivity in favor of a single enantiomer of 3 was observed.

Moreover, the lower the dr of the ligand, the larger was the net variation of ee achieved (entries 2-3-4). The

distinctive stereoselectivity of opposite diastereoisomers of conventional phosphoramidite ligands featuring

C1-symmetrical biaryl components was previously reported.48

We suggested that an initially poorly

performing (S,SP,M)-L2 can be converted to a chiral ligand with significant enantioselectivity for (S)-3

when converted to (S,SP,P)-L2 upon irradiation (entry 2). On the other hand, addition of the opposite

diastereoisomer (S,RP,M)-L2 (entry 4) provides a species more selective for (R)-3 in the non-irradiated

catalyst mixture, which strikingly appears to favor (S)-3 even upon irradiation due to the presence of the

more active photo-generated (S,SP,P)-L2 isomer (Scheme 6.4b). An equivalent trend was observed for L5.



211

Scheme 6.4. Switchable asymmetric catalysis. a) Stereodivergent copper-catalyzed conjugate addition of

diethylzinc to 2-cyclohexen-1-one by switching the chirality of ligands L (only the major diastereoisomer is

shown) upon photochemical isomerization (irradiation performed on copper-ligand mixtures in Et2O, see

Table 6.1 for details). b) Schematic top-down view of Cu-L complexes: for each (S,SP) or (S,RP)

diastereoisomer two metal-ligand complexes with opposite coupled helicity (M or P) can be selectively

addressed by irradiation with UV-light. For simplicity, the descriptor for the chirality of phosphorus in the

complexes matches that of the free ligand (see Scheme 6.2). In species Cu-(S,SP,M)-L and Cu-(S,RP,P)-L

the copper center is proposed to experience an unfavorable steric hindrance, which affects catalyst activity

and enantioselectivity.

Table 6.1. Reaction scope of stereodivergent conjugate addition of diethylzinc to 2-cyclohexen-1-one with

L1-5.

Entrya L

(S,SP,M):(S,RP,M)dr of L

b

ee of 3 with non-irradiated

catalyst mixture (%)

c

(M):(P) ratio of irr. cat. mix.

d

(S,SP,M):(S,RP,M): (S,SP,P):(S,RP,P) dr

of irr. cat. mix.d

ee of 3 with irr. cat. mix.

(%)c

1 L1 55:45 22 (R) 28:72 15:13:40:32 12 (S)

2 L2 98:2 5 (S) 14:86 14:traces:84:2 69 (S)

3 L2 86:14 26 (R) 14:86 12:2:74:12 66 (S)

4 L2 60:40 49 (R) 14:86 8:6:52:34 55 (S)

5e L3

(R,RP,P):(R,SP,P) = 95:5

67 (S) 85:15 (R,RP,P):(R,SP,P): (R,RP,M):(R,SP,M)

= 14:1:81:4

21 (S)

6 L4 92:8 43 (S) 60:40 55:5:37:3 97 (S)

7 L5 60:40 57 (R) 19:81 11:8:49:32 49 (S)

a General reaction conditions: 5 μmol of CuTC (copper(I)-thiophene-2-carboxylate), 5 μmol of

(S,SP/RP,M)-L, 63 μmol of decane (int. std.), Et2O (1.0 mL), 0.30 mmol of Et2Zn (1.0 M in hexane), 0.25

mmol of 2-cyclohexen-1-one, -30 °C, 6 h. All isolated yield ranged within 70-84%, as determined by GC-

MS analysis upon comparison with internal standard. b Determined by

1H/

31P NMR analysis of isolated

ligand mixtures from synthesis. c

Determined by chiral GC analysis of isolated product. d

Reaction with

irradiated mixture of catalyst: mixture of CuTC and L irradiated with UV-light (365 nm) over 3 h. Ratio

(S,SP/RP,M):(S,SP/RP,P) of irradiated catalyst mixture determined by chiral HPLC analysis prior addition of

other reagents. e

L3 features opposite stereodescriptors due to enantiomeric (R)-switch core. Bold values in

ratios indicate ligand isomers generating the proposed more active catalyst forms (vide infra).

Chapter 6

212

It should be noted that the absolute preference of a ligand species for a specific enantiomer of 3 is dictated

by the fixed point chirality on phosphorus [e.g. only (S)-3 using (S,RP)-L, entry 2], while the magnitude of

the enantioselectivity is governed by the reversible helicity of the switchable unit upon irradiation (e.g.

from 5% to 69% ee for (S)-3 upon irradiation of (S,SP,M)-L2 towards (S,SP,P)-L2, entry 2). Overall, a

tunable matched-mismatched interaction of the fixed point chirality on phosphorus with the dynamic chiral

induction provided by the stereogenic elements of the molecular switch can be observed. These results were

supported by kinetic experiments, performed by monitoring the conversion of 2 vs. time (Figure 6.8).

Comparison of reactions starting with pure (S,SP,M)-L2 proved that a strong increase in catalytic activity

[turnover frequency (TOF) from 57 h-1 to 281 h-1] is observed upon irradiation to 50% of (S,SP,P)-L2 with a

simultaneous increase in enantioselectivity (from 6% to 64% ee) (Figure 6.8a). On the other hand, dual

stereocontrol can be achieved upon irradiation when employing an almost equimolar ratio of

diastereoisomeric ligands like L5 [(S,SP):(S,RP)-L5 = 60:40], while maintaining comparable reaction rates

(Figure 6.8b). The more active outward facing complex (S,RP,M)-L5 then favors formation of (R)-3 (58%

ee), while after irradiation the majorly active complex (S,SP,P)-L5 is enantioselective for (S)-3 (43% ee).

This agrees fully with the results of L1 and L2 (entries 1 and 4, Table 6.1), in that (S,RP,M)-L is selective

for (R)-3 and (S,SP,P)-L favors (S)-3. However, the results obtained from reactions conducted with L3 and

L4 show a clear preference for enantiomer (S)-3 in each experiment. This suggests that the common

bis((R)-1-phenylethyl)amine dominates the observed stereodescrimination in favor of (S)-3, despite

opposite axial chiralities provided by the enantiomeric switch scaffold in L3 and L4. In spite of this, a

matched-mismatched interaction of the stereogenic elements of the chiral amine substituent and the

molecular switch can be observed. Precedent studies on conventional biaryl-based phosphoramidites

showed significant increase in ee due to the additional chirality of the amine group.30

Based on such

precedence and on the selectivities observed in the other ligands described hereto one expects the minor but

presumably more active ligands (R,SP,P)-L3 and (S,SP,P)-L4 both to favor (S)-3 due to the likewise

matched interaction of (S)-chirality of the phosphorus center with (P)-helicity of the biphenol unit, but to a

different extent as the latter is featured, respectively, by the non-superimposable (R,P)-form (non-

irradiated) or (S,P)-form (irradiated) of the switch unit, which is reflected in a higher enantioselectivity for

(S)-3 in the former with respect to the latter. Furthermore, irradiation of the ligands affords the more active

pseudoenantiomeric complexes (R,RP,M)-L3 and (S,SP,P)-L4 in greater dr (81% and 37%, respectively),

resulting in an increase in the difference as well as an inversion of their respective enantioselectivities for

(S)-3. Noteworthy, even an incomplete irradiation of L4 [(M):(P) = 60:40] provided from (S,SP,M)-L4 the

remarkably selective and active species (S,SP,P)-L4, which yielded (S)-3 with 97% ee which is attributed

due to the optimal matched interactions of seven chiral elements (i.e. (S,SP,R1N,R

2N,P=,Pa,Sa)-L4). Although

(R,SP,P)-L3 displays a similar P-helical twist of the biaryl motif, the overall matched interaction is not

equally satisfied as in the photo-generated isomer. Such performance suggest that the chiral induction

provided by (S,SP,P)-L4 most closely resembles the conventional bis((R)-1-phenylethyl)amine-(S)-BINOL-

derived phosphoramidite,52,53

a well-established ligand in copper-catalyzed asymmetric transformation

which features the optimal combination of amine and biaryl chirality (S,R,R) if compared with its

diastereoisomer (R,R,R).30

Based on this analysis, the proposed more active species for each mixture of

ligands have been indicated in Table 6.1 (see bold text in 3rd

and 6th columns).



213

Figure 6.8. Catalysis reaction kinetics. a) Reaction kinetics of copper-L catalyzed conjugate addition

followed by measuring substrate conversion and enantiomeric excess (ee) via GC-MS and chiral GC

analysis. Comparison of conversion plots with non-irradiated (left) and irradiated catalyst mixture (right).

Top: reactions performed with single diastereoisomer (S,SP,M)-L2 (as such and irradiated at 365 nm to an

(M):(P) = 50:50 mixture). Bottom: reactions performed with diastereoisomeric mixture of (S,SP,M)-

L5:(S,RP,M)-L5 = 60:40 (as such and irradiated at 365 nm to an (M):(P) = 21:79 mixture).

Chapter 6

214

6.3 Conclusions

A selection of photoresponsive chiral phosphoramidite-molecular switch derivatives L1-5 in which

chirality is dynamically transferred across from five to seven stereochemical elements [e.g. from

(S,SP,M=,Ma,Ra)-L2 to (S,SP,P=,Pa,Sa)-L2] has been designed and successfully synthesized. The unique

combination of a light-triggered molecular switch featuring a bridged biaryl-derived monodentate ligand

moiety allows reversible photo-switching between two stereochemical forms with distinct ligand properties.

The ligands were used to alter the activity and invert the stereoselectivity of the copper–catalyzed conjugate

addition of diethylzinc to 2-cyclohexen-1-one. Catalysis results supported by kinetic experiments suggest

that each diastereoisomer of the ligand provides a distinctive activity and opposite stereoselectivity in the

asymmetric catalytic event. This results in an elegant balance of two competing diasteroisomeric catalysts,

of which complementary catalytic performance is tunable upon photoisomerization due to the reversible

matched-mismatched interaction between the dynamic chirality of the switch unit and the fixed chirality of

the phosphoramidite ligand site. Coupling of reversible switching to catalytic function, as demonstrated

here, may prove to be a key design tool in the construction of future chiral catalysts that can perform

multiple tasks in a sequential manner or can be used to ―up-or-down regulate‖ catalytic pathway non-

invasively. These findings bring additional insights in the growing family of responsive chiral switches, not

only for application as tunable catalysts into the vast domain of phosphorus-based ligands for transition

metal catalysis,5,54

but more importantly as an additional step towards more sophisticated artificial systems

for responsive control of chirality.55,56


The author would like to thank P. Štacko J. C. M. Kistemaker, T. van Leeuwen and Prof. E. Otten for their

fundamental contribution to this work. Design was performed in collaboration with P. Štacko and J. C. M.

Kistemaker. Computational study was performed by J. C. M. Kistemaker and T. van Leeuwen.. X-ray

structure determination was performed by Prof. E. Otten.



215



Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe. CuTC was prepared according to the

literature procedure.57

Compound 1 was synthesized and resolved according to procedure reported in

Chapter 5. Solvents were reagent grade and distilled and dried before use according to standard procedures.

Dichloromethane, ether and toluene were used from the solvent purification system using an MBraun SPS-

800 column. Tetrahydrofuran was distilled over sodium under a nitrogen atmosphere prior to use. NEt3 was

freshly distilled over CaH2 prior to use. PCl3 was freshly distilled at reduced pressure prior to use. Column

chromatography was performed on silica gel (Silica Flash P60, 230–400 mesh, mixtures of pentane with

EtOAc, Et2O or CH2Cl2 were used as eluent as reported for each case). Components were visualized by UV

and phosphomolybdic acid or potassium permanganate staining. Progress and conversion of the reaction

were determined by GC-MS (GC, HP6890 – MS, HP5973) with an HP1 or HP5 column (Agilent

Technologies, Palo Alto, CA). NMR spectra were recorded on a Varian Gemini-200, a Varian Mercury

300, a Varian AMX400 or a Varian Unity Plus 500 spectrometer, operating at 200 MHz, 300 MHz,

400 MHz, and 500 MHz for 1H NMR, respectively. Chemical shifts are denoted in δ values (ppm) relative

to CDCl3 (1H: δ = 7.26;

13C: δ = 77.00) or CD2Cl2 (

1H: δ = 5.32;

13C: δ = 54.00). Unless mentioned

otherwise, all NMR spectra were recorded at 25 °C. For 1H NMR, the splitting parameters are designated as

follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sext (sextet), m (multiplet) and b (broad).

When mixtures of diastereoisomers are described (unless otherwise specified), the integral value of an

absorption assignable for a specific diastereoisomer is reported as the corresponding fraction of the total

number of nuclei of a specific chemical position. Mass spectra were obtained with an AEI MS-902

spectrometer (EI+) or with a LTQ Orbitrap XL (ESI+). Melting points were measured on a Büchi Melting

Point B-545 apparatus. Optical rotations were measured on a Perkin Elmer 241 Polarimeter with a 10 cm

cell (c given in g/100 mL). Chiral HPLC analysis was performed using a Shimadzu LC 10ADVP HPLC

equipped with a Shimadzu SPDM10AVP diode array detector using a Chiralpak (Daicel) AD-H column.

Elution speed was 0.5 mL/min, with mixtures of HPLC-grade heptane and isopropanol (BOOM) as eluent

and column temperature of 40 °C. Sample injections were made using an HP 6890 Series Auto sample

Injector. Chiral GC analysis was performed using a HP6890, equipped with capillary column Astec G-TA,

30m x 0.25mm, He-flow 1.0 mL/min, equipped with a flame ionization detector. UV-vis absorption spectra

were measured on a SPECORD S600 Analityk Jena spectrophotometer. CD spectra were measured on a

Jasco J-815 CD spectrophotometer. All spectra were recorded at 20 °C using Uvasol-grade dichlorometane

(Merck) as solvent. Irradiation was performed using Thorlabs M365F1 (365 nm) and M420F2 (420 nm)

fibre-coupled coupled high power LEDs. Room temperature (rt) as mentioned in the experimental

procedures, characterization and computational sections is to be considered equal to 20 °C. The chiral

descriptors for each species described in this work (e.g. (S,SP,M)-L) indicate respectively: the absolute

stereochemistry of the stereogenic center in the molecular switch core (R or S), the absolute stereochemistry

of the phosphorus center (RP or SP), and the configurational helicity and axial chirality of the switch core (P

or M). The doubly expressed point P-chirality stereodescriptor (RP/SP) throughout the text denote a mixture

of diastereoisomers with identical absolute stereochemistry and configurational helicity in the switch core

but opposite point chirality in the phosphorus center (e.g. (S,SP,M)-L indicates a mixture of (S,SP,M)-L and

(S,RP,M)-L).

Chapter 6

216


(M)-(12S)-13-(9H-fluoren-9-ylidene)-N,N,12-trimethyl-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-

f][1,3,2]dioxaphosphepin-6-amine (L1)

Compound L1 was prepared from 1 by a modified procedure previously

reported.58

A flame-dried Schlenk tube was equipped with vacuum/nitrogen

stopcock and a magnetic stirring bar and charged with racemic 1 (160 mg,

0.38 mmol), NH4Cl (4 mg, 0.07 mmol, 0.2 equiv), dry benzene (3 mL) and

tris(dimethylamino)phosphine (75 mg, 84 µL, 0.46 mmol, 1.25 equiv). The

reaction mixture was heated at reflux for 5 h. The mixture was concentrated

under reduced pressure affording a solid residue. The crude residue (56:44 mix. of diastereoisomers based

on 1H/

31P-NMR) was re-dissolved in dry Et2O (2 mL) and pentane (4 mL) was slowly added until

precipitation occurred. The precipitate was filtered on a glass fritted funnel P4 under vacuum and washed

with pentane to yield racemic L1 (85 mg, 0.173 mmol, 45%, (S,SP)-L1:(S,RP)-L1 = 91:9 dr) as yellow

powder containing a few mono-crystals. The same procedure was performed on an enantioenriched fraction

of (S,M)-1 (50 mg, 0.120 mmol, 90% ee) to yield enantioenriched (S,M)-L1 (90% ee, 91:9 dr) as yellow

powder. m.p. 196–198 °C. 1H NMR (400 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr, absorptions of only

major diastereoisomer are reported) δ 7.95–7.86 (m, 1H), 7.59–7.52 (m, 1H), 7.37 (dd, J = 7.8, 1.9 Hz, 2H),

7.31 (d, J = 8.1 Hz, 1H), 7.28–7.24 (m, 3H), 7.06 (td, J = 7.4, 1.0 Hz, 1H), 6.90 (td, J = 7.7, 1.3 Hz, 1H),

6.81 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.69–6.59 (m, 2H), 4.21 (hept, J = 6.8 Hz,

1H), 2.74–2.64 (m, 1H), 2.53 (d, J = 8.9 Hz, 6H), 2.48–2.34 (m, 2H), 1.60 (d, J = 6.9 Hz, 3H), 1.33–1.21

(m, 1H). 13

C NMR (75 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr, absorptions of only major

diastereoisomer are reported) δ 151.4 (d, J = 6.5 Hz), 149.4, 142.5, 140.7, 139.4 (d, J = 1.6 Hz), 138.5,

138.0, 137.5, 136.7, 134.6, 132.1 (d, J = 3.9 Hz), 130.6 (d, J = 1.1 Hz), 128.6 (d, J = 1.1 Hz), 128.3 (d, J =

2.0 Hz), 127.6, 127.10, 126.9, 126.6, 126.5, 124.8, 124.3, 122.1 (d, J = 2.2 Hz). 122.0, 121.4, 119.2, 118.0,

36.0, 35.8, 34.6, 31.5, 29.4, 21.7. 31

P NMR (162 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr) δ 146.1

(major), 145.5 (minor). HRMS (ESI, m/z): calcd for C32H29NO2P [M+H]+: 490.1930, found: 490.1917.

[ ] = -104 (c 0.2, CHCl3) for (S,M)-L1 (90% ee, (S,SP)-L1:(S,RP)-L1 = 91:9 dr).

(M)-(12S)-13-(9H-fluoren-9-ylidene)-N,N-diisopropyl-12-methyl-10,11,12,13-

tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-amine (L2)

Compound L2 was synthesis according to a modified published procedure.59

A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and

a magnetic stirring bar and charged with THF (1 mL) and Et3N (0.16 mL,

1.18 mmol, 7 equiv). The reaction mixture was cooled at 0 °C and PCl3

(0.016 mL, 0.18 mmol, 1.1 equiv) was added via syringe under stirring. A

flame-dried, 25 mL Schlenk tube was charged with diisopropylamine

(0.026 mL, 0.18 mmol, 1.1 equiv) and THF (0.5 mL). This mixture was added dropwise to the above

mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction mixture was let to stir at

room temperature over 2 h. A flame-dried, 25 mL Schlenk tube was charged with (S,M)-1 (70 mg,

0.17 mmol, 99% ee) and THF (1 mL). This mixture was added dropwise to the mixture of PCl3 and

secondary amine at 0 °C. The resulting mixture was warmed up to room temperature and stir overnight,

then filtered through celite, and washed with cold Et2O (2x5 mL). The organic phase was concentrated at

reduced pressure. The product was purified by column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and

stripped from CHCl3 (2x10 mL) to yield L2 (62 mg, 0.11 mmol, 62%, 99% ee, (S,SP)-L2:(S,RP)-L2 = 86:14

dr) as a yellow foam. m.p. 125–126 °C. 1H NMR (400 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ

7.99–7.92 (m, 1H), 7.63–7.56 (m, 1H), 7.48–7.39 (m, 2H), 7.36 (d, J = 8.0 Hz, 0.85H), 7.34–7.24 (m, 3H),

7.07 (t, J = 7.4 Hz, 1H), 6.98–6.82 (m, 2H), 6.74 (dd, J = 8.0, 5.6 Hz, 1.6H), 6.68 (t, J = 7.6 Hz, 1H), 4.30–

4.05 (m, 1H), 3.77 (dhept, J = 10.7, 6.6 Hz, 0.3H, minor d.), 3.37 (dhept, J = 10.6, 6.8 Hz, 1.70H, major d.),



217

2.71 (dt, J = 13.9, 3.4 Hz, 1H), 2.53–2.43 (m, 1H), 2.37 (td, J = 13.5, 4.9 Hz, 1H), 1.63 (d, J = 7.0 Hz,

2.50H), 1.59 (d, J = 7.0 Hz, 0.5H), 1.37 (dd, J = 6.8, 1.8 Hz, 1.8H), 1.32–1.24 (m, 1.5H), 1.20 (d, J =

4.2 Hz, 5.1H), 1.18 (d, J = 4.1 Hz, 5.1H). 13

C NMR (100 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ

152.5 (d, J = 8.3 Hz), 150.7, 144.2, 144.1, 141.0,140.0 (d, J = 1.5 Hz), 139.2, 139.0, 138.8, 138.5, 138.2,

138.1, 137.2 (d, J = 1.3 Hz), 134.8, 132.9, 132.92(d, J = 3.8 Hz), 131.6 (d, J = 1.0 Hz), 131.5 (d, J =

1.9 Hz), 129.1 (d, J = 1.2 Hz), 128.7 (d, J = 1.4 Hz), 128.2, 128.2, 127.8 (d, J = 1.4 Hz), 127.8, 127.7,

127.3, 127.3, 127.2, 127.2, 127.1, 125.7, 125.6, 124.7, 124.6, 123.1 (d, J = 1.6 Hz), 122.9, 122.9 (d, J =

2.5 Hz), 122.7, 122.1, 122.0 (d, J = 1.0 Hz), 119.8, 119.7, 118.8, 118.7, 45.4 (d, J = 12.5 Hz), 45.2 (d, J =

12.6 Hz), 35.6, 35.5, 32.1, 31.9, 30.0, 30.0, 24.8, 24.8, 24.7, 22.3, 22.3. 31

P NMR (162 MHz, CD2Cl2,

(S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ 149.7 (major), 147.8 (minor). HRMS (ESI, m/z): calcd for C39H33NO2P

[M+H]+: 546.2556, found: 546.2549.

The mixture of diastereoisomers of L2 ((S,SP)-L2:(S,RP)-L2 = 86:14 dr) was further purified by column

chromatography (SiO2, pentane:CH2Cl2 = 6:1) to yield L2 as two fractions with different dr (1st fraction:

31 mg, 0.056 mmol, (S,SP)-L2:(S,RP)-L2 = 98:2 dr; 2nd

fraction: 30 mg, 0.055 mmol, (S,SP)-L2:(S,RP)-L2 =

60:40 dr). 1H NMR (400 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 98:2 dr, absorptions of only major

diastereoisomer are reported) δ 7.99–7.89 (m, 1H), 7.63–7.57 (m, 1H), 7.45 (dd, J = 7.8, 1.6 Hz, 1H), 7.42

(d, J = 7.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.34–7.25 (m, 3H), 7.07 (td, J = 7.4 Hz, 1H), 6.92–6.85 (m,

2H), 6.74 (dd, J = 8.0, 5.3 Hz, 2H), 6.68 (t, J = 7.4 Hz, 1H), 4.22 (sest, J = 7.3 Hz, 1H), 3.37 (dp, J = 10.7,

6.8 Hz, 2H), 2.71 (ddd, J = 14.0, 4.1, 2.8 Hz, 1H), 2.52–2.26 (m, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.33–1.20

(m, 1H), 1.20 (d, J = 6.8 Hz, 6H), 1.19 (d, J = 6.8 Hz, 6H). 13

C NMR (100 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-

L2 = 98:2 dr, absorptions of only major diastereoisomer are reported) δ 152.5 (d, J = 8.4 Hz), 150.7, 144.1,

141.0, 140.0 (d, J = 1.7 Hz), 139.0, 138.5, 138.1, 137.2 (d, J = 1.7 Hz), 134.8, 132.9 (d, J = 3.8 Hz), 131.6

(d, J = 1.3 Hz), 128.7 (d, J = 1.4 Hz), 128.2 (2, J = 1.1 Hz), 127.7, 127.3, 127.2, 127.2, 125.6, 124.7,122.9

(d, J = 2.4 Hz), 122.1, 122.0 (d, J = 1.4 Hz), 119.7, 118.65, 45.3, 45.2, 35.6, 32.1, 30.0, 24.8, 24.7, 22.3.

[ ]

= -201 (c 0.2, CHCl3) for (S,M)-L2 (>99% ee, (S,SP)-L2:(S,RP)-L2 = 98:2 dr).

(P)-(12R)-13-(9H-fluoren-9-ylidene)-12-methyl-N,N-bis((R)-1-phenylethyl)-10,11,12,13-


Compound L3 was synthesis according to a modified published

procedure.59

A flame-dried Schlenk tube was equipped with

vacuum/nitrogen stopcock and a magnetic stirring bar. The Schlenk

tube was charged with THF (0.5 mL) and Et3N (0.27 mL, 1.9 mmol,

10 equiv). The reaction mixture was cooled at 0 °C and a solution of

PCl3 (0.017 mL, 0.19 mmol, 1 equiv) in CH2Cl2 (0.1 mL) was added

via syringe under stirring. A flame-dried, 25 mL Schlenk tube was charged with bis[(R)-1-

phenylethyl]amine (0.043 mL, 0.19 mmol, 1 equiv) and THF (1 mL). This mixture was added

dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction

mixture was stirred at room temperature over 2 h and then CH2Cl2 (1 mL) was added. A flame-dried,

25 mL Schlenk tube was charged with (R,P)-1 (80 mg, 0.19 mmol, 96% ee) and THF (0.8 mL +

0.4 mL for rinsing). This solution was added dropwise to the mixture of PCl3 and secondary amine at

0 °C. The resulting mixture was let to warm up to room temperature and stir overnight, then filtered

through celite and washed with cold Et2O (2x5 mL). The organic phase was concentrated at reduced

pressure. The product was purified by column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and

stripped from CHCl3 (2x10 mL) to yield L3 (66 mg, 0.10 mmol, 52%, 96% ee, (R,RP)-L3:(R,SP)-L3 =

95:5 dr) as a yellow foam. m.p. 201–202 °C. 1H NMR (400 MHz, CD2Cl2, (R,RP)-L3:(R,SP)-L3 = 95:5 dr,

absorptions of only major diastereoisomer are reported) δ 7.95–7.87 (m, 1H), 7.60–7.52 (m, 1H), 7.45 (d, J

= 7.7 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.35–7.23 (m, 4H), 7.18–7.09 (m, 11H), 7.06 (t, J = 7.3 Hz, 1H),

Chapter 6

218

6.94–6.83 (m, 3H), 6.70–6.62 (m, 2H), 4.47 (dq, J = 13.9, 7.1 Hz, 2H), 4.18 (h, J = 7.4, 6.5 Hz, 1H), 2.68

(dt, J = 14.0, 3.5 Hz, 1H), 2.49–2.40 (m, 1H), 2.35 (td, J = 13.5, 5.0 Hz, 1H), 1.84 (d, J = 7.1 Hz, 0.5H,

chiral amine methyl peak of minor diastereoisomer), 1.67 (d, J = 7.1 Hz, 6H), 1.61 (d, J = 6.9 Hz, 3H),

1.33–1.19 (m, 2H). 13

C NMR (100 MHz, CD2Cl2, (R,RP)-L3:(R,SP)-L3 = 95:5 dr, absorptions of only major

diastereoisomer are reported) δ 151.6 (d, J = 9.2 Hz), 149.4, 143.4, 143.2, 140.4, 139.8 (d, J = 1.7 Hz),

138.4, 137.9, 137.4, 136.7 (d, J = 1.7 Hz), 134.3, 132.4 (d, J = 3.9 Hz), 131.4 (d, J = 1.2 Hz), 128.3 (d, J =

1.6 Hz), 127.9, 127.9, 127.8, 127.7 (d, J = 1.4 Hz), 127.7, 127.4 (d, J = 2.2 Hz), 127.2, 126.8, 126.7, 126.6,

126.6, 126.5, 125.0, 124.9, 124.0, 122.4 (d, J = 2.7 Hz), 121.5 (d, J = 1.3 Hz), 121.5, 119.1, 118.1, 52.1 (d,

J = 12.1 Hz), 35.0, 31.5. 31

P NMR (162 MHz, CD2Cl2, (R,RP)-L3:(R,SP)-L3 = 95:5 dr) δ 143.4 (major),

142.6 (minor). HRMS (ESI, m/z): calcd for C46H41NO2P [M+H]+: 670.2868, found: 670.2869. [ ]

=

+296 (c 0.2, CHCl3) for (R,P)-L3 (>99% ee, (R,RP)-L3:(R,SP)-L3 = 95:5 dr).

(12S)-13-(9H-fluoren-9-ylidene)-12-methyl-N,N-bis((R)-1-phenylethyl)-10,11,12,13-



procedure.59


vacuum/nitrogen stopcock and a magnetic stirring bar and charged with

THF (0.5 mL) and Et3N (0.27 mL, 1.9 mmol, 10 equiv). The reaction

mixture was cooled at 0 °C and a solution of PCl3 (0.017 mL, 0.19 mmol,

1 equiv) in CH2Cl2 (0.1 mL) was added via syringe under stirring. A

flame-dried, 25 mL Schlenk tube was charged with bis[(R)-1-

phenylethyl]amine (0.043 mL, 0.19 mmol, 1 equiv) and THF (1 mL). This mixture was added dropwise to

the above mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction mixture was let to

stir at room temperature over 2 h and then CH2Cl2 (1 mL) was added. A flame-dried, 25 mL Schlenk tube

was charged with (S,M)-1 (80 mg, 0.19 mmol, 99% ee) and THF (0.8 mL + 0.4 mL for rinsing). This

mixture was added dropwise to the mixture of PCl3 and secondary amine at 0 °C. The resulting mixture was

let to warm up to room temperature and stir overnight, then filtered through celite and washed with cold

Et2O (2x5 mL). The organic phase was concentrated at reduced pressure. The product was purified by

column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and stripped from CHCl3 (2x10 mL) to yield L4

(50 mg, 0.08 mmol, 40%, 99% ee, (S,SP)-L4:(S,RP)-L4 = 92:8 dr) as a yellow foam. m.p. 213–215 °C. 1H NMR (400 MHz, CD2Cl2, (S,SP)-L4:(S,RP)-L4 = 92:8 dr) δ 7.96–7.88 (m, 1H), 7.61–7.52 (m, 1H), 7.45

(d, J = 7.8 Hz, 1H), 7.43–7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.32–7.24 (m, 2H), 7.20–7.11 (m, 9H),

7.07 (t, J = 7.3 Hz, 1H), 6.86 (q, J = 7.5, 6.9 Hz, 1H), 6.76–6.69 (m, 3H), 6.63–6.57 (m, 1H), 4.46–4.34 (m,

2H), 4.20 (h, J = 7.4 Hz, 1H), 2.71 (dt, J = 14.2, 3.4 Hz, 1H), 2.51–2.31 (m, 2H), 1.84 (d, J = 7.1 Hz, 0.5H,

chiral amine methyl peak of minor diastereoisomer), 1.69 (d, J = 7.1 Hz, 6H), 1.62 (d, J = 6.9 Hz, 3H), 1.27

(d, J = 7.1 Hz, 2H). 13

C NMR (100 MHz, CD2Cl2, , (S,SP)-L4:(S,RP)-L4 = 92:8 dr) δ 152.1 (d, J = 11.6 Hz),

149.7, 143.4, 143.2, 143.2, 140.4, 139.9, 138.5, 137.9, 137.4, 136.7, 134.3, 132.6, 131.6, 131.6, 128.3 (d, J

= 1.9 Hz), 128.1 (d, J = 3.1 Hz), 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.2, 126.8, 126.7, 126.6,

126.6, 125.1, 125.0, 124.0, 123.8, 122.5 (d, J = 2.8 Hz), 121.7, 121.2, 119.2, 119.2, 54.1 (d, J = 10.9 Hz),

35.0, 31.6, 29.7, 29.4, 22.6 (d, J = 12.1 Hz), 21.7. 31

P NMR (162 MHz, CD2Cl2, (S,SP)-L4:(S,RP)-L4 = 92:8

dr) δ 148.8 (major), 147.3 (minor). HRMS (ESI, m/z): calcd for C46H41NO2P [M+H]+: 670.2868, found:

670.2869. [ ] = +106 (c 0.2, CHCl3) for (S,M)-L4 (>99% ee, (S,SP)-L4:(S,RP)-L4 = 92:8 dr).



219

(M)-(1-((12S)-13-(9H-fluoren-9-ylidene)-12-methyl-10,11,12,13-tetrahydrobenzo

[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-yl)-1,2,3,4-tetrahydroquinoline (L5)


procedure.60


vacuum/nitrogen stopcock and a magnetic stirring bar. The Schlenk tube

was charged with toluene (2 mL) and PCl3 (13 µL, 0.15 mmol, 1.1 equiv),

and then cooled at 0 °C. A flame-dried, 25 mL Schlenk tube was charged

with 1,2,3,4-tethrahydroquinoline (19.7 mg, 0.15 mmol, 1.1 equiv),

toluene (0.35 mL), and Et3N (35 µL, 0.25 mmol, 1.85 equiv). This mixture

was added dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the

reaction mixture was heated at 80 °C for 6 h, and then was cooled at -78 °C slowly. A flame-dried, 25 mL

Schlenk tube was charged with (S,M)-1 (56 mg, 0.135 mmol, 99% ee) and Et3N (65 µL, 0.47 mmol) in

toluene (1.25 mL) and THF (0.4 mL). This mixture was added dropwise to the mixture of PCl3 and

secondary amine at -78 °C. The resulting mixture was let to warm up to room temperature and stir

overnight, then filtered through celite and washed with cold Et2O (2x5 mL). The organic phase was

concentrated at reduced pressure. The product was purified by column chromatography (SiO2,

pentane:CH2Cl2 = 5:1) and stripped from CHCl3 (2x10 mL) to yield L5 (43 mg, 0.074 mmol, 55%, 99% ee,

(S,SP)-L5:(S,RP)-L5 = 60:40 dr) as a yellow foam. m.p. 165-167 °C. 1H NMR (500 MHz, CD2Cl2, (S,SP)-

L5:(S,RP)-L5 = 60:40 dr) δ 8.01–7.96 (m, 0.4H), 7.96–7.91 (m, 0.6H), 7.64–7.56 (m, 1H), 7.50–7.40 (m,

3H), 7.38 (d, J = 8.1 Hz, 0.6H, major d.), 7.35–7.27 (m, 3.2H), 7.20 (d, J = 8.0 Hz, 0.4H, minor d.), 7.16–

7.04 (m, 3H), 7.02 (d, J = 7.9 Hz, 0.4H, minor d.), 6.98–6.82 (m, 3.4H), 6.80 (d, J = 7.9 Hz, 0.6H), 6.77–

6.71 (m, 1H), 6.68 (d, J = 8.0 Hz, 0.6H, major d.), 4.32–4.17 (m, 1H), 3.99–3.91 (m, 0.4H, minor d.), 3.36–

3.23 (m, 1H), 2.95–2.82 (m, 0.8H, minor d.), 2.78–2.64 (m, 3.2H) 2.52–2.44 (m, 1H), 2.40 (td, J = 13.4,

4.8 Hz, 1H), 2.08–1.91 (m, 0.8H, minor d.), 1.71–1.65 (m, 1.4H), 1.62 (d, J = 7.0 Hz, 1.8H, major d.), 1.58

(d, J = 6.9 Hz, 1.2H, minor d.), 1.35–1.17 (m, 2H). 13

C NMR (126 MHz, CD2Cl2, (S,SP)-L5:(S,RP)-L5 =

60:40 dr) δ 151.80 (d, J = 6.8 Hz), 151.2 (d, J = 7.1 Hz), 150.9, 149.6, 143.8, 143.7, 142.7, 142.5, 141.0,

140.9, 140.6, 140.6, 139.7 (d, J = 1.0 Hz), 139.3, 139.1, 138.5, 138.5, 138.2, 138.0, 137.5 (d, J =

1.1 Hz),135.0, 135.0, 131.6, 131.6, 131.5, 131.5,130.5, 130.4, 129.3 (d, J = 1.2 Hz), 129.3, 128.8 (d, J =

1.8 Hz), 128.4, 127.9, 127.8, 127.7, 127.5, 127.5, 127.4, 127.3, 127.3, 126.8 (d, J = 2.6 Hz), 126.6 (d, J =

2.2 Hz), 126.6, 125.7, 127.7, 125.6, 124.7, 124.6, 123.7 (d, J = 1.1 Hz), 122.8 (d, J = 0.9 Hz), 122.7 (d, J =

2.3 Hz),122.9, 122.5 (d, J = 2.4 Hz),122.2 (d, J = 1.4 Hz), 122.1 (d, J = 1.7 Hz), 122.0, 119.9, 119.8, 119.0,

119.0, 118.9,118.8, 118.8, 118.7, 43.2 (d, J = 3.9 Hz), 42.4 (d, J = 2.9 Hz), 35.4, 35.4, 32.0, 31.8, 30.0,

30.0, 27.9, 27.4, 24.4, 24.0, 22.24, 22.1. 31

P NMR (162 MHz, CD2Cl2, (S,SP)-L5:(S,RP)-L5 = 60:40 dr) δ

140.4 (major d.), 138.6 (minor d.). HRMS (ESI, m/z): calcd for C39H33NO2P [M+H]+: 578.2243, found:

578.2240. [ ] = +167 (c 0.2, CHCl3) for (S,M)-L5 (>99% ee, (S,SP)-L5:(S,RP)-L5 = 60:40 dr).

6.5.3 X-ray Crystallography

A racemic fraction of compound L1 (56:44 dr) was recrystallized from a solution of diethyl ether upon

addition of pentane as reported in the experimental procedure. Among various non-crystalline

agglomerates, a single crystal of (S,RP,M)-L1 was obtained. The single crystal was mounted on top of a

cryoloop and transferred into the cold nitrogen stream (100 K) of a Bruker-AXS D8 Venture

diffractometer. Data collection and reduction was done using the Bruker software suite APEX3.61

The final

unit cell was obtained from the xyz centroids of 9994 reflections after integration. A multiscan absorption

correction was applied, based on the intensities of symmetry-related reflections measured at different

angular settings (SADABS). The structures were solved by direct methods using SHELXT

62 and refinement

of the structure was performed using SHLELXL.63

The hydrogen atoms were generated by geometrical

considerations, constrained to idealized geometries and allowed to ride on their carrier atoms with an

isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms.

Crystal data and details on data collection and refinement are presented in Table 6.2.

Chapter 6

220

Table 6.2. Crystallographic data for (S,RP,M)-L1.

6.5.4 Atropisomers assignment via comparison of calculated and experimental NMR spectra

Structure optimization of diastereoisomers (S,SP,M)-L2 and (S,RP,M)-L2 was executed with DFT (b3lyp/6-

31g(d,p)) in gas-phase. The 1H-NMR signals were predicted using GIAO (mPW1PW91/6-311+g(2d,p))

method with chloroform SMD solvation model, using literature reported scaling factors.64

Calculated 1H

NMR spectra of stable isomers (S,SP,M)-L2 and (S,RP,M)-L2 were compared with corresponding

experimental spectra (Figures 6.10 and 6.11). Figures 6.9b,c illustrate the corresponding calculated

optimized geometries of predominant conformers with labelled atoms for NMR absorption assignment

listed in Table 6.3.

Calculated 1H NMR multiplet reports:

(S,SP,M)-L2: 1H NMR (400 MHz, CDCl3) δ 7.75 (1H, T) , 7.49 (1H, Q), 7.46 (1H, L), 7.36 (1H, P), 7.18

(1H, G), 7.17 (1H, H), 7.16 (1H, S), 7.13 (1H, R), 6.94 (1H, O), 6.80 (1H, J), 6.77 (1H, N), 6.74 (1H, I),

6.69 (1H, M), 6.66 (1H, K), 4.16 (1H, B), 3.31 (2H, V), 2.61 (1H, E), 2.37 (1H, D), 2.27 (1H, F), 1.57 (3H,

A), 1.14 (12H, U), 1.20 (1H, C).

(S,RP,M)-L2: 1H NMR (400 MHz, CDCl3) δ 7.78 (1H, T), 7.52 (1H, Q), 7.43 (1H, L), 7.36 (1H, ), 7.16

(1H, G), 7.29 (1H, H), 7.21 (1H, S), 7.17 (1H, R), 6.96 (1H, O), 6.81 (1H, J), 6.83 (1H, N), 6.76 (1H, I),

6.90 (1H, M), 6.65 (1H, K), 4.18 (1H, B), 3.75 (2H, V), 2.67 (1H, E), 2.39 (1H, D), 2.27 (1H, F), 1.55 (3H,

A), 1.37 (12H, U), 1.19 (1H, C).

Based on calculated chemical shifts, the experimental absorption were assigned to the major

diastereoisomer (S,SP,M)-L2 and minor diastereoisomer (S,RP,M)-L2, respectively (structures depicted in

Figure 6.9a). More precisely:

the protons (from 62-H to 76-H, assigned to absorption peak U in experimental 1H NMR spectrum) on

the four methyl substituents on the diisopropyl groups of (S,SP,M)-L2 (experimental chemical shift:

1.20–1.19 ppm, average calculated value: 1.14 ppm) resonate at lower frequency than (S,RP,M)-L2

(experimental chemical shift: 1.37 ppm, average calculated value: 1.26 ppm);

the two tertiary protons (58-H and 60-H, assigned to absorption peak V in experimental 1H NMR

spectrum) on the diisopropyl groups of (S,SP,M)-L2 (experimental chemical shift: 3.37 ppm, average

chem formula C32 H28 N O2 P µ(Mo K ), cm

-1

0.143

Mr 489.52 F(000) 516

cryst syst triclinic temp (K) 100(2)

color, habit light yellow, block range (deg) 2.967 – 27.872

size (mm) 0.25 x 0.21 x 0.08 data collected (h,k,l) -12:12, -13:13, -17:17

space group P -1 no. of rflns collected 47480

a (Å) 9.6686(15) no. of indpndt reflns 5852

b (Å) 10.4782(15) observed reflns 5017 (Fo 2 (Fo))

c (Å) 13.3775(18) R(F) (%) 3.92

V (Å3) 1229.7(3) wR(F

2) (%) 10.32

, deg 106.231(6) GooF 1.030

, deg 94.610(7) Weighting a,b 0.0490, 0.7448

, deg 106.368(6) params refined 328

Z 2 restraints 0

calc, g.cm-3

1.322 min, max resid dens -0.397, 0.359



221

calculated value: 3.31 ppm) resonate at lower frequency than (S,RP,M)-L2 (experimental chemical

shift: 3.77 ppm, average calculated value: 3.75 ppm);

the protons (from 45-H to 47-H, assigned to absorption peak A in experimental 1H NMR spectrum) on

methyl substituent at the stereogenic center of (S,SP,M)-L2 (experimental chemical shift: 1.63 ppm,

average calculated value: 1.57 ppm) resonate at higher frequency than (S,RP,M)-L2 (experimental

chemical shift: 1.59 ppm, average calculated value: 1.55 ppm).

Figure 6.9. a) Schematic structure representation of diasteroisomers (S,SP,M)-L2 (amine substituent sin

with methyl substituent in the switch unit) and (S,RP,M)-L2 (amine substituent anti with methyl substituent

in the switch unit), proton labelled according to assignment via analysis of experimental NMR spectra (vide

infra). b) Calculated optimized geometries of (S,SP,M)-L2 (front and back view). c) Calculated optimized

geometries of (S,RP,M)-L2 (front and back view). Calculations and rendering performed by J.C.M.

Kistemaker and T. van Leeuwen.

Chapter 6

222

Table 6.3. List of 1H NMR chemical shifts of labelled atoms for diastereoisomer assignment, obtained and

assigned via experimental 1H NMR and calculation studies.

Experimental 1H NMR absorptions

chemical shift (ppm)

Calculated magnetic shielding (left) and 1H NMR absorptions

chemical shift (ppm, right)

Atom label Major diast. Minor diast. (S,SP,M)-L2 (S,RP,M)-L2

37-H (T) 7.99–7.89 7.99–7.89 23.33 7.75 23.30 7.78

34-H (Q) 7.63–7.57 7.63–7.57 23.61 7.49 23.58 7.52

42-H (L) 7.45 7.45 23.64 7.46 23.68 7.43

32-H (P) 7.42 7.42 23.75 7.36 23.75 7.36

41-H (G) 7.36 7.36 23.95 7.18 23.97 7.16

51-H (H) 7.34–7.25 7.34–7.25 23.96 7.17 23.83 7.29

36-H (S) 7.34–7.25 7.34–7.25 23.97 7.16 23.92 7.21

35-H (R) 7.34–7.25 7.34–7.25 24.00 7.13 23.96 7.17

31-H (O) 7.07 7.07 24.22 6.94 24.18 6.96

44-H (J) 6.92–6.85 6.92–6.85 24.36 6.80 24.36 6.81

30-H (N) 6.92–6.85 6.92–6.85 24.40 6.77 24.34 6.83

52-H (I) 6.74 6.74 24.43 6.74 24.41 6.76

33-H (M) 6.74 6.74 24.48 6.69 24.26 6.90

43-H (K) 6.68 6.68 24.52 6.66 24.53 6.65

19-H (B) 4.22 4.30–4.05 27.26 4.16 27.23 4.18

60-H (V) 3.37 3.77 28.01 3.46;

3.31 (avg.) 27.25 4.16; 3.75 (avg.)

58-H (V) 3.37 3.77 28.35 3.16;

3.31 (avg.) 28.14 3.34; 3.75 (avg.)

49-H (E) 2.71 2.71 28.95 2.61 28.89 2.67

38-H (D) 2.53–2.43 2.53–2.43 29.21 2.37 29.19 2.39

50-H (F) 2.37 2.37 29.32 2.27 29.32 2.27

47-H (A) 1.63 1.59 29.67 1.95; 1.57 (avg.) 29.66 1.96; 1.55 (avg.)

76-H (U) 1.20 1.37 29.98 1.67; 1.14(avg.) 30.40 1.29; 1.37 (avg.)

45-H (A) 1.63 1.59 30.15 1.51; 1.57 (avg.) 30.13 1.53; 1.55 (avg.)

70-H (U) 1.20 1.37 30.16 1.50; 1.14 (avg.) 30.34 1.34; 1.37 (avg.)

71-H (U) 1.20 1.37 30.25 1.42; 1.14 (avg.) 30.59 1.10; 1.37 (avg.)

74-H (U) 1.20 1.37 30.42 1.27; 1.14 (avg.) 30.19 1.48; 1.37 (avg.)

46-H (A) 1.63 1.59 30.42 1.27; 1.57 (avg.) 30.52 1.17; 1.55 (avg.)

72-H (U) 1.20 1.37 30.46 1.23; 1.14 (avg.) 30.05 1.60; 1.37 (avg.)

39-H (C) 1.33–1.20 1.32–1.24 30.49 1.20 30.50 1.19

75-H (U) 1.20 1.37 30.52 1.17; 1.14 (avg.) 30.29 1.38; 1.37 (avg.)

64-H (U) 1.19 1.37 30.59 1.11; 1.14 (avg.) 30.39 1.29; 1.37 (avg.)

67-H (U) 1.19 1.37 30.60 1.10; 1.14 (avg.) 30.71 1.00; 1.37 (avg.)

68-H (U) 1.19 1.37 30.67 1.04; 1.14 (avg.) 30.45 1.23; 1.37 (avg.)

63-H (U) 1.19 1.37 30.83 0.89; 1.14 (avg.) 30.85 0.87; 1.37 (avg.)

66-H (U) 1.19 1.37 31.07 0.67; 1.14 (avg.) 30.41 1.27; 1.37 (avg.)

62-H (U) 1.19 1.37 31.18 0.57; 1.14 (avg.) 30.34 1.33; 1.37 (avg.)



223

Figure 6.10. 1H NMR spectrum comparison of experimental (top) and calculated optimized structures

(bottom) of major diastereoisomer (S,SP,M)-L2 (CD2Cl2). Atom label assignment as listed in Table 6.3.

Figure 6.11. 1H NMR spectrum comparison of experimental (top) of a mixture of (S,SP,M)-L2:(S,RP,M)-L2

= 65:35 and calculated optimized structures (bottom) of minor diastereoisomer (S,RP,M)-L2 (CD2Cl2).

Atom label assignment as listed in Table 6.3. Resolved absorption peaks of major diastereoisomer (S,SP,M)-

L2 marked with a bar and should be ignored.

Chapter 6

224

6.5.5 Irradiation experiments: analysis by UV-vis absorption and CD spectroscopy

A solution of ligand L in dichloromethane (L1, 91:9 dr, 7.0·10-5

M; L2, 98:2 dr, 5.5·10-5

M; L3, 95:5 dr,

4.8·10-5

M; L4, 92:8 dr, 5.8·10-5

M; L5, 60:40 dr, 7.0·10-5

M) was transferred in a fluorescence quartz

cuvette with magnetic stirrer and degassed with argon under stirring for 5 min. The forward and backward

irradiation process was monitored by UV-vis absorption spectroscopy via time-course measurement

(wavelength range 300–650 nm, scan periods of 20 s). After starting the time-course measurements, the

sample was irradiated under stirring with the proper LED source positioned perpendicularly to the analysis

path of the spectrophotometer (average irradiation time: 5 min at 365 nm, 10 min at 420 nm). To ensure

that the PSS was reached, irradiations were continued until no further changes in the absorption spectra

were observed. Five cycles of forward and backward irradiation were performed sequentially on each

sample. CD spectra were recorded for the same starting solution of L and after reaching the photostationary

state, respectively, at 365 nm and 420 nm during the first irradiation cycle. UV-vis and CD spectra of L2

are reported in the main text (Figure 6.2). UV-vis and CD spectra of L1-3-4-5 are reported in Figure 6.13.

6.5.6 Irradiation experiments: analysis by 1H NMR and

31P NMR spectroscopy

Ligand L (~4.0 mg) was dissolved in CD2Cl2 (0.65 mL). The sample was placed in an NMR tube together

with a sealed capillary containing concentrated H3PO4 (int. std. for 31

P NMR) and 1H NMR,

31P NMR and

gCOSY spectra were recorded. The sample was subsequently diluted with analytical grade CH2Cl2 (ca.

15 mL), transferred in a scintillation vial with a mangetic stirrer, sealed with a rubber septum and purged

via a needle with flow of nitrogen for 10 min. The septum was removed and the solution was irradiated

through the vial opening over 20 min under stirring by using the proper LED source (365 nm or 420 nm)

oriented vertically. The conversion towards either the isomer (S,M)-L at 365 nm or the isomer (S,P)-L at

420 nm was monitored periodically by transferring aliquots of the solution in a 1 mm path length quartz

cuvette and monitoring the change in UV-vis absorption spectra profile. To ensure that the PSS was

reached, irradiation was continued until no further changes in the spectra were observed. Five cycles of

forward and backward irradiation were performed sequentially on the same sample. The solution of L was

concentrated at reduced pressure at a temperature below 40 °C to avoid any thermal induced isomerization.

The residue was redissolved in CD2Cl2 (0.65 mL) and 1H NMR,

31P NMR, and gCOSY spectra were

recorded for each PSS mixture during the first irradiation cycle. For (S,SP,M)-L2 (98:2 dr), 1H and

31P NMR of the starting solution, PSS365 and PSS420 mixtures are reported in Figure 6.2 with assignment of

main distinctive peaks.

365 nm

(S,SP,M)-L

O

ONP

(S,SP,P)-L

R

R'

O

ON P

R

R'

(S,RP,M)-L

O

ONP

R

R'+

(S,RP,P)-L

O

ON P

R

R'

420 nm

+

Stable state diastereisomers Metastable state diastereisomers

CH2Cl2

Figure 6.12. Schematic representation of the photochemical E-Z isomerization of (S,SP/RP,M)-L to

(S,SP/RP)-L.



225

Chapter 6

226

In previous page: Figure 6.13. Photochemical isomerization study of ligands L1-L3-4-5 by UV-vis

absorption and CD spectroscopy. a) Photochemical E-Z isomerization of species (S,SP/RP,M)-L1-4-5 to

(S,SP/RP,P)-L1-4-5 and (R,RP/SP,P)-L3 to (R,RP/SP,M)-L3. Only the major diastereoisomer is shown.

Diasteroisomeric mixtures as reported in Scheme 6.3. Carbon and phosphorus configurations are preserved

upon switching. b-e) Left: UV-vis absorption spectral changes of the switching process of L1-3-4-5

(CH2Cl2, 2-5·10−5

M). Starting isomer (S,SP/RP,M)-L1-4-5 and (R,RP/SP,P)-L3 in black. Irradiation at 365

nm towards (S,SP/RP,P)-L1-4-5 and (R,RP/SP,M)-L3, respectively, afforded PSS365 mixtures (red).

Irradiation at 420 nm of the previous PSS365 mixtures resulted in reversed E-Z isomerization affording a

new PSS420 mixtures (blue). Inserts display irradiation cycles between the two PSS‘s mixtures for each

compound. Right: Corresponding experimental CD spectral changes of previous samples Note: PSS ratios

determined by 1H/

31P NMR analysis of the irradiated solutions.

The relative integration of the 31

P NMR absorptions of (S,SP/RP,M)-L and (S,SP/RP,P)-L (sum of

diastereoisomers) revealed PSS ratios in CH2Cl2 at 365 nm and 420 nm of (S,M)-L:(S,P)-L listed as follows

for each ligand.

L1: 31

P NMR (162 MHz, CD2Cl2) 147.16 (S,SP,M), 146.5 (S,RP,M), 145.1 (S,RP,P), 145.1 (S,SP,P).

PSS365 mixture → (S,SP/RP,M)-L1:(S,SP/RP,P)-L1 = 16:84.

PSS420 mixture → (S,SP/RP,M)-L1:(S,SP/RP,P)-L1 = 77:23.

L2: 31

P NMR (162 MHz, CD2Cl2) 150.3 (S,SP,M), 145.1 (S,RP,P), 145.1 (S,SP,P).

PSS365 mixture → (S,SP,M)-L2:(S,SP,P)-L2 = 26:74.


L3: 31

P NMR (162 MHz, CD2Cl2) 144.8 (R,SP,M), 144.1 (R,RP,P), 144.1 (R,RP,M), 143.2 (R,SP,P).

PSS365 mixture → (R,RP,P)-L3:(R,RP,M)-L3 = 26:74.

PSS420 mixture → (R,RP,P)-L3:(R,RP,M)-L3 = 89:11.

L4: 31




L5: 31






227

Figure 6.14. 1H NMR and

31P NMR spectra of L1 (dr (S,SP):(S,RP) = 56:44, 4.0 mg, CD2Cl2 (0.65 mL),

25 °C): a) (S,SP/RP,M)-L1; b) after irradiation with UV light (365 nm) over 20 min of (S,SP/RP,M)-L1

towards (S,SP/RP,P)-L1 (PSS365 (M):(P) = 16:84); c) after irradiation with visible light (420 nm) over

20 min of PSS365 mixture towards (S,SP/RP,M)-L2 (PSS420 (M):(P) = 77:23). Residual solvent peak region

(4.80–5.50 ppm) cut for clarity. Insert: 31

P NMR spectra of corresponding sample.

Chapter 6

228



25 °C): a) (S,SP,M)-L2; b) after irradiation with UV light (365 nm) over 20 min of (S,SP,M)-L2 towards

(S,SP,P)-L2 (PSS365 (M):(P) = 26:74); c) after irradiation with visible light (420 nm) over 20 min of PSS365

mixture towards (S,SP,M)-L2 (PSS420 (M):(P) = 87:13). Residual solvent peak region (4.80–5.80 ppm) cut

for clarity. Insert: 31




229


31P NMR spectra of L3 (dr (R,RP):(R,SP)= 95:5, 4.0 mg, CD2Cl2 (0.65 mL),

25 °C): a) (R,RP/SP,P)-L3; b) after irradiation with UV light (365 nm) over 20 min of (R,RP/SP,P)-L3

towards (R,RP/SP,M)-L3 (PSS365 (P):(M) = 26:74); c) after irradiation with visible light (420 nm) over

20 min of PSS365 mixture towards (R,RP/SP,P)-L3 (PSS420 (P):(M) = 89:11). Residual solvent peak region



Chapter 6

230










231








Chapter 6

232

6.5.7 General procedures for the copper-catalyzed enantioselective additions of diethylzinc to 2-

cyclohex-2-enone and kinetic experiments

A Schlenk tube equipped with a stirring bar was charged with CuTC (0.005 mmol, 0.02 equiv) and the

specific ligand (S*,SP/RP,M*)-L (0.005 mmol, 0.02 equiv). The tube was sealed with a rubber septum and

connected to a vacuum/nitrogen line, then evacuated and backfilled with nitrogen three times. Dry diethyl

ether (1.0 mL) was added and the solution was stirred at room temperature over 5 min. Where reported, the

catalyst mixture was irradiated with 365 nm or 420 nm light (LED source) over 3 h under stirring at rt. The

PSS ratio of L was measured by CSP-HPLC analysis of an aliquot diluted in n-heptane:2-propanol = 95:5

and filtered through a syringe filter (see following section). Decane (0.012 mL, 0.063 mmol, 0.25 equiv,

int. std.) was injected via syringe and the Schlenk tube was transferred in a pre-cooled bath at -30 °C. After

10 min of stirring, a solution of diethylzinc (1.0 M in hexanes, 0.300 mL, 0.300 mmol, 1.2 equiv) was

added dropwise and the reaction mixture was stirred over 5 min. 2-Cyclohexen-1-one (24 mg, 0.024 ml,

0.250 mmol) was added dropwise and the solution was stirred at this temperature over 6 h. Aq. sat. NH4Cl

(3 mL) was added, the mixture was let to warm up to room temperature and the aqueous layer was

extracted with Et2O (3 x 3 mL). The combined organic layer was washed with brine, dried over anhydrous

MgSO4 and filtered. The crude mixture was submitted to GC-MS analysis to measure conversion and yield

by comparison with internal standard based on calibration curves. The volatiles were then removed at

reduced pressure (P > 600 mbar) and the residue was analyzed by 1H NMR spectroscopy to confirm the full

conversion of the starting material. The isolated yield was not determined due to volatily of product.

Purification by column chromatography (SiO2 pentane:Et2O = 4:1) yielded the pure product 3-

ethylcyclohexanone 3 as colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.46–1.48 (m, 8H), 1.42–1.17(m, 3H),

0.88 (t, J = 7.3, 3H). 13

C NMR (300 MHz, CDCl3) δ 212.2, 47.8, 41.5, 40.8, 30.9, 29.3, 25.3, 11.1. MS (EI)

for C8H14O: m/z 126 (M+). Enantiomeric excess (ee) of 3 was determined by Chiral GC analysis (Astec G-

TA, 30m x 0.25mm, He-flow 1.0 mL/min, isocratic 95 °C, Rt = 29.5 min (R), Rt = 31.8 min (S); or start at

40 °C, gradient 10 °C/min, hold at 95 °C, Rt = 33.6 min (R), Rt = 36.1 min (S). A variation in the

temperature program for Chiral GC analysis was due to change of the capillary column during this study.

The absolute configuration of major enantiomer of the product was assigned by comparison of the sign of

the optical rotation with reported data.65

The kinetic experiments (conversion vs. time) were performed by

monitoring the progress of the reaction over time. Aliquots (0.05 mL) of the reaction mixture were

withdrawn and quenched in a Et2O:MeOH = 3:1 solution (0.50 mL). Determination of the conversion was

performed by GC-MS analysis on each aliquot upon comparison with int. std. based on calibration curves.

Determination of the enantiomeric excess was performed by Chiral GC analysis on few selected aliquots

(start, middle, end of reaction).

6.5.8 HPLC analysis of irradiated catalyst mixture

Chiral HPLC analysis of each catalyst mixture obtained upon irradiation at 365 nm afforded the estimated

ratio of (M):(P) species. Prior addition of the substrate, an aliquot of the catalyst mixture was diluted with a

mixture of heptane:2-propanol = 95:5 and filtered with a syringe filter. Analysis was performed on CSP-

HPLC: Chiralpak AD-H, heptane:2-propanol = 97:3, flow rate = 0.5 mL/min, column temperature = 40 °C.

Proportional quantitative analysis was obtained by setting the PDA detector at the specific isosbestic point

(L1 - λ = 362 nm; L2 - λ = 362 nm; L3 - λ = 364 nm; L4 - λ = 364 nm; L5 - λ = 363 nm) as determined by

the UV-vis abs. analysis (vide supra).



233

6.6 References


10206.

(2) Kinbara, K.; Aida, T. Chem. Rev. 2005, 105, 1377–1400.

(3) Browne, W. R.; Feringa, B. L. Nat. Nanotechnol. 2006, 1, 25–35.



(5) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis, and Supplements 1 and

2; Springer, 2004.

(6) Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3–12.

(7) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chemical Reviews. American Chemical Society

2007, pp 5759–5812.

(8) Yu, J.; RajanBabu, T. V.; Parquette, J. R. J. Am. Chem. Soc. 2008, 130, 7845–7847.

(9) Desmarchelier, A.; Caumes, X.; Raynal, M.; Vidal-Ferran, A.; Van Leeuwen, P. W. N. M.; Bouteiller, L.

J. Am. Chem. Soc. 2016, 138, 4908–4916.




(13) Yamamoto, T.; Yamada, T.; Nagata, Y.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 7899–7901.






(19) Eigen, M.; Wilkins, R. G. In Mechanisms of Inorganic Reactions; American Chemical Society:

Washington, 1965; 55–80.

(20) Otsuki, J.; Akasaka, T.; Araki, K. Coordination Chemistry Reviews. 2008, pp 32–56.

(21) Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 12005–

12006.


(23) Schliwa, M. Molecular Motors; Wiley-VCH Verlag GmbH, 2006.


(25) Miyake, H.; Tsukube, H. Chem. Soc. Rev. 2012, 41, 6977–6991.

(26) Shinoda, S. Chem. Soc. Rev. 2013, 42, 1825–1835.

(27) Boiocchi, M.; Fabbrizzi, L. Chem. Soc. Rev. 2014, 43, 1835–1847.


(29) Ousaka, N.; Takeyama, Y.; Iida, H.; Yashima, E. Nat. Chem. 2011, 3, 856–861.

(30) Teichert, J. F.; Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486–2528.


124, 5037–5051.

(32) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353.


2016, 22, 13478–13487.

(34) The light-generated metastable states of this class of molecular switches displayed thermal decay

processes with remarkably long half-lives (t½ at 20 °C up to 1.3 years), allowing both pseudoenantiomers

of the molecular switches to be utilized without continuous irradiation for extended periods of time.


16784–16787.

(36) Greb, L.; Lehn, J.-M. J. Am. Chem. Soc. 2014, 136, 13114–13117.

(37) Vlatkovic, M.; Feringa, B. L.; Wezenberg, S. J. Angew. Chemie - Int. Ed. 2016, 55, 1001–1004.

(38) Pérez, M.; Fañanás-Mastral, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L. Nat. Chem.

2011, 3, 377–381.

(39) Zhao, D.; Fañanás-Mastral, M.; Chang, M.-C.; Otten, E.; Feringa, B. L. Chem. Sci. 2014, 5, 4216–4220.

(40) Buter, J.; Heijnen, D.; Vila, C.; Hornillos, V.; Otten, E.; Giannerini, M.; Minnaard, A. J.; Feringa, B. L.

Angew. Chemie - Int. Ed. 2016, 55, 3620–3624.



Chapter 6

234

(43) Grabulosa, A. In P-Stereogenic Ligands in Enantioselective Catalysis; Royal Society of Chemistry:

Cambridge, 2011; pp 5–16.

(44) Imamoto, T.; Kikuchi, S. I.; Miura, T.; Wada, Y. Org. Lett. 2001, 3, 87–90.

(45) The value of the phosphorus pyramidal inversion energy depends on parameters such as steric hindrance

and electron richness. Tertiary phosphines have racemization barriers energy higher than 120 kJ mol-1

,

corresponding to equilibration temperatures exceeding 100 °C with in some cases half-lives of

racemization processes in the time range of hours at such conditions.

(46) Reetz, M. T.; Ma, J.-A.; Goddard, R. Angew. Chemie Int. Ed. 2005, 44, 412–415.

(47) The P-chirogenic monodentate phosphoramidite ligands L were expected to be configurationally stable

during the photochemical isomerization and when used in a transition metal-catalyzed reaction.

(48) van Leeuwen, T.; Gan, J.; Kistemaker, J. C. M.; Pizzolato, S. F.; Chang, M.-C.; Feringa, B. L. Chem. Eur.

J. 2016, 22, 7054–7058.

(49) Gavrilov, K. N.; Benetsky, E. B.; Boyko, V. E.; Rastorguev, E. A.; Davankov, V. A.; Schäffner, B.;

Börner, A. Chirality 2010, 22, 844–848.

(50) Trost, B. M.; Bringley, D. A.; Silverman, S. M. J. Am. Chem. Soc. 2011, 133, 7664–7667.

(51) The two additional stereodescriptors (R1N,R

2N) for the amine unit are identical in L3 and L4 in all states

and have been omitted for simplicity.

(52) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chemie Int. Ed. 1997,

36, 2620–2623.

(53) van Zijl, A. W.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2004, 346, 413–420.

(54) Walsh, P.; Kozlowski, M. Fundamentals of asymmetric catalysis; University Science Books, 2009.


(56) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; Royal Society of Chemistry: Cambridge, 2007.

(57) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748–2749.

(58) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry 1994, 5, 699–708.

(59) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A. Synthesis (Stuttg). 2004, 2004, 2586–

2590.

(60) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2012, 134, 4812–4821.

(61) Bruker, (2016). APEX3, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.

(62) Sheldrick, G. M. Acta Crystallogr. Sect. A, Found. Adv. 2015, 71, 3–8.

(63) Sheldrick, G. M. Acta Crystallogr. A. 2008, 64, 112–122.

(64) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J. Chem. Rev. 2012, 112, 1839–1862.

(65) Rachwalski, M.; Jarzyński, S.; Leśniak, S. Tetrahedron: Asymmetry 2013, 24, 1117–1119.

Chapter 7 Chapter 6

Studies towards a Photoswitchable Chiral Organic

Phosphoric Acid based on an Overcrowded Alkene

for Organocatalyzed Asymmetric Transformations

This chapter describes the study towards the synthesis and application of a photoswitchable chiral

phosphoric acid based on a second generation molecular motor core. Direct derivatization of the 2,2’-

biphenol-derived chiral molecular switch described in Chapter 5 provided the target compound. Its

photoswitching properties were characterized by NMR, UV-vis and CD spectroscopy. The potential for

application of the chiral phosphoric acid as switchable organocatalyst in asymmetric transformations was

investigated. In order to increase catalytic activity and stereoselectivity, derivatization in the 3,3’-positions

of the biphenyl core was attempted.

Chapter 7

236

7.1 Introduction

The activation of a substrate by a chiral catalyst is now regarded as one of the most powerful strategies that

can be employed in the art of asymmetric synthesis.1 The development of small-molecule hydrogen-bond

donors has received a tremendous amount of attention, and the quest to reach the levels of control that

nature can achieve is a constant challenge.2 Brønsted acids have proven themselves to be highly efficient

and versatile catalysts for an ever expanding list of synthetic transformations.3 Their high efficiency relies

on the underlying concept of achieving LUMO-activation of substrates via acid catalysis within a

constricted chiral cavity. Upon protonation of the electrophile, a higher reactivity toward the nucleophile is

triggered while effectively preventing access to a single prochiral substrate face, thereby allowing an

asymmetric reaction to occur in a stereoselective fashion. Due their ease of synthesis and derivatization,

BINOL-phosphoric acid derivatives such as TRIP and TIPSY or vaulted phosphoric acids derived from

biaryl diols like VAPOL (Figure 7.1) have established themselves as most valuable players in the field.3

Figure 7.1. Established examples of chiral phosphoric acid catalysts.

They achieved this status by being highly versatile, easily tunable catalysts and have been shown to

catalyze a plethora of asymmetric transformations typically using operationally simple and mild reaction

conditions. Representative applications of chiral phosphoric acid are enantioselective metal-free reductive

amination,4–7

allylboration8–10

and Friedel–Crafts alkylation11–13

(Scheme 7.1). Extensive investigation

successfully broadened their use in over a hundred different reaction types (e.g. acetalization,14

aldol

reaction,15

Mannich reaction,16

Hetero-Diels–Alder reaction,17

C-H activation,18

etc.).

Studies towards a Photoswitchable Chiral Organic Phosphoric Acid based on an Overcrowded Alkene for

Organocatalyzed Asymmetric Transformations

237

Scheme 7.1. Representative applications of chiral phosphate derived Brønsted Acid in organocatalysis.

Common elements of phosphoric acid catalysts are: a rigid chiral aromatic backbone with possibility for

functionalization; Brønsted acidic and basic catalytic sites; tunable aromatic groups in proximity of the

catalytic center (Figure 7.2). These features were initially conceived by Sir John Cornforth, after a detailed

analysis of the requirements of the ideal catalyst to perform stereospecific hydration of alkenes.19

Figure 7.2. Design comparison between current BINOL-based phosphoric acids (left) and phosphinic acid

catalysts (right) developed by Cornforth.19

It should be noted that such strong chiral induction is only governed by the characteristic steric hindrance

around the phosphoric acid functionality. In such organocatalysts derived from a C2-symmetric biaryl

backbone, the phosphorus center could be described as pseudochiral or P-chirotopic according to the

Chapter 7

238

definition of Mislow and Siegel.20

It is noteworthy that during a reaction course, the P-chirotopic

phosphorus center becomes P-chirogenic by interaction with a prochiral substrate. Hence, asymmetric

induction is achieved via desymmetrization of the C2-symmetric Brønsted acidic/basic center by generating

a diastereoisomeric activated complex with the prochiral substrate. On the other hand, few unconventional

P-chirogenic21

organocatalysts22

with acidic properties have been described to date.23–25

Previously in our group, M. Vlatkovic conducted a study on the development of the first photoswitchable

phosphoric acid catalysts based on second generation molecular motors (Scheme 7.2).26

However their

challenging syntheses were not successful. The high sterically demanding overcrowded alkene core

prevented the homocoupling of the halogenated alkene precursor AP towards the creation of the C2-

symmetric binaphthyl-derived core featured in PA1 and PA2.

Scheme 7.2. Proposed design for photoswitchable phosphoric acids by M. Vlatković.26

Indeed, the proposed systems suffered from an overly complicated design and highly hindered structures.

Moreover, their operating mode relies on the cooperative photoswitching of both overcrowded alkene units

to achieve effective inversion of the chiral space around the phosphoric acid functionality. However, such

double isomerization process could potentially be affected by intramolecular quenching or detrimental

increase of steric hindrance upon photochemical E-Z isomerization of the first alkene functionality, thus

preventing or obstructing the photoswitching of the second one. The study was eventually redirected

towards the investigation of the photochemically and thermally induced isomerization of the single-alkene

precursor and two of its derivatives.


7.2.1 Design

Due to the plethora of successful applications of chiral phosphoric acids in asymmetric catalysis and chiral

induction, we decided to design a switchable chiral phosphoric acid upon derivatization of the previously

described bis(2-phenol)-substituted molecular switch 1 (Scheme 7.3). The proposed design was conceived

by merging the chiral biaryl-functionalized switch 1 with a flexible 2,2‘-biphenyl phosphoric acid

derivative. The study conducted on 1 (see Chapter 5) revealed a strong helicity-transfer of the switch‘s

chromophore to the biphenyl due to the high flexibility of the upper half‘s six membered ring. This was

expressed in the torsion angle of the biaryl moiety observed via X-ray crystal structure analysis of 1 (ω =

55.71°) and one of its phosphoramidite derivatives L1 (ω = 46.03° in solid state, see Chapter 6).

Calculation and experimental evidence supported the concept of coupled transfer of helicity with inversion

of local chirality around the coordinating center upon irradiation. Dual stereocontrol was demonstrated for

1 in the asymmetric catalyzed organozinc addition to aldehydes. A combination of change in catalytic

activity and enantioselectivity was observed for its phosphoramidite ligand derivatives L1–5 in the

asymmetric copper–catalyzed conjugated addition of diethylzinc to 2-cyclohexen-1-one. Similarly, we



239

envisioned switchable phosphoric acid catalyst 2 to provide dynamic asymmetric induction upon

photoisomerization when applied in an organocatalytic transformation. Moreover, due to the large variety

of phosphoric acid-catalyzed reactions, such design holds great expectations for the development of the first

artificial switchable catalyst capable of dynamically regulate a stereoselective tandem reaction.

Scheme 7.3. Proposed design of a photoswitchable phosphoric acid 2,2‘-biphenyl-substituted overcrowded

alkene 2, with axial helicity and chirality (green) of the 2,2‘-biphenyl core coupled to axial helicity (blue)

and point chirality (red) of the molecular switch scaffold. Here assigned descriptors are based on the

structure of compound (S)-1 (for explanation of the chiral descriptors, vide infra). Two states with opposite

coupled helicity can be selectively addressed by irradiation with UV-light: (S,M,Ra)-2 (S); (S,P,Sa)-2 (MS).

The system described herein features three stereochemical elements (see Scheme 7.3). The first element is

the stereogenic center of the switch (highlighted in red), which can exist with either the R or S

configuration. The second element is the helicity of the overcrowded alkene (highlighted in blue), which is

under thermal diastereoselective control by the configuration of the stereogenic center and can be inverted

upon photoisomerization. More precisely, the more stable diastereoisomer (stable state) of the R enantiomer

will adopt a P helicity, while the photo-generated diastereoisomer with higher energy (metastable state) will

adopt an M helicity. Third is the axial chirality of the biaryl unit (highlighted in green), which can be

assigned to either Ra or Sa according to the CIP rules. In Chapter 5 we demonstrated that the biaryl unit of

the parent compound 1 can only adopt a conformation in which the lower aryl group is parallel to the

fluorenyl lower half. By calculation and experimental evidence, the other conformations, with the biaryl

orientated perpendicular with respect to the lower half, were found to induce significant steric strain.

Despite such diastereotopic constraint, two distinct atropisomers were observed for both stable and

metastable states of compound 1. The singly ortho-substituted lower phenol group was in fact demonstrated

to rotate along the aryl-aryl bond, yielding a mixture of syn-conformer (S,M,Ra)-1 and anti-conformer

(S,M,Sa)-1. Such biaryl inversion implies a large variation of the aryl-aryl torsional angle (Δθ ≈ 180 °) upon

isomerization between o conformers (see Chapter 5, Figure 7.5.3). A thermodynamically favored cyclic

seven-membered ring conformation generated upon internal coordination via hydrogen bonding of the two

hydroxyl-substituents was proposed. Calculation and experimental evidence suggested that such

conformation has access to a transition state with a small barrier for biaryl isomerization, allowing for a fast

exchange of two atropisomers in solution at room temperature. Similarly to our previous study, we

expected conformations of 2 with matching helicities of biaryl and overcrowded alkene units to be highly

favored (Scheme 7.4b-c).

Chapter 7

240

Scheme 7.4. Example of top-down schematic view along the central double bond and front structural view

of S-(S,M,Ra)-2. Assigned stereodescriptors based on the structure of compound (S)-2. b) Schematic

representation of the two possible conformations of the biaryl moiety in the stable isomer. The conformer

with the aryl perpendicular to the lower half (right) experiences sterical hindrance. c) Schematic

representation of switching process between the stable state S-(S,M,Ra)-2 and metastable state MS-(S,P,Sa)-

2.

Hence, our proposed model entails a coupled helical-to-axial transfer of helicity, in which the most favored

conformation of the lower aryl substituent is parallel to the fluorenyl lower half of the switch core in either

stable and metastable states. Compared with the parent compound 1, the tricyclic biaryl unit of phosphoric

acid 2 permits a much more limited range of biaryl torsional angles. Similarly to the proposed cyclic seven-

membered ring conformation of 1, the covalently bound biphenyl-2,2′-diyl hydrogenphosphate unit is

expected to have access to a transition state with a small barrier for biaryl isomerization. Therefore, only

the conformation equivalent to the syn-conformer of 1 is allowed, i.e. (S,M,Ra)-2, while the conformation

equivalent to the anti-conformer of 1, i.e. (S,M,Sa)-2, is simply not structurally accessible (see Scheme

7.4b). Such constraint results in both helicity (P/M) and absolute axial chirality (Ra/Sa) of the biaryl unit to

be inextricably connected to the helicity (P/M) of the overcrowded alkene chromophore, having identical

biaryl and alkene helicities in each isomer. Two stereodescriptors (R/S and P/M) would be sufficient for the

description of any expected isomer reported in this work. However, three stereodescriptors (R/S, P/M and

Ra/Sa) would be used to highlight the coupled three-fold transfer of chirality within the system. Scheme

7.4c illustrates the switching process between stable state (S,M,Ra)-2 and metastable state (S,P,Sa)-2. We

envisioned that upon irradiation with UV-light the upper half containing the biaryl motif rotates with

respect to the fluorenyl lower half yielding a metastable state with opposite helicity (P→M) and inverted

biaryl axial chirality (Ra→Sa).

It should be noted that the chiral molecular switch backbone of 2 lacks of the C2-symmetry characteristic of

common BINOL-derived phosphoric acid catalysts. Such aspect has already been discussed for the

analogous phosphoramidite derivatives described in Chapter 6, which feature a fixed P-chirogenic

phosphorus center and a C1-symmetric chiral switch core. However, we envisioned a different behavior for

the design of 2 herein reported, due to its P-chirotopic center (Scheme 7.5). Indeed, the phosphoramidite

ligands L1–5 were obtained as a mixture of diasteroisomers, each of the latter displaying a distinctive



241

activity and opposite stereoselectivity in the asymmetric copper–catalyzed conjugated addition of

diethylzinc to 2-cyclohexen-1-one. It should be stressed that in L1–5 the reversal of helical and axial

chirality provided by the switch unit is not followed by an inversion of the phosphorus center. Hence, the

photo-generated metastable state (S,SP,P,Sa)-L would resemble the enantiomer of the stable state of the

opposite diastereoisomer (R,SP,P,Sa)-L (Scheme 7.5a). Consequently, a sharp change in catalytic activity

and stereoselectivity was observed. In comparison, the dynamic exchange of axial chirality should not, in

principle, significantly affect the catalytic potency of the P-chirotopic phosphoric acid center in 2. Due to

proton shift, the Brønsted acidic (P–OH) and basic (P=O) catalytic sites can exchange to provide the most

favorable substrate coordination and subsequent activation. Despite the tunable chiral induction provide by

the switch unit, the phosphoric center remains P-chirotopic until an activated catalyst-substrate complex is

formed. Therefore, we can suggest that upon irradiation and subsequent inversion of the local biaryl axial

chirality, the metastable state (S,P,Sa)-2 would effectively resemble the enantiomer of the stable state

(S,M,Ra)-2 (Scheme 7.5b), providing an opposite chiral induction in a stereoselective event while

maintaining a high catalytic efficiency.

Scheme 7.5. Comparison between P-chirogenic phosphoramidite switch derivatives L (see Chapter 6) and

P-chirotopic phosphoric acid derivative 2.

Compared with the design of PA1 and PA2 proposed by M. Vlatkovic (see Scheme 7.2), the switchable

photoswitchable phosphoric acid 2 features: simpler structural and operational designs, easier access to

large amount of enantioenriched starting material via chiral resolution, successful precedence of effective

reversible transfer of chirality. However, due the lower chiral constriction around the phosphoric acid site

of 2, functionalization of the 3,3‘-biaryl positions may be required to achieve efficient chiral transfer

towards the catalysis products.

In summary, our proposal is based on the following elements: a) the selective and reversible photo-

isomerization of the overcrowded alkene bond; b) the unique change in helicity featured by molecular

motors and switches; c) the coupled change in axial chirality of the biaryl core achieved via a central-to-

helical-to-axial transfer of chirality, d) the use of a switchable biaryl phosphoric acid functionality with

potentially manifold applications in asymmetric catalysis and chiral recognition.

Chapter 7

242

7.2.2 Synthesis

The synthesis of photoswitchable phosphoric acid 2 starting from 2,2‘-biphenol-derived molecular switch 1

is illustrated in Scheme 7.6 (for synthesis and chiral resolution of 1, see Chapter 5). Optically enriched

(S,M,Ra/Sa)-1 (90% ee) was reacted with POCl3 to yield (S,RP/SP,M,Ra)-3, which was obtained as 55:45

mixture of two diastereoisomers due to the newly generated P-chirogenic center. Upon heating at reflux in

pyridine in the presence of water, 3 was converted to the target compound (S,M,Ra)-2 as a single

diastereoisomer (95% yield over two steps, 90% ee).

Scheme 7.6. Synthesis of phosphoric acid switch derivative 2.

7.2.3 NMR spectroscopy

In order to investigate the photochemical behavior of 2, an NMR sample of stable state S-(S,M,Ra)-2 in

CDCl3 was irradiated with UV light (365 nm) for 60 min at room temperature. A schematic representation

of the photochemical E-Z isomerization of 2 with partial assignment of absorptions is presented in Figure

7.3a. 1H NMR spectra were taken before (Figure 7.3b), during (Figure 7.3c) and after irradiation (Figure

7.3d). Upon irradiation a new set of absorptions with intensities increasing over time was observed, which

is indicative of the photo-induced isomerization to the metastable state MS-(S,P,Sa)-2. At the

photostationary state, the relative integration revealed a final ratio of, respectively, S-(S,M,Ra)-2:MS-

(S,P,Sa)-2 = 20:80. The reverse photoisomerization towards the stable state was observed upon irradiation

of the sample with visible light (420 nm) over 180 min. 1H NMR spectra were also taken during (Figure

7.3e-f) and after irradiation (Figure 7.3g) at longer wavelength. The original set of absorption assigned to

the stable state was recovered. No evidence of decomposition was observed as suggested by the clean

profile of the final spectrum. At the photostationary state, the relative integration revealed a final ratio of,

respectively, S-(S,M,Ra)-2:MS-(S,P,Sa)-2 = 85:15. This preliminary experiment demonstrates the high

photoswitching efficiency of 2 in terms of PSS ratios and resistance to prolonged irradiation, as opposed to

the more sensitive precursor 1 (see Chapter 5).



243

Figure 7.3. Schematic representation of the photochemical E-Z isomerization of stable state S-(S,M,Ra)-2 to

metastable state MS-(S,P,Sa)-2. 1H NMR spectra of 2 (4.0 mg, CDCl3 (0.65 mL), 25 °C): b) S-(S,M,Ra)-2;

c-d) after irradiation with UV light (365 nm) over 30 min and 60 min, respectively, of S-(S,M,Ra)-2 to MS-

(S,P,Sa)-2 (PSS365 S:MS = 20:80); e-f-g) after irradiation with visible light (420 nm) over 60 min, 120 min

and 180 min, respectively, of PSS365 mixture towards S-(S,M,Ra)-2 (PSS420 S:MS = 85:15). Partial

absorptions assignment indicated by letters.

Chapter 7

244


The switching properties of (S)-2 were monitored by UV-vis absorption and circular dichroism (CD)

spectroscopy (Figure 7.4). A solution of S-(S,M,Ra)-2 (90% ee, chloroform, 6.2·10−5

M) in a quartz cuvette

was purged with argon and irradiated at room temperature towards either the metastable state using UV

light (365 nm, Figure 7.4a, black to red gradient) or the stable state using visible light (420 nm, Figure 7.4b,

red to blue gradient). The reversible photochemical E-Z isomerization was found to be characterized by a

clear isosbestic point at 367 nm, indicating the absence of side reactions. A bathochromic shift of the major

absorption band (π→π*) of about 40 nm was observed, indicative of an increase in alkene strain and

consistent with other second generation motors and switches as is expected for the metastable form MS-

(S,P,Sa)-2.27

In parallel, the same starting solution S-(S,M,Ra)-2 (90% ee, chloroform, 6.2·10−5

M) was

subjected to CD spectroscopy in order to perform a qualitative analysis of the change in its helical structure

(Figure 7.4c). The compound displayed a strong Cotton effect in the area of ~250–320 nm and slightly

smaller Cotton effects of opposite sign at higher wavelengths (λ > 320 nm). The presence of such negative

Cotton effect around 400 nm is an indication of the characteristic helical shape of the overcrowded alkenes

studied in our group. Upon irradiation with 365 nm light an inversion of the absorption band was observed,

which is indicative of an inversion in helicity and shows that the photochemical isomerization of the stable

S-(S,M,Ra)-2 to the metastable MS-(S,P,Sa)-2 has occurred. Upon irradiation with 420 nm light, the original

absorption band could be partially recovered.

Figure 7.4. a) Experimental UV-vis absorption spectra of stable (S,M,Ra)-2 (90% ee, CHCl3, 6.2·10−5

M,

black) and irradiation with UV-light (365 nm) of (S,M,Ra)-2 towards metastable state affording a PSS365

mixture (S:MS = 20:80, red) with isosbestic point at 367 nm. b) Experimental UV-vis absorption spectra of

irradiation of the previous PSS365 sample using visible light (420 nm), resulting in reversed E-Z

isomerization towards the stable state affording a new PSS420 mixture (S:MS = 85:15). c) Experimental and

CD spectra of (S)-2 (CHCl3, 6.2·10−1

M): black, starting stable state (S,M,Ra)-2; red: CD spectra of PSS365

mixture; blue: CD spectra of PSS420 mixture. Note: PSS ratios determined by 1H NMR analysis.


Having established the two-step reversible switching process of 2, we investigated its catalytic properties

by its use as a chiral catalyst in a few model asymmetric organocatalysis reactions.3 Due to its ability to

change chiral helicity upon application of an external stimulus and proven versatility of chiral phosphoric

acids in organocatalysis, we envisioned such system to permit dual stereocontrol in a variety of Brønsted

acid catalyzed transformations. Ultimate display of unprecedented efficiency in photoswitchable catalysis

would be the consecutive stereoselectivity control in a one-pot multi-step synthetic sequence. The assisted

tandem transformation may be composed of two processes generating distinct stereogenic centers.28

Noteworthy, the configuration of the secondly generated stereogenic center may be subject to stereospecific

substrate control exerted by the previously generated stereogenic center rather than by stereoselective

induction from the chiral catalyst. A large variety of switchable systems based on external activation of a

Brønsted acid and base catalysts have been reported.29–35

However, very limited examples have been shown

to achieve dual stereocontrol.36–39

In particular, no precedent system was harnessing the internal transfer



245

from helical to axial to point chirality before the work reported in this thesis. Because the field has been

extensively analyzed, we suggest the reader to refer to the recent comprehensive reviews for further

details.40–44

Five previously reported Brønsted acid-catalyzed transformations were selected for the testing of 2: a) aldol

reaction;45

b) Friedel–Crafts alkylation;12

c) Strecker reaction;46

d) reductive amination;6 e) allylboration of

aldehydes.8 The reactions were chosen based on the following criteria: low catalyst loading, high selectivity

in previously reported studies, commercial accessibility of substrates, mild reaction conditions to avoid

thermal relaxation of the metastable state, similar reaction media to possibly extend the system towards a

tandem synthetic sequence. The results of the catalysis tests using (S,M,Ra)-2 are presented in Scheme 7.6.

Scheme 7.7. Attempted Brønsted acid-catalyzed transformations using (S,M,Ra)-2. No asymmetric

induction was achieved in any of the tested reactions. Yield in absence of catalyst, as reported by

references: a) 0%;45

b) <5%;12

c) 0%,46

d) NR;6 e) NR.

8 NR = not reported.

Chapter 7

246

Unfortunately, slow reaction rates (conversions from 20% up to 90% after 7 d) and no asymmetric

induction were observed in each case. It should be noted that most of the selected transformations were

optimized and developed upon use of TRIP and TiPSY catalysts, featuring large substituents in proximity

of the catalytic pocket. However, the methodology for three-component Strecker reaction reported by Ma

and co-workers does make successful use of the unsubstituted BINOL-derived phosphoric acid.8

However,

only racemic products were obtained, unless the corresponding catalyst derivative featuring phenanthren-9-

yl-substituted acid at the 3,3‘-positions of the binaphthyl scaffold was used (73%, 40% ee). The catalytic

activity has been shown to vary greatly depending on the nature of the phosphoric acid.47,48

Rueping and

Leito disclosed a full study on establishing an acidity scale for the commonly used Brønsted acid

catalysts.49

The study investigated the correlation between Brønsted acidity and reactivity. A Nazarov

cyclization was chosen as a model reaction because no product inhibition occurred. The result was a clear

relationship between the observed rate constant and the acidity of the catalyst. In general, the more acidic

catalysts resulted in higher rate constants. BINOL-derived phosphoric acid diesters BPA1–5 displayed pKa

values in acetonitrile in the range of 12–14 (Figure 7.5). More precisely, BPA4 and BPA5 were found to

have pKa values of 13.3 and 14.0, respectively, and a difference in reaction rate of approximately two-fold

in favor of the first. Notably, BPA5 and 2 feature a less extended aromatic system than BPA4, thus relating

the lower proton acidity with reduced capacity to stabilize the generated anionic charge upon deprotonation.

On the other hand, BPA1 was reported to be the most acidic, arguably due to a less hindered acid center

which could allow a more efficient stabilization of the generated local charge by the polar solvent.

Figure 7.5. Acidity scale for selected BINOL-derived Brønsted acids

It should be pointed out that enantioselectivity is dependent on catalyst architecture. Nevertheless,

activation (and thus reactivity) can be directly correlated to acidity if no catalyst inhibition occurs. It

appeared clear from the disappointing catalysis tests and the extremely limited number of applications of

unsubstituted BINOL-derived phosphoric acids in catalysis46,50

, that a structural improvement of our design

was needed.

7.2.6 Attempted synthesis of 3,3’-distituted biaryl switch core For the introduction of substituents at the 3,3′-positions of BINOL-derivatives, the most commonly used

routes by research groups include: MOM-protection of BINOL; installation of either boronic esters or

halogen substituents at the 3,3′-positions using, respectively, a lithiation-borylation or a lithiation-

halogenation strategy; installation of aryl substituents via palladium-catalyzed cross-coupling; MOM-

deprotection; phosphorylation.3,51

Inspired by previously reported catalytic systems based, we proposed an

analogous retrosynthetic analysis of 3,3‘-biaryl substituted phosphoric acid-switch derivative 4 as presented

in Scheme 7.8.



247

Scheme 7.8. Proposed retrosynthetic analysis of phosphoric acid 4 featuring a 3,3‘-disubstituted-biaryl

switch core.

Unfortunately, reaction of (S,M,Ra/Sa)-1 with MOM-Cl in presence of sodium hydride yielded the desired

product 7 in poor yield (20%), which was obtained as a 80:20 mixture of syn- and anti-conformers (Scheme

7.9).

Scheme 7.9. Synthesis of 2,2‘-bis-MOM-protected biaryl switch-derivative 7.

The major isolated fraction (75%) was composed of a single MOM-protected compound, and was

displaying an unusual absorption pattern different from common overcrowded alkene species, as observed

by 1H NMR spectroscopy analysis. In particular the distinctive heptet assigned to the proton at the

stereogenic center was not observed (expected signal: heptet, δ = 4.2–3.8 ppm, J = 7.0–7.4 Hz, 1H).

Structure 8 was proposed, which could be obtained upon base-triggered addition of the lower phenolate

anion to the overcrowded alkene functionality. Such unexpected decomposition path for 1 and its triflate

derivatives was also observed in presence of other strong inorganic bases such as sodium hydroxide and

potassium hydroxide, while the corresponding dimethylated precursor was stable under the identical

conditions for an indefinite period of time (see Chapter 8). An alternative procedure for MOM-protection of

binaphthol derivatives previously reported52

was also tested, using NaH (2.2 equiv), MOM-Cl (2.4 equiv)

in THF (0.03 M). However, similar low selectivity and yield towards the bis-protected switch derivative 7

were observed. A posteriori, alternative methodologies for MOM-protection of alcohols involving use of

MOM-chloride in presence of a milder organic base such as iPr2NEt53,54

or iPr2NEt and catalyst DMAP55,56

could have resulted in a higher selectivity (see Chapter 6, Phosphoramidite synthesis).

The synthesis of 3,3‘-dibromo-2,2‘-bis-MOM-protected- biaryl switch 9 from 7 was attempted by a

modified procedure previously reported.57

Double ortho-lithiation of (S,M,Ra/Sa)-7 was conducted with

tBuLi at low temperature, followed by lithium-halogen exchange upon addition of 1,2-dibromo-1,1,2,2-

tetrachloroethane (Scheme 7.10).

Scheme 7.10. Synthesis of 3,3‘-dibromo-2,2‘-bis-MOM-protected biaryl switch-derivative 10.

Chapter 7

248

Three distinct fractions were obtained upon purification of the reaction residue by column chromatography.

As suggested by the 1H NMR spectra, each species was still funtionalized with two MOM-protecting

groups. The 1H NMR spectrum of the major early fraction (Rf = 0.6, pentane:EtOAc = 20:1) displayed two

sets of absorptions in 75:25 ratio which were lacking the typical pattern of the overcrowded alkene

functionality. Similar to compound 8, the distinctive heptet assigned to the proton at the stereogenic center

was not observed, which is an indication of the decomposed switch core. The 1H NMR spectrum of the

middle fraction (Rf = 0.45, pentane:EtOAc = 20:1) displayed two sets of absorptions in an 85:15 ratio

(Figure 7.6).

Figure 7.6. Top: Structure of (S,M,Ra/Sa)-9 with highlighted proton assignment. Bottom: 1H NMR

(400 MHz, CDCl3) of isolated middle fraction upon halogenation of 7 towards 9 with expansion of

aromatic region. Proton G (expected singlet peak) could not be assigned.



249

The absorptions assigned to the major species were found coherent with an intact overcrowded alkene

functionality. Consistency with the structure of product (S,M,Ra)-9 (21% yield) obtained via successful

double lithium-halogen exchange was hypothesized upon analysis of the gCOSY spectrum (Figure 7.7).

Figure 7.7. gCOSY (400 MHz, CDCl3) of previous sample.

However, the total integral of the aromatic proton absorptions was found equal to 11 units (expected

aromatic proton count: 12). The assignment of the identified absorptions was executed by elucidating the

correct cross-peak signals from the gCOSY spectrum (Figure 7.8). The missing absorption was assigned to

the aromatic proton in the upper phenol ring in meta to the MOMO-substituent (expected signal: singlet,

1H). The presence of the unidentified absorption underneath the residual solvent peak cannot be excluded.

Out of the second set of absorptions (minor species of a 85:15 mixture) observed in the 1H NMR spectrum

of the middle fraction, only few resolved absorptions could be clearly characterized, due to their low

intensity and major overlap with the absorptions previously assigned to product (S,M,Ra)-9. The

unidentified minor species was hypothesized to be assigned to either the opposite anti-conformer (S,M,Sa)-9

or the mono-halogenated intermediates 10 or 11. The final fraction (Rf = 0.25, pentane:EtOAc = 20:1)

was mainly composed of unreacted substrate 7. Due to the low yield obtained in the 3,3‘-biaryl

functionalization steps, the study described herein was eventually interrupted.

Chapter 7

250

Figure 7.8. Expansion of aromatic region from gCOSY (400 MHz, CDCl3) of previous sample.

A larger amount of enantiomerically enriched biphenol switch 1 was in fact required to continue the

optimization of the synthetic route towards a more structurally complex switchable phosphoric acid

derivative. Moreover, the valuable compound 1 constituted also the starting material for the development of

the chiral switchable bis-phosphine ligand described in Chapter 8. Eventually the limited amount of time

left did not allow synthesizing other batches of 1 to proceed further with the parallel investigation for these

two projects.

7.3 Conclusion

The synthesis of photoresponsive phosphoric acid 2 based on a molecular switch core is reported. The

proposed design implies a coupled helical-to-axial transfer of chirality, in which the hybrid chirality

generated by the stereogenic center and the dynamic helical structure of the overcrowded alkene is

transferred to the helical and axial chirality of the biaryl unit. Thus, the local chirality of the biaryl derived

phosphoric acid motif can be reversibly controlled upon irradiation via photochemical E-Z isomerization

(PEZI). Experimental analysis by UV-vis absorption, CD and 1H NMR spectroscopy proved the reversible

photoswitching properties of 2. Its applicability as a switchable stereoselective organocatalyst was



251

investigated in a selection of previously reported Brønsted acid-catalyzed transformations. Unfortunately,

slow reaction rates and no asymmetric induction were observed in each case. In attempt to increase

catalytic efficiency and asymmetric induction, a more complex design of a 3,3‘-biaryl substituted

phosphoric acid switch derivative 4 was proposed. The attempted synthesis was complicated by low

yielding MOM-protection and ortho-functionalization of the starting 2,2‘-biphenol derivative 1 and was

eventually interrupted due to lack of time and starting material 1. Despite the unfinished study, this

responsive system holds promise to modulate catalysts activity and switch stereoselectivity with high

spatio-temporal control ultimately arriving at a catalyst that can perform multiple enantioselective

transformation in a sequential manner. In addition, this switch system has considerable potential as chirality

selector for a wide range of applications, beyond the field of asymmetric catalysis, such as control of

supramolecular architecture, liquid crystal morphology and chiral recognition.

Chapter 7

252



General experimental details can be found in Chapters 5 and 6.


(12S,13bR)-6-chloro-13-(9H-fluoren-9-ylidene)-12-methyl-10,11,12,13-

tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepine 6-oxide (3).

Phosphorochloridate 3 was prepared from 1 by a


A flame-

dried Schlenk tube was equipped with

vacuum/nitrogen stopcock and a magnetic stirring bar.

The tube was charged with 2,2‘-biphenol derived

switch (S,M,Ra/Sa)-1 (60 mg, 0.144 mmol) and three

cycles of vacuum and backfilling of Argon was applied. Dry CH2Cl2 (2 mL) and freshly distilled NEt3 (44

mg, 0.06 mL, 0.432 mmol, 3 equiv) were added. POCl3 (44 mg, 0.027 mL, 0.288 mmol, 2.1 equiv) was

added at 0 °C and the solution was stirred at rt over 16 h, until TLC indicated that the reaction was

completed. The reaction was quenched with water (5 mL) and the mixture was diluted with CH2Cl2 (10

mL). The organic phase was washed with brine (5 mL), dried over Na2SO4, filtered and the solvent was

removed under reduced pressure. The product phosphorochloridate (S,RP/SP,M,Ra)-3 (68 mg, 0.137 mmol,

95%) was obtained without further purification in a 55:45 mixture of two diastereoisomers as a yellow

foam solid. The absolute configurations of the diastereoisomers were not assigned. 1H NMR (400 MHz,

CDCl3, A:B = 55:45 mixture of diastereoisomers) δ 7.92–7.85 (m, 1H, A+B), 7.57–7.51 (m, 1H, A+B),

7.51–7.46 (m, 1H, A+B), 7.47–7.42 (m, 1.5H, A+B), 7.41–7.32 (m, 1.5H, A+B), 7.32–7.25 (m, 3H, A+B),

7.11–7.04 (m, 1H, A+B), 7.02–6.94 (m, 1.2H, A), 6.94–6.89 (m, 0.9H, B), 6.87–6.79 (m, 2H, A+B), 6.60

(dt, J = 7.9, 0.8 Hz, 0.55H, A), 6.53 (dt, J = 7.9, 0.9 Hz, 0.45H, B), 4.21 (app. hept, J = 7.0 Hz, 1H, A+B),

2.82–2.74 (m, 1H, A+B), 2.56–2.42 (m, 2H, A+B), 1.60 (app. dd, J = 10.0, 7.0 Hz, 3H, A+B), 1.38–1.23

(m, 2H, A+B). 31

P NMR (162 MHz, CDCl3, A:B = 55:45 mixture of diastereoisomers) δ 10.76 (A), 10.40

(B).

(12S,13bR)-13-(9H-fluoren-9-ylidene)-6-hydroxy-12-methyl-10,11,12,13-

tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepine 6-oxide (2).

Phosphoric acid 2 was prepared from 3 by a modified procedure previously

reported.59

A Schlenk tube was equipped with a magnetic stirring bar and

charged with phosphorochloridate (S,RP/SP,M,Ra)-3 (68 mg, 0.137 mmol, 90%

ee). A 1:1 mixture of pyridine/water (2 mL) was added and the mixture was

heated at reflux over 2 h. After cooling, CH2Cl2 (10 ml) was added and the

organic layers is washed with aq. HCl 1M (3x8 mL) to remove pyridine

residues unitl acqueous layer was pH=1-2. The organic layer was washed with brine (10 mL) and dried

over Na2SO4, filtered and the solvent was removed under reduced pressure. The product was purified by

column chromatography (SiO2, CH2Cl2:MeOH= 10:1) to yield phosphoric acid (S,M,Ra)-2 (65 mg,

0.137 mmol, quant., 90% ee) as a dark yellow solid. m.p. 226–228 °C. 1H NMR (400 MHz, CDCl3) δ 7.88

(dd, J = 5.9, 3.2 Hz, 1H), 7.54 (dd, J = 5.5, 3.3 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 8.4 Hz, 2H),

7.32–7.23 (m, 5H), 7.01–6.89 (m, 2H), 6.86 (d, J = 3.9 Hz, 2H), 6.72 (q, J = 3.7 Hz, 1H), 6.68 (d, J = 7.8

Hz, 1H), 4.46 (s, 2H), 4.19 (h, J = 7.2 Hz, 1H), 2.73–2.64 (m, 1H), 2.51–2.34 (m, 2H), 1.59 (d, J = 6.9 Hz,

3H), 1.35–1.20 (m, 1H). 13

C NMR (75 MHz, CDCl3) δ 141.7, 140.8, 140.4, 138.5, 137.9, 137.3, 136.7,

135.1, 130.7, 129.4, 129.3, 128.4, 127.3, 127.2, 126.8, 126.6, 126.5, 124.8, 124.2, 124.1, 123.7, 121.7,

121.3, 119.3, 118.1, 34.6, 31.4, 29.7, 29.4, 21.6. 31

P NMR (162 MHz, CDCl3) δ 3.76. HRMS (ESI, m/z):



253

calcd for C30H24O4P [M+H]+: 479.1407, found: 479.1401. [ ]

-41.6 (c 0.17, CHCl3) for (S,M,Ra)-2 (90%

ee); [ ] -17.7 (c 0.27, MeOH) for (S,M,Ra)-2 (90% ee).

9-((2S,8R)-7-(methoxymethoxy)-8-(2-(methoxymethoxy)phenyl)-2-methyl-3,4-dihydronaphthalen-

1(2H)-ylidene)-9H-fluorene (7)

Bis-MOM-protected 2,2‘-biphenol switch 7 was prepared from 1 by a modified

procedure previously reported.60

A flame dried Schlenk tube was equipped with

a magnetic stirring bar and charged with NaH (60% dispersion in oil, 88 mg,

1.32 mmol, 2.4 equiv), dry THF (6 mL) and dry DMF (2 mL). After the

temperature was lowered to 0° C, a solution of (S,M,Ra/Sa)-1 (230 mg, 0.55

mmol, 1 equiv) was added dropwise and the mixture was stirred for 8 h at room

temperature. The reaction was quenched by adding 10 mL of water, extracted with EtOAc (3 x 10 mL), the

combined organic phase was washed with brine (2 x 10 mL), dried over MgSO4, filtered and the solvent

was removed under reduced pressure. 1H NMR analysis of the crude residue revealed a 1:6 mixture of

species 7:8. The residue was purified by column chromatography (SiO2, pentane:EtOAc = 8:1) to yield bis-

MOM-protected 2,2‘-biphenol switch (S,M,Ra/Sa)-7 (40 mg, 0.08 mmol, 14%) in a 80:20 mixture of

atropisomers as a yellow foam. 1H NMR (300 MHz, CDCl3, A:B = 80:20 mixture of diastereoisomers) δ

7.84–7.77 (m, 0.8H, A), 7.77–7.66 (m, 0.4H, B), 7.65–7.60 (m, 0.8H, A), 7.50 (d, J = 7.6 Hz, 0.8H, A),

7.36–7.23 (m, 5H, A+B), 7.22–7.09 (m, 1.7H, A+B), 7.01 (t, J = 9.3 Hz, 0.2H, B), 6.97–6.81 (m, 3.6H,

A+B), 6.75–6.67 (m, 0.8H, A), 6.63 (d, J = 8.1 Hz, 0.2H, B), 6.46 (t, J = 7.1 Hz, 0.2H, B), 5.17 (d, J = 6.5

Hz, 0.8H, A), 5.06 (t, J = 6.2 Hz, 0.5H, B), 4.99 (t, J = 5.8 Hz, 1H, A+B), 4.92 (d, J = 6.6 Hz, 0.2H, B),

4.72 (d, J = 6.9 Hz, 0.8H, A), 4.52 (d, J = 6.9 Hz, 0.8H, A), 4.12 (h, J = 7.2 Hz, 0.8H, A), 4.02 (h, J = 7.5

Hz, 0.2H, B), 3.38 (s, 2.4H, A), 3.36 (s, 0.6H, B), 3.33 (s, 2.4H, A), 3.33 (s, 0.6H, B), 2.71–2.60 (m, 1.2H,

A+B), 2.48–2.28 (m, 2H, A+B), 1.55 (d, J = 6.9 Hz, 2.4H, A), 1.02–0.82 (m, 5.1H, A+B). 13

C NMR (75

MHz, CDCl3, A:B = 80:20 mixture of diastereoisomers) δ 156.2, 154.6, 154.3, 154.2, 146.3, 144.7, 140.4,

140.3, 139.1, 138.9, 138.8, 138.5, 138.3, 138.3, 137.7, 136.1, 135.3, 135.0, 131.8, 130.2, 128.4, 128.2,

128.1, 126.9, 126.8, 126.7, 126.7, 126.6, 126.4, 126.4, 126.3, 126.1, 126.0, 125.5, 124.9, 124.4, 124.4,

124.3, 120.2, 120.1, 119.3, 119.2, 118.9, 118.2, 116.4, 116.0, 114.2, 113.9, 96.4, 95.5, 95.1, 95.0, 63.4,

63.1, 63.0, 61.2, 55.8, 55.7, 55.4, 35.1, 31.6, 29.7, 29.4, 29.4, 28.8, 26.7, 22.7, 22.3.

(6S,6aR)-6a-(9H-fluoren-9-yl)-1-(methoxymethoxy)-6-methyl-4,5,6,6a-tetrahydrobenzo[kl]xanthene

Major decomposition of the overcrowded alkene functionality occurred

during the synthesis of 7 from 1, as determined by 1H NMR spectroscopy

of the isolated early fraction after flash column chromatography. The

structure of the compound was eventually assigned to cyclized species 8

(205 mg, 0.44 mmol, 81%). 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 8.0

Hz, 1H), 8.09–7.98 (m, 1H), 7.75–7.68 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H),

7.42–7.36 (m, 2H), 7.30 (d, 2H), 7.28–7.24 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.10–7.02 (m, 2H), 6.90 (td, J

= 7.6, 1.2 Hz, 1H), 5.82 (d, J = 7.7 Hz, 1H), 5.38 (d, J = 6.7 Hz, 1H), 5.31 (d, J = 6.7 Hz, 1H), 4.66 (s, 1H),

3.59 (s, 3H), 2.60 (ddd, J = 17.9, 10.8, 7.3 Hz, 1H), 2.16–2.00 (m, 2H), 1.10–0.98 (m, 0H), 0.95 (d, J = 6.9

Hz, 3H), 0.90–0.69 (m, 2H).

Chapter 7

254

Synthesis of 9-((2S,8R)-7-(methoxymethoxy)-8-(2-(methoxymethoxy)phenyl)-2-methyl-3,4-

dihydronaphthalen-1(2H)-ylidene)-9H-fluorene (9)

The synthesis of 3,3‘-dibromo-2,2‘-bis-MOM-protected- biaryl switch 9 from 7

was attempted by a modified procedure previously reported.57

A flame dried

Schlenk tube was equipped with a magnetic stirring bar and charged with bis-

MOM-protected 2,2‘-biphenol switch (S,M,Ra/Sa)-7 (23 mg, 0.05 mmol, 1

equiv). Dry THF (1.5 mL) was added and the solution was cooled to -78 °C.

tBuLi (1.9 M in hexane, 0.048 mL, 0.091 mmol, 2 equiv) was added slowly and

the solution was stirred for 1 h. Then the solution was warmed to 0 °C and 1,2-

dibromo-1,1,2,2-tetrachloroethane (45 mg, 0.14 mmol, 3 equiv) was added. The mixture was warmed up to

room temperature overnight before quenching with saturated aq. NH4Cl (4 mL) solution. The layers were

separated and the aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were

dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified

by column chromatography (SiO2, pentane:EtOAc = 20:1) to afford three distinct fractions. The 1H NMR

specra of all the species were still displaying the typical absorptions of both MOM-protecting groups. The

spectrum of the early fraction (Rf = 0.6, pentane:EtOAc = 20:1, ca. 12 mg) displayed two sets of

absorptions in a 75:25 ratio which were lacking the typical pattern of the overcrowded alkene functionality.

The spectrum of the middle fraction (Rf = 0.45, pentane:EtOAc = 20:1) displayed two sets of absorptions in

a 85:15 ratio. Consistency with the structure of product (S,M,Ra)-9 (7 mg, 0.011mmol, 21% yield) was

hypothesized upon analysis of the gCOSY spectrum (see main text). 1H NMR (400 MHz, CDCl3, major

species) δ 7.64 (d, J = 7.4 Hz, 1H), 7.41–7.38 (m, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.14 (td, J = 5.5, 2.7 Hz,

1H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H),

6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 6.26 (t, J = 7.5 Hz, 1H), 5.01 (d, J = 6.3 Hz, 1H), 4.82 (d,

J = 6.3 Hz, 1H), 4.33 (d, J = 4.2 Hz, 1H), 3.88 (p, J = 6.7 Hz, 1H), 3.80 (d, J = 4.3 Hz, 1H), 3.20 (s, 3H),

2.99 (s, 3H), 2.81 (t, J = 13.8 Hz, 1H), 2.58 (d, J = 14.7 Hz, 1H), 1.85 (d, J = 12.6 Hz, 1H), 1.75–1.65 (m,

1H), 1.38 (d, J = 6.7 Hz, 3H). Note: one expected absorption peak (s, 1H) was missing and hypothesized to

be hidden underneath the residual solvent peak. 13

C NMR (101 MHz, CDCl3) δ 152.7, 152.7, 146.0, 144.6,

141.7, 140.0, 139.0, 139.0, 138.6, 136.9, 136.8, 133.7, 133.4, 127.2, 127.0, 126.1, 126.1, 125.9, 124.8,

124.6, 123.1, 120.4, 118.7, 118.4, 113.1, 97.9, 94.9, 57.1, 55.8, 35.3, 33.1, 29.7, 27.3, 20.8. HRMS (ESI,

m/z): calcd for C34H30O4 [M-2HBr]+: 502.2139, found: 502.2195. The unidentified minor species was

hypothesized to be assigned to either the opposite anti-conformer (S,M,Sa)-9 or the mono-halogenated

intermediates 10 or 11. 1H NMR (400 MHz, CDCl3, minor unknown species, partial spectrum) δ 7.68 (t, J =

7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.30–7.10 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.07 (d, J = 6.8 Hz, 1H),

4.89 (d, J = 6.8 Hz, 1H), 4.43 (s, 2H), 3.32 (s, 3H), 3.04 (d, J = 2.3 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H). The

later fraction (Rf = 0.25, pentane:EtOAc = 20:1) was mainly composed of unreacted substrate 7 (6 mg,

0.011 mmol, 26% recover).

7.4.3 1H NMR spectroscopy.

The stable form of phosphoric acid (S,M,Ra)-2 (~4.0 mg) was dissolved in CDCl3 (0.65 mL). The sample

was placed in an NMR tube and irradiated towards the metastable state (S,P,Sa)-2 with UV light at 365 nm

at a distance of ca. 2 cm from the LED source. 1H NMR spectra of the sample were taken before, during

and after irradiation at rt. No further changes were observed after 60 min of irradiation. The relative

integration of the absorptions in 1H NMR spectra revealed a PSS365 mixture of (S,M,Ra)-2: (S,P,Sa)-2 =

20:80. The sample was subsequently irradiated towards the stable state (S,P,Sa)-2 with visible light at 420

nm at a distance of ca. 2 cm from the LED source. 1H NMR spectra of the sample were taken before, during

and after irradiation at rt. No further changes were observed after 180 min of irradiation. The relative

integration of the absorptions in 1H NMR spectra revealed a PSS420 mixture of (S,M,Ra)-2: (S,P,Sa)-2 =

85:15. 1H NMR of the starting solution of stable state, PSS365 and PSS420 and intermediate state are reported

in Figure 7. of the main text with assignment of main distinctive peaks.



255

7.4.4 UV-vis and CD spectroscopy.

A solution of stable form of phosphoric acid (S,M,Ra)-2 in spectroscopic grade chloroform (6.2·10-5

M) was

transferred in a fluorescence quartz cuvette with magnetic stirrer and degassed with argon under stirring for

5 min. The forward and backward irradiation process from the stable isomer to the metastable isomer was

monitored by UV-vis absorption spectroscopy time-course measurement (wavelength range 300–650 nm,

scan periods of 20 s). After starting the time-course measurements, the sample was irradiated under stirring

with the proper LED source perpendicularly to the analysis path of the spectrophotometer (3 min at

365 nm, 3 min at 420 nm). To ensure that the PSS was reached, irradiations were continued until no further

changes in the absorption spectra were observed. CD spectra were recorded for the same starting solution of

stable form of (S,M,Ra)-2 and after reaching the photostationary state at 365 nm and 420 nm (mixture of

stable form (S,M,Ra)-2 and metastable form (S,P,Sa)-2). UV-vis and CD spectra are reported in main text

(Figure 7.).

7.4.5 Catalysis tests

Brønsted acid catalyzed asymmetric aldol reaction

The aldol reaction was attempted by a modified procedure previously reported.45

A flame-dried Schlenk

tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was charged with

phosphoric acid (S,M,Ra)-2 (2.4 mg, 0.005 mmol, 0.05 eq, 90% ee), ethyl glyoxalate (50% in toluene) (20

mg, 0.1 mmol, 1 equiv) and cyclohexanone (98 mg, 1 mmol, 10 equiv). The reaction mixture was stirred at

0 °C over 7 d. The volatiles were removed under reduced pressure and the crude was purified by flash

column chromatography (SiO2, pentane:EtOAc= 3:1). No trace of the expected product ethyl 2-hydroxy-2-

(2-oxocyclohexyl)acetate was detected by 1H NMR, as compared with the previously reported physical

data.45

Major syn-isomer. Rf = 0.2 in cyclohexane:EtOAc, 70:30. 1H NMR (400 MHz, CDCl3) δ 4.61 (d, J

= 1.6 Hz, 1H, CHOH), 4.19 (q, J = 7.0 Hz, 2H), 2.91 (s, 1H, OH), 2.78–2.70 (m, 1H), 2.44–2.38 (m, 1H),

2.34–2.20 (m, 1H), 2.06–1.97 (m, 1H), 1.92–1.78 (m, 3H), 1.65–1.53 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H).

Minor anti–isomer: 1H NMR (400 MHz, CDCl3) δ 4.18 (qd, J = 7.0 and 2 Hz, 2H), 3.95 (d, J = 3.2 Hz,

1H), 3.08 (s, 1H), 2.92–2.85 (m, 1H), 2.39–2.31 (m, 1H), 2.28–2.17 (m, 1H), 2.10–1.95 (m, 2H), 1.93–1.79

(m, 2H), 1.71–1.52 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H).

Brønsted acid catalyzed asymmetric Friedel-Crafts alkylation

The Friedel-Crafts alkylation was attempted by a modified procedure previously reported.12

A flame-dried

Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was

charged with phosphoric acid (S,M,Ra)-2 (3.0 mg, 0.0063 mmol, 0.05 eq, 90% ee), powdered 4Å molecular

sieves (15 mg), and trans-2-nitrostyrene (37.3 mg, 0.25 mmol, 2 equiv). Dry benzene (0.3 mL) and dry

dichloroethane (0.3 mL) were added. The mixture was cooled at -30 °C. At this temperature, indole (14.6

mg, 0.125 mmol, 1 equiv) was added to the mixture. After being stirred at this temperature for 7d, the

reaction mixture was poured on silica gel column and purified by flash column chromatography (SiO2,

pentane:EtOAc= 20:1 to 5:1) to yield racemic 3-(2-nitro-1-phenylethyl)-1H-indole (22 mg, 0.082 mmol,

65%) as a yellow solid. The physical data of the product were identical in all respects to those previously

reported.12

1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.37–7.18 (m, 7H),

7.09–7.03 (m, 2H), 5.19 (t, J = 8.0 Hz, 1H), 5.07 (dd, J = 12.5, 7.5 Hz, 1H), 4.94 (dd, J = 12.5, 8.2 Hz, 1H). 13

C NMR (100 MHz, CDCl3) δ 139.1, 136.4, 128.9, 127.7, 127.5, 126.6, 122.7, 121.6, 119.9, 118.9, 114.4,

111.3, 79.5, 41.5. GC-MS (EI, m/z): calcd for C16H15N2O4 [M+H]+: 267.11, found: 267.12. Chiral

separation was achieved by chiral HPLC analysis (Chiralpak AD-H, hept:2-propanol = 90:10, flow 0.75

mL/min, 40 °C, Rt: 32.9 min (1st) and 36.4 min (2

nd)).

Chapter 7

256

Brønsted acid catalyzed asymmetric three-component Strecker reaction

The Strecker reaction was attempted by a modified procedure previously reported.46

In a Glove-box, a

screw capped vial was charged with a magnetic stir bar, phosphoric acid (S,M,Ra)-2 (7.1 mg, 0.015 mmol,

0.1 eq, 90% ee), powdered 4Å molecular sieves (25 mg), 4-methoxylaniline (18.5 mg, 0.25 mmol, 1 equiv),

phenol (14.1 mg, 0.15 mmol, 1 equiv), toluene (0.5 mL), acetophenone (19.8 mg, 0.019 mL, 0.165 mmol,

1.1 equiv) and TMSCN (22.3 mg, 0.030 mL, 0.225 mmol, 1.5 equiv). The resulting mixture was stirred at

40 °C during 7 d. However, TLC showed incomplete conversion. The reaction solution was concentrated

under vacuum, and the residue was purified by flash column chromatography (SiO2, pentane:EtOAc= 20:1

to 10:1) to yield racemic 2-(4-methoxyphenylamino)-2-phenylpropanenitrile (12 mg, 0.045 mmol, 30%) as

a white solid. The phosphoric acid 2 (6.7 mg, 0.014 mmol, 92%) was recovered by further flushing the

column (eluent: CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to

those previously reported.[46

1H NMR (400 MHz, CDCl3) δ 7.65–7.36 (m, 5H), 6.71–6.55 (m, 4H), 3.70 (s,

3H), 1.92 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ154.2, 140.3, 137.4, 129.4, 128.8, 125.3, 121.2, 118.5,

114.6, 58.4, 55.7, 33.2. GC-MS (EI, m/z): calcd for C16H17N2O [M+H]+: 253.13, found: 254.11; calcd for

C16H16NO [M-CN]+: 226.12, found: 226.31. Chiral separation was achieved by chiral HPLC analysis

(Chiralpak AD-H, hept:2-propanol = 85:15, flow 0.5 mL/min, 40 °C, Rt: 19.3 min (1st) and 24.0 min (2

nd)).

Brønsted acid catalyzed asymmetric reductive amination

The reductive amination was attempted by a modified procedure previously reported.[6

In a Glove-box, a

screw capped vial was charged with a magnetic stir bar, phosphoric acid (S,M,Ra)-2 (4.8 mg, 0.01 mmol,

0.1 eq, 90% ee), powdered 4Å molecular sieves (20 mg), 4-methoxylaniline (12.3 mg, 0.10 mmol, 1 equiv)

and Hantzsch ester (30.4 mg, 0.12 mmol, 1.2 equiv). Dry benzene (0.5 mL) was added, followed by

acetophenone (36.0 mg, 0.30 mmol, 3 equiv). The reaction mixture was heated with stirring to 50 °C. After

4 d, the reaction mixture was filtered through a plug of silica, eluting with Et2O to remove the molecular

sieves and unreacted Hantzsch ester, then concentrated under reduced pressure. The residue was purified by

flash column chromatography (SiO2, pentane:Et2O= 10:1 to 5:1) to yield racemic 4-methoxy-N-(1-

phenylethyl)aniline (12 mg, 0.045 mmol, 30%) as a white solid. The non-reduced imine intermediate 4-

methoxy-N-(1-phenylethylidene)aniline was isolated as major product (12 mg, 0.053 mmol, 52%). The

phosphoric acid 2 (4.3 mg, 0.009 mmol, 90%) was recovered by further flushing the column (eluent:

CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to those previously

reported.[6

1H NMR (300 MHz, CDCl3) δ 6.70–6.67 (m, 2H), 7.38–7.26 (m, 4H), 7.26–7.22 (m, 1H), 6.50–

6.47 (m, 2H), 4.41 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H). 13


151.9, 145.5, 128.7, 126.9, 125.9, 114.8, 114.6, 55.8, 25.2. GC-MS (EI, m/z): calcd for C15H17NO [M+H]+:

227.13, found: 227.13. Chiral separation was achieved by chiral GC analysis (Chirasil-Dex-CB, 150 °C

isotherm for 150 min, 1 mL/min, Rt: 79.91 min (1st) and 81.43 min (2

nd)).

Chiral Brønsted acid-catalyzed allylboration of aldehydes

The allylboration of aldehydes was attempted by a modified procedure previously reported.[8

A flame-dried

Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was

charged with phosphoric acid (S,M,Ra)-2 (4.8 mg, 0.010 mmol, 0.1 eq, 90% ee), freshly distilled

benzaldehyde (10.6 mg, 0.011 mL, 0.10 mmol, 1 equiv) and dry toluene (1.5 ml). The reaction mixture was

then cooled to -30 °C followed by the addition of allyl boronic acid pinacol ester (20.0 mg, 22 µL, 0.12

mmol, 1.2 equiv). The mixture was stirred over 3 d at this temperature. Aq. 1M HCl (3 mL) was added and

the reaction mixture was stirred for 15 min, then extracted with Et2O (3 x 3 mL). The collected organic

fractions were washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and the solvent was

removed under reduces pressure. The residue was purified by flash column chromatography (SiO2,

pentane:EtOAc= 10:1) to yield racemic 1-phenylbut-3-en-1-ol (13.5 mg, 0.09 mmol, 90%) as a white solid.

The phosphoric acid 2 (4.2 mg, 0.009 mmol, 88%) was recovered by further flushing the column (eluent:



257

CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to those previously

reported.[8

1H NMR (400 MHz, CDCl3) δ 7.35–7.20 (m, 5H), 5.85–5.71 (m, 1H), 5.16–5.10 (m, 2H), 4.72

(dd, J = 7.6, 5.6 Hz, 1H), 2.54–2.43 (m, 2H), 2.00 (br s, 1H). 13

C NMR (50 MHz, CDCl3) δ 144.6, 135.2,

129.1, 128.2, 126.5, 119.0, 74.0, 44.5. GC-MS (EI, m/z): calcd for C10H13O [M+H]+: 149.09, found:

149.18. Chiral separation was achieved by chiral HPLC analysis (Chiralpak OD-H, hept:2-propanol = 98:2,

flow 0.7 mL/min, 40 °C, Rt: 20.2 min (1st) and 21.9 min (2

nd)).

7.5 References


(2) Bernardi, L.; Fochi, M.; Comes Franchini, M.; Ricci, A. Org. Biomol. Chem. 2012, 10, 2911–2922.

(3) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047–9153.

(4) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781–3783.

(5) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chemie - Int. Ed. 2005, 44, 7424–7427.

(6) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86.

(7) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830–5831.

(8) Jain, P.; Antilla, J. C. J. Am. Chem. Soc. 2010, 132, 11884–11886.

(9) Jain, P.; Wang, H.; Houk, K. N.; Antilla, J. C. Angew. Chemie Int. Ed. 2012, 51, 1391–1394.

(10) Rodríguez, E.; Grayson, M. N.; Asensio, A.; Barrio, P.; Houk, K. N.; Fustero, S. ACS Catal. 2016, 6,

2506–2514.

(11) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292–293.

(12) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chemie Int. Ed. 2008, 47, 4016–4018.

(13) He, Y.; Lin, M.; Li, Z.; Liang, X.; Li, G.; Antilla, J. C. Org. Lett. 2011, 13, 4490–4493.

(14) Kim, J.; Čorić, I.; Vellalath, S.; List, B. Angew. Chemie - Int. Ed. 2013, 52, 4474–4477.

(15) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430–3431.

(16) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008, 350, 399–402.

(17) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem. Soc. 2009, 131, 12882–12883.

(18) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133, 6166–6169.

(19) Cornforth, J. Proc. R. Soc. London, Ser. B 1978, 203, 101–117.

(20) Mislow, K.; Siegel, J. J. Am. Chem. Soc. 1984, 106, 3319–3328.

(21) P-Chirogenic is related to a compound with a phosphorus asymmetric center.

(22) Dutartre, M.; Bayardon, J.; Jugé, S. Chem. Soc. Rev. 2016, 45, 5771–5794.

(23) Ferry, A.; Stemper, J.; Marinetti, A.; Voituriez, A.; Guinchard, X. European J. Org. Chem. 2014, 2014,

188–193.

(24) Uraguchi, D.; Kinoshita, N.; Ooi, T. J. Am. Chem. Soc. 2010, 132, 12240–12242.

(25) Nishikawa, Y.; Nakano, S.; Tahira, Y.; Terazawa, K.; Yamazaki, K.; Kitamura, C.; Hara, O. Org. Lett.

2016, 18, 2004–2007.

(26) Vlatkovic, M. Dynamic control of chiral space, PhD thesis, University of Groningen, 2016.


2016, 22, 13478–13487.

(28) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chemie - Int. Ed. 2012, 51, 9684–9688.


(30) Berryman, O. B.; Sather, A. C.; Lledó, A.; Rebek, J. Angew. Chemie Int. Ed. 2011, 50, 9400–9403.



Chem. Soc. 2009, 131, 357–367.


Chem. Sci. 2015, 6, 140–143.

(34) Schmittel, M.; De, S.; Pramanik, S. Angew. Chemie Int. Ed. 2012, 51, 3832–3836.









Chapter 7

258



(45) Pousse, G.; Le Cavelier, F.; Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582–3585.

(46) Zhang, G.-W.; Zheng, D.-H.; Nie, J.; Wang, T.; Ma, J.-A. Org. Biomol. Chem. 2010, 8, 1399–1405.

(47) Christ, P.; Lindsay, A. G.; Vormittag, S. S.; Neudörfl, J.-M.; Berkessel, A.; O‘Donoghue, A. C. Chem. - A

Eur. J. 2011, 17, 8524–8528.

(48) Yang, C.; Xue, X.-S.; Jin, J.-L.; Li, X.; Cheng, J.-P. J. Org. Chem. 2013, 78, 7076–7085.

(49) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I. Angew. Chemie Int. Ed. 2013, 52,

11569–11572.

(50) Khan, I. A.; Saxena, A. K. J. Org. Chem. 2013, 78, 11656–11669.

(51) Jacques, J.; Fouquey, C. Org. Synth. 1989, No. 67, 1.

(52) Shi, M.; Wang, C. J. Tetrahedron Asymmetry 2002, 13, 2161–2166.

(53) Bernet, B.; Bishop, P. M.; Caron, M.; Kawamata, T.; Roy, B. L.; Ruest, L.; Sauvé, G.; Soucy, P.;

Deslongchamps, P. Can. J. Chem. 1985, 63, 2810–2814.

(54) Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L. J. Am. Chem. Soc. 2002,

124, 13342–13343.

(55) Hook, J. M.; Mander, L. N. J. Org. Chem. 1980, 45, 1722–1724.

(56) Mander, L. N.; Mclachlan, M. M. J. Am. Chem. Soc.. 2003, 125, 2400–2401.

(57) Castelló, L. M.; Hornillos, V.; Vila, C.; Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Org. Lett.

2015, 17, 62–65.

(58) Hrdina, R.; Guénée, L.; Moraleda, D.; Lacour, J. Organometallics 2013, 32, 473–479.

(59) Zhang, Y.; Lim, C.-S.; Sim, D. S. B.; Pan, H.-J.; Zhao, Y. Angew. Chemie Int. Ed. 2014, 53, 1399–1403.

(60) Gong, L.; Luo, Z.; Liu, Q.; Mi, A.; Jiang, Y. Chiral catalyst, process for preparing the same and its use in

the oxidate coupling of naphthols. US20050256345 A1, 2005.

Chapter 8 Chapter 8

Study towards a Photoswitchable Chiral Bidentate

Phosphine Ligand based on an Overcrowded Alkene

for Metal-catalyzed Asymmetric Transformations

This chapter describes the study towards the synthesis and application of a photoswitchable chiral

bis(diphenylphosphine)-ligand based on a second generation molecular motor core. We envisioned a large

variation of axial chiral induction and steric hindrance induced around the coordinated metal center upon

photochemical isomerization of the responsive ligand. Derivatization of the 2,2’-bisphenol-functionlized

chiral molecular switch described in Chapter 5 provided the bis-triflate-intermediate. Several metal-

catalyzed aryl phosphination methodologies previously developed for conventional biaryl scaffold were

attempted. However, the target compound was not obtained. Experimental evidence suggests that the highly

hindered structure of the designed bidentate ligand may even preclude the proposed synthetic route at all.

An alternative proposal to develop a photoswitchable Brønsted acid catalyst based on an analogous

diphenylphosphine-hydroxyl derivative is presented.

Chapter 8

260

8.1 Introduction

8.1.1 Design of natural and artificial metal complexes

The ability to reversibly control the shape of structures at the nano-scale is a highly challenging and

attractive target of modern molecular design. Indeed, such molecular devices constitute powerful tools for

achieving switchable chiral induction. Chiral inversion and asymmetric induction processes play an

important role in host-guest chemistry, self-assembly and molecular recognition, as well as in nature.1–4

They are in fact known to affect the properties and functions of DNA5 and proteins.

6 Inspired by nature, the

dynamic cooperative effects and correlated motions of artificial chiral supramolecular structures held

together by weak intermolecular interactions such as hydrogen bonding, metal coordination, π-π

interactions, Coulomb forces, dipole-dipole interactions, and van der Waals forces have led to the

development of complex molecular assemblies that can be used for switching7–10

and amplification of

chirality.11–18

The versatile coordination chemistry and stereo-dynamics of chiral metal complexes that

exploit transfer of chirality from ligands to metal centers19

can be used to mimic such processes, to devise

chiral switches that respond to external stimuli, and to develop supramolecular architectures exhibiting

chiral amplification and memory.20–26

Since the first separation of enantiomeric octahedral cobalt complexes achieved by Werner in 1911,27

chemists have progressively developed deeper knowledge and control of chirality in coordination species.28

A major breakthrough was accomplished with the stereoselective synthesis of metal complexes via

introduction of chiral, non-racemic coordinating ligands. Several examples of supramolecular designs29

based on chiral organometallic structures have been crafted in the past decades, ranging from mononuclear

complexes to oligo- or polynuclear assemblies, helicates, catenanes, knots, rotaxanes,29,30

and polyhedral

three-dimensional structures.31,32

Chiral metal complexes are now extensively used in several

enantioselective catalytic synthetic methodologies by the pharmaceutical industry.33

Stereodiscrimination is

also an invaluable feature of modern chiral polymerization catalysts, which can give access to polymers

with highly controlled tacticity and consequent tailored mechanical properties.34

The ability to exert spatio-

temporal control in a polymerization process by means of a responsive stereodynamic catalyst is a concrete

example of industrial application of such an underdeveloped concept.2

8.1.2 Asymmetric transformation of stereodynamic biaryls

Biaryls such as BINOL35

and BINAP36

are certainly listed among the most widely recognized

atropisomeric inductors and constitute the main scaffold of several families of rigid chiral ligands exploited

in asymmetric synthesis. Their C2-symmetric 1,1‘-binaphthyl scaffold lacks of stereogenic centers, however

it features an element of axial chirality due to the restricted rotation around the aryl-aryl bond. The dihedral

angle between the two naphthyl halves is approximately 90°, which makes such framework capable of

providing a strong chiral induction. It is no coincidence that extensive development and application of

binaphthyl-based catalyst in asymmetric synthesis was achieved in the past decades.37–39

On the other hand,

several stereodynamic bidentate ligands that effectively amplify chirality at a metal center have been

reported to improve both selectivity and efficiency of asymmetric catalysts. A small selection of previously

reported catalysts based on metal complexes featuring stereolabile ligands is presented in Figure 8.1.40–49

Study towards a Photoswitchable Chiral Bidentate Phosphine Ligand based on an Overcrowded Alkene for

Metal-catalyzed Asymmetric Transformations

261

Figure 8.1. Previously reported catalysts based on metal complexes featuring stereolabile ligands.

The rotation energy barrier of biaryls can usually be explained on the basis of steric and electronic

substituent effects.50

Their conformational stability mainly depends on the presence of bulky ortho-

substituents. Meta-substituents further enhance steric hindrance to rotation through the so-called buttressing

effect: they reduce the flexibility of ortho-substituents and therefore enhance steric repulsion during

rotation about the chiral axis. The energy barrier to atropisomerization steadily increases with the steric

demand of the groups due to both enthalpic and negative entropic contributions. The latter originates from

the compromized rotational freedom of ortho-substituents in the crowded transition state. Electronic effects

play a secondary role due to enhanced CH/π-interactions, which becomes the predominant effect on the

rotational energy barrier upon promoting out-of-plane bending via less sterically hindered transition states.

The conformational stability of bridged biaryl units varies significantly with ring size. As a rule of thumb,

biaryls that possess one bridging atom are not stable to rotation to room temperature even if the remaining

two ortho-positions are occupied by bulky groups.51,52

An increase in bridge length enhances the torsion

angle between the two aryl rings and raises the energy barrier to racemization. Nevertheless, with a five- or

six-membered ring may still undergo rotation around the chiral axis, unless bulky ortho-substituents are

present in the bridged biaryl framework.53–59

Biaryl containing seven-membered or larger rings are

generally as stable as their unbridged analogs.60–63

By analogy with the stabilization of interconverting

axially chiral ligands by incorporation of a rigid bridge, coordination of a bidentate biaryl to a metal center

can significantly enhance the rotational energy barrier. Mikami,40,41,64

Jacobsen45

and Katsuki65

introduced

the concept of asymmetric activation of a stereolabile racemic catalysts derived from conformationally

unstable ligands with a non-racemic chiral activator. Such concept is based on rapidly interconverting chiral

catalysts, for example racemic BIPHEP-derived transition metal complexes, that are converted to a

diastereomerically enriched or pure catalytic species through addition of an enantiopure activator. For

example, 2,2‘-bis(diarylphosphino)biphenyls such as BIPHEP and DM-BIPHEP undergo rapid rotation

about the chiral axis at room temperature.66

However, the conformational stability of these diphosphines

increases upon metal complexation. The addition of enantiopure diamines to ruthenium and rhodium

Chapter 8

262

complexes of BIPHEP and DM-BIPHEP has been reported to give diastereoisomers that are stable to

isomerization at room temperature. Notably, the rapid racemization of BIPHEP is due to its ortho-

disubstituted biphenyl structure, as opposed to the conformationally stable ortho-tetrasubstituted biphenyl

ligand MeOBIPHEP (see Scheme 8.49). Achiral ligands can exist as a fluxional mixture of chiral and

enantiomeric conformers. Interaction with another chiral compound can render the equienergetic and

equally populated chiral conformation diastereomeric. Since diastereoisomers differ in energy, the ligand is

likely to preferentially occupy one chiral conformation. The presence of an enantiopure compound can

therefore induce a conformational bias in an achiral ligand resulting in amplification of chirality. In

contrast, Walsh‘s approach utilises stereolabile achiral activators, such as chiral diamine or diimine, to

optimize the performance of a chiral enantiopure BINOL-derived catalyst that is inherently stable to

racemization. 46–48

The preferential population of one chiral conformation of the stereolabile achiral

activator amplifies the asymmetric environment of the enantiopure catalyst, thus providing and

enhancement in asymmetric induction.

8.1.3 Photoswitchable metal complexes for asymmetric catalysis

The attractive prospects on the development and applications of stimuli-responsive catalysts have been

extensively explained throughout this thesis. Initial efforts were mainly devoted to the ON–OFF switching

of catalytic activity.67–69

Later, remarkable reversal of enantioselectivity in asymmetric catalysis has been

achieved using solvent responsive helical polymers,70

light-triggered organocatalysts71,72

and redox

sensitive metal complexes.73

As previously remarked in Chapter 6, a highly desirable feature of an ideal

responsive stereoselective catalyst is the ability to readily modify the chiral configuration of its active form.

In the case of homogenous catalysts based on metal complexes, some of the previously described systems

rely on the isomerization of photoresponsive coordination ligands before the addition of the metal

source.74,75

Such an approach is exploited because the formation of the active catalyst might impede the

efficient reconfiguration, either due to slow metal-ligand dissociation processes in multi-dentate

complexes76

or quenching of the photo-generated excited state via internal energy transfer influenced by the

metal center.77

Moreover, the use of multi-dentate responsive ligands characterized by a large variation in

geometry and distance of coordination sites between the interchangeable states, may lead to the

reconfiguration among mono- and oligomeric structures with divergent catalytic performances.74,75

On the

other hand, the optimal stereoselective metal-based catalyst should feature a limited number (ideally two)

of enantiomeric or pseudoenantiomeric active forms. The latter should also be interchangeable in their

coordinated states, providing access to chiral catalysts that could perform multiple enantioselective

transformation in a sequential manner without the need of an intermediate metal-decomplexation step.

Although it is difficult to switch the chirality of conventional ligands, artificial light-driven molecular

switches and motors provide a unique platform to achieve this goal.78–80

Branda and co-workers reported a

dithienylethene-based switch in asymmetric catalysis, which represents the first reported example of

modulation of stereoselectivity of a copper-catalyzed reaction by light (Scheme 8.1).81

They designed a

chiral bis(oxazoline) ligand with a switchable dithienylethene bridge unit, which allowed the selectivity of a

cyclopropanation reaction to be controlled with light. The approach exploited the differences in steric

interactions between the open and closed forms. In the open form o-L1, the two oxazoline moieties of the

ligand can bind copper(I) providing moderate enantioselectivities in the cyclopropanation of styrene (30–

50% ee). In the closed form c-L1, the two oxazolines are far apart, in an anti orientation, and cannot

provide bidentate coordination for the copper(I) atom. On using the ring-closed form, a significant drop in

enantioselectivity (5% ee) for the same catalyzed reaction was observed, although when a PSS mixture

consisting of 23% of the closed form was used, no significant drop in enantioselectivity was observed.

Unfortunately, this system is not effective in switching the selectivity in situ due to the low PSS. The same

group also developed a dithienylethene photoswitch bearing phosphine groups, displaying steric and

electronic differences between two photogenerated isomers.82

The coordination chemistry of this ligand



263

was demonstrated by preparing a gold(I) complex and a phosphine selenide. However, no catalytic

application was presented in the study.

Scheme 8.1. Photoswitching of a dithienylethane-based oxazoline ligand L1 that shows different

stereoselectivities in the copper-catalyzed asymmetric cyclopropanation of styrene developed by Branda

and co-workers.81

Craig and co-workers presented the first application of a photoswitchable bis-phosphine ligand in

enantioselective catalysis.83

Ligand L2 couples an achiral stilbene molecular photoswitch to the biaryl

backbone of a tetrasubstituted chiral bis-phosphine ligand analogous to MeOBiphep (Scheme 8.2).

Photochemical manipulation of ligand geometry is allowed without perturbing its electronic structure and

coordinating abilities. (E)-L2 and (Z)-L2 were isolated from the irradiated ligand mixture using column

chromatography. The changes in catalyst activity and selectivity displayed in palladium-catalyzed Heck

arylations and Trost allylic alkylations upon switching were attributed to intramolecular mechanical forces,

which varied the dihedral angle of the biaryl motif and consequently the catalyst performance. Although, in

all cases, the Z-isomer demonstrated higher selectivity than the E-isomer, reaction with either isomer

resulted in the same major enantiomer of the product (despite differing degrees of enantioselectivity). No

inversion of axial chirality of the biaryl bis-phosphine catalytic module was achieved upon switching of

such a stilbene actuator design, which resulted in the lack of stereoinversion when applied to the

asymmetrically catalyzed transformation.

Chapter 8

264

Scheme 8.2. Photoswitchable stilbene-derived biaryl bis-phosphine ligand L2 developed by Craig and co-

workers.83

Unidirectional rotary molecular motors based on overcrowded alkenes can intrinsically act as multistage

chiral switches as we have recently shown in the design of three-stage organocatalysts71,72

and bis-

phosphine ligands for metal catalysts.75

The design used to date is based on first generation molecular

motors,84

of which core is composed of two identical halves each bearing one functional group of the

catalytic pair. The photochemical and thermal isomerizations resulting in unidirectional rotation around the

central overcrowded alkene bond provide stepwise control over the helicity of the bifunctional bidentate

ligand L3 and spatial distance between the coordinating phosphine substituents. As the photochemically-

generated isomer (P,P)-(Z)-L3 and subsequent thermally-triggered isomer (M,M)-(Z)-L3 are pseudo

enantiomers, chiral products (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone with opposite absolute

configuration are obtained when these isomers are used in a palladium-catalyzed enantioselective allylic

substitution (Scheme 8.3).75

However, the thermally induced process of helix inversion between the

pseudoenantiomeric forms (P,P)-(Z)-L3 and (M,M)-(Z)-L3 is not per se reversible. Indeed, starting from

the isomer (P,P)-(Z)-L3, three consequent isomerization (light-heat-light) are required to recover the initial

isomer (M,M)-(Z)-L3.84

Hence, fully reversible handedness switching of chiral inductors remains highly

challenging so far. In case of non-labile coordination complexes, bridging the two halves to construct a

stable cyclic structure via metal complexation would also impede the characteristic isomerization cycle.

Further reversal of ligand chirality would require decomplexation of the active catalyst, for example upon

addition of a sequestering agent.



265

Scheme 8.3. Stereodivergent synthesis of (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone via palladium-

catalyzed enantioselective allylic substitution by switching the chirality of bis-phosphine ligand based on a

first generation molecular motor (Z)-L3 developed by Feringa and co-workers.75

In recognizing this, we decided to develop novel switchable bidentate bis-phosphine ligand based on the

scaffold of second generation molecular motors. Such a new design would feature a symmetrical fluorenyl

half, which would provide access to only two possible diastereoisomeric interconvertible forms and

consequently simplify the switching process. Light should allow non-invasive and dynamic control of

multistage ligand chirality, introducing simple yet efficient designs of programmable coordination

complexes.85

Fascinating prospects in the control of functions would arise from such a strategy (note that

dynamic chiral metal complexes were recently used in chiral recognition,86,87

transmission of chirality,88

chiral amplification89

and asymmetric catalysis73–75

).


8.2.1 Design

Chapter 5 describes the development of a photoresponsive molecular switch 1 featuring a versatile 2,2‘-

bisphenol motif in which chirality is transferred across three stereochemical elements (Scheme 8.4a).

Starting from the isomer (S,M=,Ma)-1, the photochemical E-Z isomerization (PEZI) of the helical-shaped

central alkene bond towards the isomer (S,P=,Pa)-1 allows via coupled motion the reversible control of the

helical and axial chirality of the biaryl motif. Successful application as stereodynamic chiral ligand in a

catalyzed asymmetric 1,2-addition of diethylzinc to benzaldehydes was demonstrated. Furthermore we

Chapter 8

266

previously proposed that such dynamic chiral selector could be derivatized to extend its applications into

more sophisticated catalytic systems. Indeed, in Chapter 6 we described the development of five chiral

photoresponsive phosphoramidite ligands derived from 1. The latter were successfully applied as tunable

ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexen-1-one. Control

over catalytic activity and stereoselectivity was achieved upon photo-induced isomerization using variable

diastereoisomeric mixtures of phosphoramidite-switch derivatives. Analogously, an attempt to develop a

switchable chiral phosphoric acid based on the same scaffold for application in photoswitchable

organocatalysis is presented in Chapter 7. Parallel to the last project, we envisioned such a biaryl-

functionalized core to be a promising candidate for developing the first bis-phosphine ligand based on a

second generation molecular switch 2, capable of providing light-triggered stereodynamic control in a

catalytic transformation upon metal complexation (Scheme 8.4b-c).

Scheme 8.4. Design of chiral photoresponsive bis-phosphine ligand 2. a) Previously described chiral 2,2‘-

bisphenol -susbtituted switch 1. b) Front structural view of metal complex with photoswitchable 2,2‘-

bis(phosphine) biphenyl-substituted overcrowded alkene-derivative 2 with axial helicity and chirality

(black) of the 2,2‘-biphenyl core coupled to helicity (blue) and point chirality (red) of the molecular switch

scaffold. Descriptors are based on the structure of compound (S)-2 (for explanation of the chiral descriptors,

vide infra). c) Schematic top-down view of metal complexes MLn-(S)-2: two metal-ligand complexes with

opposite coupled helicity (M or P) can be selectively addressed by irradiation with UV-light: MLn-

(S,M,Ra)-2 and MLn-(S,P,Sa)-2.

In the photoresponsive bis-phosphine catalyst previously developed by our group,75

the cooperative

catalytic action was achieved by interaction of two ligating groups each attached to one half of a light-

driven unidirectional four-stage cycle first generation molecular motor.71,72,75

Such a design is limited to the

effective cooperative catalytic activity between two groups located on structurally distant points of the

photoresponsive scaffold only in the corresponding Z-isomers. Moreover, the four-stage cycle leads to a

complex mixture of four isomers upon multiple irradiation cycles, due to the incomplete conversion toward



267

the metastable isomer during each photochemical isomerization process. In comparison, we envisioned

metal complex of compound 2 to be switchable between only two possible forms displaying coupled alkene

and biaryl helicities (M and P, Scheme 8.4c). Due to the symmetric fluorenyl substituent, the design

described herein would display a strong reversible transfer of helicity to the biaryl motif with limited

variation in morphology of the switch unit. Consequently, we envisioned a sharp reversal of

stereoselectivity while retaining high catalytic activity, as opposed to previous switchable catalyst designs

based on first generation molecular motors featuring Z and E isomers with large differences in shape and

catalytic efficiency.

The system described herein features four stereochemical elements.90,91

The first element is the fixed

stereogenic center (R or S) of the switch unit (highlighted in red). The second element is the helicity of the

overcrowded alkene (highlighted in blue), which is under thermal control by the configuration at the

stereogenic center but can be inverted between right-handed (P=) or left-handed (M=) upon

photoisomerization. More precisely, the more stable diastereoisomer of the R enantiomer will adopt a P

helicity, while the photo-generated diastereoisomer with higher energy will adopt an M helicity. The third

and fourth elements are, respectively, the helical geometry (Pa or Ma) and axial chirality (Ra or Sa) of the

biaryl unit (black), which are dictated via steric repulsion by the helicity of the alkene. In Chapter 5 we

showed that amongst the four theoretically possible conformations of a biaryl unit, only conformations in

which the non-annulated aryl group was parallel to the fluorenyl lower half were adopted. The other

conformations, with the aryl orientated perpendicular with respect to the lower half, were expected to

induce significant steric strain (see Scheme 8.5). Similar to the previously described coupled transfer of

dynamic chirality displayed by 1, the true helicity of the biaryl is inextricably connected to the helicity of

the overcrowded alkene chromophore, and is identical to it in each of the isomers. Analogously, two

atropisomers of 2 having identical alkene and biaryl helicity but opposite biaryl axial chirality are expected.

Therefore, three stereodescriptors (R/S, P/M and Ra/Sa) will be sufficient for the description of any expected

isomer reported in this work (unless indicated otherwise for more clear description). So for isomer (R,P,Sa)-

2: R = configuration of stereogenic center, P = helicity of alkene and biaryl, Sa = axial chirality of biaryl

(Scheme 8.4c). The doubly expressed axial stereodescriptor (Ra/Sa) throughout the text denotes a mixture of

rotamers with identical absolute stereochemistry at the stereocenter and configurational helicity (S,M,Ra/Sa

means a mixture of atropisomers S,M,Ra and S,M,Sa). Similarly to the phosphoramidite-switch derivatives

previously described in Chapter 6, our goal was to achieve reversible external control of chirality in a chiral

metal complex. We proposed that the tunable helicity (P or M) of the switch core in turn would dictate the

preferential axial configuration (Ra or Sa) of the desirable syn conformation of the biaryl moiety and

eventually, for instance, the configuration (R or S) of a newly formed stereogenic center when applied to an

enantioselective catalytic event.

Scheme 8.5 illustrates the envisioned interplay of dynamic stereochemical elements of bis-phosphine ligand

(S)-2 before and after metal complexation and the light-triggered switching process between the two

proposed diasteroisomeric species. Two rotamers, displaying syn or anti conformation of the biphenyl, are

expected for each helical diastereoisomer (S,M) and (S,P), respectively. Due to the steric hindrance caused

by the phosphine substituents, high energy barrier for biaryl axial inversion is envisioned in the free ligand

2. Thus no inversion of axial chirality is expected upon light-triggered inversion of helicity, namely M,Sa-

anti ⇄ P,Sa-syn and P,Ra-syn ⇄ P,Ra-anti. However, the helicity of the alkene and biaryl units are still

expected to convert through a coupled motion to accommodate the alkene bond isomerization (Scheme

8.5a). On the other hand, the bidentate metal complex is envisioned to permit the axial inversion of the

biaryl unit between the parallel and perpendicular conformations, respectively, for instance, between

M=,Ma,Ra-syn and M=,Pa,Sa-syn (Scheme 8.5b). If compared to monodentate anti-isomers, bidentate

coordination species are envisioned to have access to transition states with lower energy barrier for biaryl

axial inversion. Notably, both mono- and bidentate coordination species MLn-2 are possible. However, only

the isomers with syn conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal

center and successfully transfer the chirality within a catalytically active complex. Therefore, we

Chapter 8

268

envisioned that the parallel syn-conformer of the bidentate complex M=,Ma,Ra-syn would be largely

thermodynamically favored and be present as the major species at the equilibrium. In summary, isomers

with syn conformation and coupled helicity are expected to interconvert upon irradiation, while isomers

with anti conformation would either isomerize to corresponding energetically favored syn isomers or

spectate as catalytically inactive monodentate complexes (Scheme 8.5c). Overall, two main syn conformers

with opposite axial chirality would be selectively addressable by means of light-irradiation with appropriate

wavelength, giving access to a reversibly switchable chiral metal complex for catalytic applications.

Scheme 8.5. a) Schematic representation of switching process between the rotamers of free ligand (S)-2. b)

Depiction of the possible mono- and bidentate coordination species MLn-(S)-2. Only the isomer with syn

conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal center and successfully

transfer the chirality within a catalytically active complex. c) Schematic representation of switching process

between the rotamers of metal complexes MLn-(S)-2. Note: for monodentate coordination species, the

proposed metal coordination position at the upper phosphine moiety of the biaryl was arbitrary chosen.

8.2.2 Retrosynthetic analysis

The proposed retrosynthetic analysis of switchable metal complex with bis-phosphine ligand 2 from

bisphenol -derived switch 1 is presented in Scheme 8.6.

Scheme 8.6. Proposed retrosynthetic analysis of switchable bis-phosphine ligand 2 from bisphenol -derived

switch 1.

Metal complex MLn-2 could be obtained from free ligand 2 upon metal complexation. The target

photoresponsive ligand 2 was envisioned to be accessible via metal-catalyzed phosphination of bis-triflate

3. For comparison, BINAP is prepared from BINOL via nickel-catalyzed phosphination of its bis-triflate

https://en.wikipedia.org/wiki/1,1%27-Bi-2-naphthol

https://en.wikipedia.org/wiki/Triflate



269

derivative with diphenylphosphine.92

Similarly, bis-triflate 3 can be obtained from 1 upon reaction with

triflic anhydride.

8.2.3 Derivatization of resolved bisphenol derivative

The synthesis of bis-triflate switch derivative 3 starting from 2,2‘-bisphenol -derived molecular switch 1 is

illustrated in Scheme 8.7. A previously described, (S)-1 is obtained after resolution as a mixture of

interconverting conformers, i.e. (S,M,Ra)-1 and (S,M,Sa)-1 (hence, indicated as (S,M,Ra/Sa)-1; for synthesis

and chiral resolution of 1, see Chapter 5). Optically enriched (S,M,Ra/Sa)-1 (99% ee) was reacted with triflic

anhydride and pyridine in dichloromethane to yield a mixture of Ra-syn conformer (S,M,Ra)-3 and Ma-anti

conformer (S,M,Sa)-3 in a ratio of Ra-syn:Ma-anti = 40:60, as determined via 1H NMR analysis of the crude

mixture.

Scheme 8.7. Synthesis of conformers of bis-triflate switch derivative 3.

Chapter 5 describes the assignment of conformers (R,P,Sa)-1 and (R,P,Ra)-1 based on experimental and

calculated chemical shifts of the corresponding 1

H NMR spectra. Despite the difference in absolute

chemical shift value, the relative position of the experimentally assigned absorptions peaks for the

atropisomer in the experimental 1H NMR spectra are in full agreement with the corresponding calculated

absorption peaks. Notably, almost every resonance absorption of the syn isomer (R,P,Sa)-1 resonates at

higher frequency than the minor anti isomer (R,P,Ra)-1. By comparison with experimental 1H NMR spectra

of (S,M,Ra/Sa)-1 (Figure 8.2a), the isolated early (Figure 8.2b) and later fraction (Figure 8.2c) obtained after

flash column chromatography of the mixture were similarly assigned to the Ra-syn and Ma-anti conformers

of 3, (S,M,Sa)-3 and (S,M,Ra)-3, respectively, based on the relative position of each distinctive resonance

absorptions. Each single atropisomer was analyzed via 1H NMR spectroscopy before and after prolonged

heating (solution in toluene, 110 °C for 6 h). No isomerization towards the other conformer was observed.

Compared with bisphenol 1, bis-triflate 3 displayed a much higher thermal stability for the biaryl axial

isomerization, as no internal hydrogen bonding can take place between the two protected phenolic moieties

of the biaryl unit. This behavior is indicative of the importance of a cyclized intermediate which can give

access to a transition state with a low energy barrier for biaryl isomerization in order to achieve an efficient

coupled transfer of helicity within a reversible bidentate coordinating species.

Chapter 8

270

Figure 8.2. Comparison of 1H NMR spectra (CDCl3) of: a) interconverting atropisomers (S,M,Ra/Sa)-1 (see

Chapter 5 for full assignment); b) isolated atropisomer (S,M,Sa)-3; c) isolated atropisomer (S,M,Ra)-3.

8.2.4 Metal-catalyzed phosphorylation

Initial investigation of NiCl2(dppe)-catalyzed double phosphination or phosphorylation reactions with

either diphenylphosphine (Scheme 8.8a),92

diphenylphosphine-borane complex (Scheme 8.8a)93

or

diphenylphosphine oxide (Scheme 8.8b)94

were conducted on (S,M,Ra)-3 by modified procedures

previously reported for bis-triflate derivatives of BINOL. However, the tested conditions resulted in no

conversion towards either bis-diphenylphosphine derivative 2 or bis-diphenylphosphineoxide derivative 4.

Notably, substrate 3 was recovered in approximately 90% in all cases.



271

Scheme 8.8. Attempted NiCl2(dppe)-catalyzed phosphination and phosphorylation reactions of bis-triflate

derivative (S,M,Ra)-3.

Our experiments suggest that the procedure successfully implemented on naphthalene derivatives cannot be

extended to this less activated biphenyl substrate. We continued our endeavor by exploring the palladium-

catalyzed phosphorylation of aryl triflates in combination with phosphine oxide reduction. Previously

reported substituted BINAP and BIPHEP derivatives were synthesized via a four-step sequence of

phosphorylation (1) - phosphine oxide reduction (2) - phosphorylation (1) - phosphine oxide reduction (2)

(Scheme 8.9).38,95–97

As opposed to the Nickel-catalyzed processes, it appears that the first phosphine oxide

group deactivates the single substituted intermediate towards a second phosphorylation step. Upon

reduction of the phosphine oxide substituent, a second one can be subsequently installed. However, such

alternative route via a four-step sequence would be detrimental for the final yield of target compound 2.

Scheme 8.9. Retrosynthetic analysis of bis(diphenylphosphine) derivatives via four-step sequence of

palladium-catalyzed phosphorylation (1) of aryl triflates and phosphine oxide reduction (2).

Each conformer of bis-triflate 3 was successfully submitted to palladium-catalyzed phosphorylation with

diphenylphosphine oxide. Reactions were successfully conducted in presence of PdCl2(dppp) (dppp =

bis(diphenylphosphino)propane) (Scheme 8.10a-b) or PdOAc2 and dppb (dppb =

bis(diphenylphosphino)butane) (Scheme 8.10c) to yield the diphenylphosphino-triflate derivative 5 with

Chapter 8

272

moderate to good yield.98

Theoretically, substitution of a single triflate substituent could provide two

distinct regioisomers of the monophosphorylated biaryl derivative 5 (phosphine oxide on the upper ring and

triflate on the lower, and vice versa), each as a mixture of two conformers (syn and anti). Notably, a

common single isomer of the monosubstituted diphenylphosphine oxide-triflate product was obtained,

regardless of the starting bis-triflate conformer. By comparison with the 1H NMR spectra of the starting

materials, conformer (S,M,Ra)-5 was proposed as the obtained species. We hypothesized the opposite

conformer to be much more sterically hindered. Therefore, upon prolonged heating necessary to achieve

full conversion in the phosphorylation reaction, both conformers of 3 are transformed upon biaryl inversion

into the same most stable isomer of product (S,M,Ra)-5, either during or after the palladium-catalyzed

substitution. However, analysis with 2D-NMR techniques did not help to achieve full certainty about the

actual substitution pattern and conformation of the analyzed isomer among the four possible species.

Further investigation was not conducted due to interruption of the project (vide infra). On the other hand,

the proposed structure of 5 is consistent with the mechanism of base-promoted degradation of triflate

shown in Scheme 8.15 (vide infra).

Scheme 8.10. PdCl2(dppp)- and PdOAc2(dppb)-catalyzed phosphorylation reaction of bis-triflate 3 to

diphenylphosphine oxide-triflate 5.

8.2.5 Phosphine oxide reduction

Following the precedent literature, we proceeded with the reduction of the mono-substituted phosphine

oxide 5. Various conditions for phosphine oxide reduction of 5 were tested by modified procedures

previously reported.99

We suspected an inconvenient sensitivity of the overcrowded alkene functionality of

5 towards harsh reductive conditions. Hence, we initially opted for a highly selective and mild phosphine

oxide reduction methodology previously tested in our group for an analogous phosphine derivative based

on a first generation molecular motor.100

Beller and co-workers developed a highly chemoselective metal-

free reduction of phosphine oxides to phosphines in the presence of catalytic amounts of specific

phosphoric acid esters and methyldiethoxylsilane HSiMe(OEt)2.101



273

Scheme 8.11. Tested conditions for the phosphine oxide reduction of (S,M,Ra)-5 to (S,M,Ra)-6.

Other reducible functional groups such as ketones, aldehydes, olefins, nitriles, and esters are well-tolerated

under the reported optimized conditions. Basic workup with methanolic KOH was required to cleave the P-

Si bond of the phosphonium cation after reduction with silane species to isolate the phosphine products.

When such conditions were tested on 5 (Scheme 8.11a, Figure 8.3a), we observed major decomposition of

the overcrowded alkene functionality (see also Chapter 7). Analysis of the crude before basic workup via 1H/

31P NMR spectroscopy (Figure 8.3a-b, Figure 8.4) showed 45% conversion of 5 (δP = 27.8 ppm) (Figure

8.3a and Figure 8.4a) to a different unidentified species (δP = 19.0 ppm) (Figure 8.3b and Figure 8.4b),

which displayed phosphorus chemical shift not consistent with conventional phosphine ligands (0 ppm > δP

> -20 ppm). We supposed this observed new species to be a phosphorus-silane adduct, which was also

analyzed via 1H/

31P NMR spectroscopy (Figure 8.3c and Figure 8.4c) after purification. The target reduced

product diphenylphosphine-triflate 6 (δP = -12.9 ppm) was observed in the crude mixture only as minor

component (Figure 8.3b-c and Figure 8.4b-c). We continued our screening by testing the conditions for

deoxygenation of phosphine oxides using triphenylphosphine or triethylphosphite as an oxygen acceptor in

presence of large excess of trichlorosilane, as reported by Spencer and co-workers.102

Reaction of 5 with

triphenylphosphine resulted in no conversion of the substrate (Scheme 8.11b). On the other hand, reaction

of 5 with triethylphosphite afforded product 6 in moderate yield (30%) together with an inseparable side-

product (Scheme 8.11c), which appeared consistent with a by-product of tetrahydrofuranas suggested by 1H

NMR analysis of the isolated fraction (not shown). Another methodology for reduction of phosphine oxides

to phosphines uses a combination of titanium(IV) isopropylate and triethoxysilane, as reported by Lin and

Chapter 8

274

co-workers in the synthesis of 4,4′-substituted-xylBINAP ligands.38

No basic workup was reported for such

procedure, which was considered a promising approach to tackle the sensitivity to strong bases of the

switch scaffold described hereto. However, we observed no conversion of the substrate when applied to 5

(Scheme 8.11d). Eventually, we tested a conventional reduction methodology with diisopropylethylamine

and trichlorosilane in large excess.96

To our delight, very good selectivity was observed by analysis of the

crude with 1H/

31P NMR spectroscopy (Figure 8.3d and Figure 8.4d), which displayed high conversion (>

90%) of (S,M,Ra)-5 to (S,M,Ra)-6. The desired product was also obtained in good isolated yield (75%).

Figure 8.3. Comparison of 1H NMR spectra (CDC3) of: a) (S,M,Ra)-5; b) crude reaction mixture obtained

after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing reduced phosphine

components from previous mixture; d) isolated (S,M,Ra)-6 obtained after conditions indicated in Scheme

8.11e.



275

Figure 8.4. Comparison of 31

P NMR spectra (CDCl3) of: a) (S,M,Ra)-5 (δP = 27.8 ppm); b) crude reaction

mixture obtained after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing

reduced phosphine components (δP = 19.0 ppm and δP = -12.9 ppm) from previous mixture; d) isolated

(S,M,Ra)-6 (δP = -12.9 ppm) obtained after reduction conditions indicated in Scheme 8.11e (with

phosphoric acid as internal reference, δP = 0 ppm).

8.2.6 Attempted second metal-catalyzed phosphorylation

(S,M,Ra)-6 was subjected to the same conditions for palladium-catalyzed phosphorylation previously

described for 3 (Scheme 8.12).98

Unfortunately, the reaction yielded the oxidized substrate

diphenylphosphine oxide-triflate (S,M,Ra)-6 as major component. Oxidation of the substrate may have

occurred due to the oxidative properties of DMSO or via oxygen exchange with diphenylphosphine oxide at

high temperature. However, Spencer and co-workers reported that the latter pathway requires the presence

of trichlorosilane, as employed in their phosphine oxide reduction methodology.102

The detrimental

contamination of the reaction mixture with oxygen cannot be excluded either. Notably, no trace of the

expected diphenylphosphine-diphenylphosphine oxide 7 was detected by 1H/

31P NMR analysis. Such

phenomenon suggests that the highly hindered structure of the designed bidentate ligand and the low

reactivity of aryl triflate in metal-catalyzed substitution reactions may preclude the proposed synthetic route

employed so far.

Chapter 8

276

Scheme 8.12. Attempted conditions for PdOAc2(dppb)-catalyzed phosphorylation reaction of

diphenylphosphino-triflate 6 to diphenylphosphino-diphenylphosphine oxide 7.

In Chapter 3 we demonstrated how even the switch central scaffold (e.g. 5,8-dimethylthiochromene upper

half – fluorenyl lower half) plays an important role in the reactivity of their substituents. In the case

described in fact, the copper-catalyzed aromatic Finkelstein reaction allowed to exchange a bromine atom

for an iodine atom, incrementing significantly the conversion of the halogenated switch derivative in the

palladium-catalyzed Buchwald-Hartwig coupling. Therefore, in an attempt to exclude the low reactivity of

the triflate substituent of compound 6 towards the phosphorylation step among the plausible causes of its

failed conversion to 7, a triflate-halogen exchange step was considered. Indeed, metal-catalyzed

phosphorylation of aryl bromides and iodides is widely applied alternative methodology to synthesize

phosphine-based ligands.103,104

Hayashi and co-workers reported a solid methodology for transformation of

aryl triflates, alkenyl sulfonates and phosphates to aryl halides and alkenyl halides, respectively, by treating

them with LiBr/NaI and [Cp*Ru(MeCN)3]OTf in dimethylimidazolinone (DMI). Aryl triflates undergo

oxidative addition to a ruthenium(II) complex to form η1-arylruthenium intermediates, which are

subsequently transformed to the corresponding halides. For comparison, bis-triflate 3, diphenylphosphine

oxide-triflate 5, and diphenylphosphine-triflate 6 were treated according to the reported procedures. Bis-

triflate (S,M,Ra)-3 was successfully converted to what was assigned as the bromide-triflate (S,M,Ra)-8 (full

conversion, yield not determined, Scheme 8.13a), obtained by flash column chromatography together with

large amount of not removable DMI. It should be noted how only the triflate group on the upper phenyl

ring of the biaryl motif reacted to the tested conditions. On the other hand, diphenylphosphine oxide-triflate

(S,M,Ra)-5 gave no conversion towards either the corresponding diphenylphosphine oxide-bromide

(S,M,Ra)-9 or diphenylphosphine oxide-iodide (S,M,Ra)-10 (Scheme 8.13b). Lastly, diphenylphosphine-

triflate (S,M,Ra)-6 also gave no conversion towards the corresponding diphenylphosphine-iodide (S,M,Ra)-

11 (Scheme 8.13c). From the performed experiments, it appears that the triflate group on the lower phenyl

ring of the biaryl motif suffers from a general low reactivity towards metal-complex catalyzed substitution.

This could be due to its hindered position, almost sandwiched between the upper biaryl substituent and the

fluorenyl lower half of the switch module. The limited space may in fact not allow the catalyst to

successfully approach the aryl-triflate bond, thus preventing the oxidative addition and eventually any sort

of subsequent substituent exchange.



277

Scheme 8.13. Attempted conditions for [Cp*Ru(MeCN)3]OTf-catalyzed triflate-halogen exchange of bis-

triflate 3, diphenylphosphine oxide-triflate 5, and diphenylphosphino-triflate 6 to their corresponding

halogenated derivatives 8,9-10 and 11.

The synthesis of bis-diphenylphosphine ligand 2 was not accomplished according to the proposed synthetic

route (Scheme 8.6). A different approach could have been considered, possibly installing the phosphine

substituents on the biaryl unit before the creation of the overcrowded alkene function required for the

photoresponsive properties. However, such approach would need a totally different synthetic sequence and

would not exploit the already developed synthesis and chiral resolution of 2,2‘-bisphenol switch derivative

1 presented in Chapter 5. An alternative resolution strategy must be considered beforehand, for example via

formation of diastereoisomeric metal complexes of the target bisphosphine ligand with enantiopure

reusable resolving reagent as very last step (Scheme 8.14).105–107

Scheme 8.14. Proposed resolution of 2 with stoichiometric formation of diastereoisomeric palladium-

phosphine ligand complex.

Chapter 8

278

8.2.7 Development of photoswitchable chiral Brønsted acid

At this phase of the research project, a very small timeframe was left. Among the limited amount of

feasible options, we proposed to redirect the project goal to the development of a 2-diphenylphosphino-2‘-

hydroxy-1,1‘-biphenyl-derived overcrowded alkene 12 as a switchable chiral Brønsted acid (Figure 8.5).

Chiral Brønsted acid catalysis has been one of the growing fields in modern organic synthesis.108

Urea/thioureas,109

TADDOL,110

and phosphoric acids111,112

have been widely used as catalysts in various

asymmetric syntheses. Therefore, it would be interesting to extend the area of application of

photoswitchable chiral catalyst to the field of Brønsted acid catalysis. Our design was inspired by the

previously reported optically active (S)-2-hydroxy-2‘-diphenylphosphino-1,1‘-binaphthyl ((S)-HOP) and its

derivatives, which were successfully applied in asymmetric catalysis either as free organocatalysts or as

Lewis acid-assisted Brønsted acids (LBAs). Chen and co-workers described the application of 2-

diphenylphosphino-2‘-hydroxy-1,1‘-biphenyl as bifunctional organocatalyst for aza-Morita-Baylis-Hillman

(aza-MBH) reaction and domino reaction (aza-MBH followed by a Michael addition and aldol/dehydration

reaction) between N-sulfonated imines and acrolein.113

Shi and co-workers reported the use of (S)-HOP and

few of its functionalized derivatives as chiral phosphine Lewis bases in the catalyzed asymmetric aza-

Baylis-Hillman reaction of N-sulfonated imines with activated olefins.114

The study revealed that the phosphine

atom acted as a Lewis base to activate the Micheal acceptor, and the phenolic OH acted as a Lewis acid (BA) through

intramolecular hydrogen bonding with the oxygen atom of carbonyl group to stabilize the in situ formed key enolate

intermediate. In addition, the intramolecular hydrogen bonding between the phenolic OH and the nitrogen anion

stabilized by the sulfonyl group can give a relatively stable or rigid transition state for achieving high enantioselectivity

in the aza-Baylis-Hillman reaction. The same group later extended the catalytic methodology to a selection of chiral

phosphine Lewis bases bearing multiple phenol groups and closely related to HOP.115

Yamamoto and co-

workers developed a LBA derived from (S)-HOP with La(OTf)3 as a Lewis acid activator, which was

applied to the catalytic enantioselective protonation reaction of silyl enol ether of 2-aryl cyclic ketones in

the presence of methanol.116

Figure 8.5. Proposed design of photoswitchable chiral Brønsted acid 12, inspired by phosphine-hydroxyl-

biaryl Brønsted acid catalysts previously reported.

An alternative approach would be the synthesis of an analogue of the 2-(diphenylphosphino)-2‘-methoxy-

1,1‘-binaphthyl ligand (MOP) developed by Hayashi and co-workers upon methylation of (S)-12.117

Having already developed a synthetic route to phosphorylated intermediate 5, we hypothesized to prepare

12 via hydrolysis of the unreacted triflate substituent and subsequent reduction of the phosphine oxide

group. The hydrolysis of 5 was attempted using sodium hydroxide, a strong inorganic base, according a

modified procedure previously reported (Scheme 8.15).37



279

Scheme 8.15. Attempted conditions for hydrolysis of triflate substituent of 5 towards diphenylphosphine

oxide-hydroxyl derivative 15, which instead yielded the hypothesized by-products 16 and 16’ upon addition

of generated phenolate anion to the overcrowded alkene bond, according to the illustrated proposed

mechanism.

No conversion to the desired product 15 was observed as determined by NMR analysis of crude. Major

decomposition of the switch functionality occurred as determined by 1H NMR spectroscopy (Figure 8.6).

Complete hydrolysis of the triflate substituent was determined as observed by lack of any resonance peak in

the 19

F NMR spectrum. Notably, two sets of resonances with an approximate ratio of 70:30 were observed

in the 1H/

31P NMR spectra (Figure 8.6 and insert).


31P NMR (insert) spectra (CDCl3) of proposed atropisomers 16 and 16’ obtained

after hydrolysis of 5.

We proposed a mechanism involving initial hydrolysis of the triflate group to the corresponding phenolate

anion 13, followed by biaryl axial inversion and addition of the hydroxyl substituent to the upper carbon

atom of the overcrowded alkene bond to afford a tetracyclic anion intermediate 14 with a fluorenyl

substituent on the tetrasubstituted carbon of the newly formed pyranyl ring. Upon acid workup, the

Chapter 8

280

carbanion located on the position 9 of the fluorenyl substituent is then protonated to give a mixture of two

atropisomeric by-products 16 and 16’ (the sets of NMR resonances were not assigned to the corresponding

isomers). The driving force of such an unexpected decomposition mechanism is proposed to be the

decrease of steric hindrance and loss of torsion strain experienced by the overcrowded alkene bond, which

is consequently transmitted to the whole structure via tight coupled transfer of helicity. Moreover, the

fluorenyl anion substituent of 18 is expected to be highly energetically favored due to the aromatic

electronic configuration (14 electrons). In a comparative experiment, the same procedure described for the

attempted hydrolysis of 5 to 15 was applied to the deprotonation of bisphenol 1 and hydrolysis of bis-

triflate 3, respectively, affording in either case 19 upon reaction with sodium hydroxide (Scheme 8.16) or

potassium hydroxide.

Scheme 8.16. Decomposition of compounds 1 and 3 towards 19 upon reaction with sodium hydroxide.

Side: structural view of proposed most stable conformer of 19.

The same single set of absorptions was observed in the 1H NMR spectrum. No resonance was observed in

the 19

F NMR spectra of the crude obtained from reaction with 3. A common product as assigned to

structure 19 was suggested to be similarly obtained, after hydrolysis of triflate groups in case of 3, via

addition of phenolate anion to the alkene bond according to an analogous mechanism. Notably, unlike the

decomposition of 5, a single species was observed by 1H NMR analysis after reaction of 1 or 3 (Figure 8.7).

Figure 8.7. 1H NMR spectra (CDCl3)of product of obtained after treatment of 1 or 3 with strong inorganic

bases.



281

The characteristic resonances that support the proposed structure of 19 are the singlet at δ = 3.70 ppm,

assigned to the dibenzylic proton (Ha) in position 9 of the fluorenyl substituent, and the singlet at δ = 4.67

ppm, assigned to the single phenolic proton (Hb). Notably, the doublets at δ = 8.03 ppm and δ = 5.86 ppm

were assigned, respectively, to the aromatic protons in the positions 1 (Hc) and 8 (Hd) of the fluorenyl

substituent. The chemical shift of their absorption resonances were justified according to their distinctive

position relative to the central tetracyclic unit and consequent unusual magnetic environment. In particular,

it should be noted how the proton Hd is nearly facing the delocalized electronic orbital of the lower phenol

ring of the biaryl unit, thus experiencing a strongly shielding effect which lowers its chemical shift below

the expected range of common aromatic protons.

We proposed to circumvent issue of the instability of such phenol derivatives to strong bases by avoiding

the need of hydrolysing the unreacted triflate group. Upon careful dosage of triflic anhydride, we proposed

to convert bisphenol derivative 1 to a singly substituted triflate-hydroxyl derivative, which could be singly

phosphorylated without need of protecting the second phenol functionality. However, the reaction of

(R,P,Sa/Ra)-1 in such conditions (Scheme 8.17) yielded a mixture of two proposed rotamers of the product

in a ratio of 65:35, as analyzed by 1H/

19F NMR spectroscopy.

Scheme 8.17. Synthesis of conformers of triflate-hydroxyl derivative 20 from 1 (or proposed alternatively

substituted derivatives 21).

The structure of the observed species were assigned to conformers (R,P,Sa)-20 and (R,P,Ra)-20,

respectively, which feature the same substitution pattern of the biaryl unit but opposite biaryl axial chirality.

Such assignment was proposed by comparison of the 1H NMR spectra of substrate 1 (Figure 8.8a) with the

singly triflate-substituted products 20 (Figure 8.8b) and the corresponding isolated bis-triflate conformers 3

(Figure 8.8c-d), similarly to the previous cases (vide supra). However, a different regioisomeric structure

21 featuring opposite substituent position on the biaryl unit could also be consistently proposed. Notably,

the same ratio of conformers was observed in the starting material 1 and in the obtained product 20. This

could suggest that species 1 and 20 feature an equal difference in free energy between the corresponding

conformers (R,P,Sa) and (R,P,Ra). On the other hand, the substitution of the hydroxyl groups with non-

coordinating substituents (e.g. via hydrogen bonding) could in fact quench the biaryl axial isomerization,

thus fixing the ratio of the conformers displayed in 1 up to the derivatives 20 and 3. Interestingly, CSP-

HPLC analysis of the atropisomeric mixture of 20 displayed two sharp elution peaks, which may suggest

that no interconversion occurs between the two isomers at the tested analytical conditions. Moreover, when

a sample of the latter was subjected to EXSY experiment at 60 °C in CDCl3 to possibly observe a rapid

interconversion of the two coexisting species of 20, no exchange of excited resonance peaks was observed,

Chapter 8

282

which corroborates the lack of exchange between the two proposed atropisomeric structures even at slightly

higher than ambient temperatures. Such behavior is very different from what was observed for 1 (see

Chapter 5). This phenomenon could be explained via two hypotheses: 1) the energy barrier for biaryl axial

inversion of conformers 20 is higher than for 1 (see Chapter 5 for details) and could not be observed at the

applied conditions, as it would require higher temperatures; 2) the obtained product is a mixture of a single

conformer of 20 and 21, respectively, which are coincidentally also stable to biaryl axial inversion at such

conditions. However, the latter hypothesis seemed less likely. Regardless, no further investigation was

conducted to elucidate such point as it was not the main goal of the project.

Figure 8.8. Comparison of 1H NMR spectra (CDC3) of: a) (R,P,Sa/Ra)-1; b) mixture of conformers (R,P,Sa)-

20 and (R,P,Ra)-1; c) (S,M,Sa)-3; d) (S,M,Ra)-3.

The isolated mixture of conformers of 20 was submitted to the same conditions for palladium-catalyzed

phosphorylation previously described for 5 (Scheme 8.18). Unfortunately, the expected diphenylphosphine-

hydroxyl derivative 15 was not observed, while substrate 20 was not recovered. In fact, the reaction yielded

a complex mixture of by-products that could not be clearly identified even after 1H/

19F/

31P NMR analysis of

the various fractions obtained after column chromatography. Two early fractions displaying a single 19

F

NMR resonance absorption were lacking of the overcrowded alkene functionality resonances in the 1H

NMR spectra and of any 31

P NMR resonance absorption. The middle fraction, which displayed the



283

distinctive overcrowded alkene functionality resonances in the 1H NMR spectra and a single

19F NMR

resonance absorption was lacking of any 31

P NMR resonance absorption. The latter fraction, which

displayed five distinct 31

P NMR resonance absorptions and a single 19

F NMR resonance absorptions was

lacking of any overcrowded alkene functionality resonances as observed in the 1H NMR spectra. In

conclusion, the synthetic route towards the Brønsted acid 12 was not completed.

Scheme 8.18. Attempted synthesis of photoswitchable chiral Brønsted acid 12 via phosphorylation of 20

and consequent not tested phosphine oxide reduction of 15.

Due to the insurmountable complications encountered during the development of an effective switchable

bisphosphine ligand or Brønsted acid catalyst based on a reversibly photo-responsive bifunctional

overcrowded alkene, the venture of designing a novel phosphine-based catalyst for dynamic control of

light-assisted synthetic transformations was interrupted.

8.3 Conclusions

This chapter describes the study towards a bidentate biaryl bis(diphenylphosphine) ligand based on an

overcrowded alkene for photoswitchable asymmetric homogeneous metal-catalyzed transformation. The

design of the system implies a reversible change of helicity of the overcrowded alkene central scaffold

which produces a consequent inversion of helical and axial chirality of the biaryl unit. The absolute

stereochemistry is overall governed by the fixed point chirality sited in the stereocenter of the molecular

switch. An efficient coupled motion with effective inversion of the local chirality surrounding the

coordinated metal center is envisioned to occur only in the bidentate metal-ligand complex. The formation

of a seven-membered ring metallacyclic structure is key for lowering of the energy barrier for biaryl axial

inversion, as such species was expected to have access to a transition state characterized by a lower energy

if compared with the free ligand. We proposed a synthetic route of bisphosphine ligand 2 starting from 2,2‘-

bisphenol functionalized molecular switch 1 previously described in Chapter 5. Derivatization of the

bisphenol moiety to the corresponding bis-triflate 3 yielded a mixture of separable non-interconverting

atropisomers. Initial unsuccessful tests were conducted according to nickel-catalyzed phosphination or

phosphorylation methodologies previously reported for conventional binaphthyl-based scaffolds. The lower

reactivity of the biphenyl bis-trilate unit of 3 required a more robust yet laborious multi-step approach

comprising sequences of palladium-dppp/dppb-catalyzed phosphorylation and consequent phosphine oxide

reduction. Both atropisomers of 3 yielded a single isomer of singly phosphorylated derivative 5, which was

reduced to the corresponding diphenylphosphine-triflate 7 with trichlorosilane and ethyldiisopropylamine.

No substitution of the second triflate moiety was achieved by following the conditions of the previously

successful phosphorylation step. We attempted to enhance the reactivity of the lower leaving group via

ruthenium-catalyzed triflate-bromide/iodide exchange. Unfortunately, no conversion of 7 was observed. We

hypothesized that the steric hindrance around the lower triflate group caused by the molecular switch core

interferes with the catalytic system, thus precluding any further transformation via metal-catalyzed

substitution. The synthesis of the target bidentate ligand 2 was not accomplished. We proposed to redirect

the goal of the project to the development of a chiral photoswitchable Brønsted acid catalyst 12 featuring

diphenylphosphine and phenol functionalities on the biphenyl unit. Hydrolysis of the triflate group of 5

Chapter 8

284

with strong inorganic bases resulted in loss of the overcrowded alkene motif, possibly via addition of the

generated phenolate anion to the alkene bond to generate a tetracyclic structure. The same reactivity was

observed for bisphenol 1 and bis-triflate 3. Our hypothesis implies an energetically favorable loss of steric

strain and bond torsion that, unexpectedly, drives the addition of a phenolate to an alkene bond. Finally, we

also proposed to synthesize 12 via palladium-catalyzed phosphorylation of the monotriflate derivative 20.

However, this approach was found not fruitful, indicating a detrimental sensitivity of the phenol to tested

conditions. This study describes a novel approach to a truly reversible photoswitchable chiral bidentate

metal-complex. Notably, application of an externally triggered multistate chiral catalyst in tandem catalysis

is still an undisclosed achievement. Our investigation provides valuable insight into the requirements for

the design of more effective and complex responsive systems, which may allow the photocontrol of catalyst

activity and selectivity in multicomponent reactions. Key to the successful development of these future

catalysts will be a deeper understanding of the compatibility of ancillary functional groups with the stability

of the overcrowded alkene functionality and the introduction of more reactive substituent to ensure higher

versatility during the catalyst development and synthesis.



285



General experimental details can be found in Chapters 5 and 6.


(1R,7S)-8-(9H-fluoren-9-ylidene)-7-methyl-1-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-5,6,7,8-

tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3).

A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a

magnetic stirring bar. A solution of 2,2‘-bisphenol derived switch (S,M)-1 (400 mg,

0.96 mmol) in dry CH2Cl2 (4 mL) was injected under nitrogen. To this solution was

added dry pyridine (0.21 mL, 2.60 mmol, 2.7 equiv), followed by triflic anhydride

(0.34 mL, 2.02 mmol, 2.1 equiv) slowly at 0 °C . The reaction mixture was stirred

at 0 °C for 3 h, at which time TLC indicated that the reaction was completed. The

reaction mixture was diluted with CH2Cl2 (10 mL) and washed subsequently with aq. 1 M HCl (10 mL), aq.

1 M NaHCO3 (10 mL), and brine (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered

and the solvent was removed under reduced pressure. The product was purified by column chromatography

(SiO2, pentane:CH2Cl2 = 5:1 to 1:1) to yield bis-triflate 3 (570 mg, 0.83 mmol, 86%) as a 40:60 mixture of

stable atropisomers as a yellow foam. The isolated early fractions were assigned to pure (S,M,Ra)-3 (190

mg, 0.28 mmol, 29%). The middle fractions were assigned to a mixture of (S,M,Ra)-3 and (S,M,Sa)-3. The

isolated later fractions were assigned to pure (S,M,Sa)-3 (300 mg, 0.44 mmol, 46%). (S,M,Ra)-3 (early

fraction): Rf: 0.82, pentane:CH2Cl2 = 5:1. m.p. 171.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.73–7.57 (m, 3H),

7.55 – 7.44 (m, 2H), 7.34–6.99 (m, 8H), 6.83 (ddd, J = 8.2, 6.5, 2.1 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 3.96

(h, J = 7.3 Hz, 1H), 2.76 (dt, J = 15.8, 4.2 Hz, 1H), 2.51–2.32 (m, 2H), 1.36–1.18 (m, 1H), 1.27 (d, J = 7.0

Hz, 3H). 13

C NMR (100 MHz, CDCl3) δ 146.6, 146.5, 142.9, 142.9, 140.7, 140.6, 139.8, 138.7, 137.8,

136.4, 133.2, 130.4, 129.3, 128.4, 128.0, 127.9, 127.2, 127.0, 126.7, 126.6, 124.9, 124.5, 121.3, 120.1,

119.7, 119.5, 118.4 (q, J = 319.9 Hz), 118.3 (q, J = 319.9 Hz), 35.3, 31.8, 29.2, 20.3. 19

F NMR (282 MHz,

CDCl3) δ -74.15, -74.58. HRMS (ESI, m/z): calcd for C32H23F6O6S2 [M+H]+: 681.0835, found: 681.0830.

(S,M,Sa)-3 (later fraction): Rf: 0.65, pentane:CH2Cl2 = 5:1. m.p. 174.8 °C. 1H NMR (400 MHz,

CDCl3) δ 7.77 (dd, J = 6.7, 1.9 Hz, 1H), 7.56 (dd, J = 6.7, 1.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.47 (d, J =

8.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 8.1, 1.9 Hz, 1H), 7.30–7.22 (m, 3H), 7.13 (t, J = 7.5 Hz,

1H), 7.08–7.03 (m, 1H), 7.00–6.90 (m, 3H), 6.67 (d, J = 7.9 Hz, 1H), 4.16 (h, J = 7.2 Hz, 1H), 2.82–2.72

(m, 1H), 2.53–2.40 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H), 1.31–1.19 (m, 1H). 13


148.7, 146.4, 143.1, 140.9, 140.5, 139.9, 139.2, 137.8, 137.2, 136.4, 133.2, 130.2, 129.6, 128.9, 128.0,

127.7, 127.2, 127.0, 126.0, 125.4, 124.6, 123.9, 121.7, 119.7, 119.1, 119.0, 118.4 (q, J = 319.9 Hz), 118.4

(q, J = 319.9 Hz), 34.4, 30.8, 29.2, 21.9. 19

F NMR (376 MHz, CDCl3) δ -74.08, -74.23. HRMS (ESI, m/z):

calcd for C32H23F6O6S2 [M+H]+: 681.0835, found: 681.0830.

2-((1R,7S)-2-(diphenylphosphoryl)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-tetrahydronaphthalen-

1-yl)phenyl trifluoromethanesulfonate (5).

Diphenylphosphine oxide-triflate 5 was prepared from 3 by a modified procedure



vacuum/nitrogen stopcock and a magnetic stirring bar. In a glovebox, the Schlenk

tube was charged with bis-triflate (S,M,Ra)-3 (90 mg, 0.132 mmol),

diphenylphosphine oxide (110 mg, 0.530 mmol, 4 equiv) and dichloro[1,3-

bis(diphenylphosphino)propane]palladium(II) [PdCl2(dppp)] (15.6 mg, 0.026

mmol, 0.2 equiv). The Schlenk tube was removed from the glovebox and attached to a nitrogen line. Dry

dimethyl sulfoxide (1 mL) and diisopropylethylamine (0.122 mL, 0.793 mmol, 6 equiv) were added by

syringe. The mixture was heated with stirring at 110 °C for 24 h. After being cooled to room temperature,

Chapter 8

286

the reaction mixture was concentrated under reduced pressure to give a dark brown residue, which was

diluted with EtOAc (10 mL). The organic phase was washed with aq. 3M HCl (10 mL), brine (10 mL),

dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. The product

was purified by column chromatography (SiO2, pentane:EtOAc = 5:1 to 2:1) to yield diphenylphosphine

oxide-triflate (S,M,Ra)-5 (63 mg, 0.085 mmol, 65%) as a yellow foam. The procedure was performed using

the other conformer (S,M,Sa)-3 (100 mg,0.147 mmol) as substrate to yield the same isomer of product

(S,M,Ra)-5 (90 mg, 0.122 mmol, 83%) as a yellow foam. Rf 0.23 in pentane:EtOAc = 4:1. m.p. 233-234 °C. 1H NMR (400 MHz, CDCl3) δ 7.78–7.69 (m, 2H), 7.66–7.50 (m, 5H), 7.50–7.43 (m, 3H), 7.43–7.34 (m,

3H), 7.30–7.23 (m, 3H), 7.23–7.13 (m, 3H), 6.99 (ddd, J = 8.6, 7.5, 1.7 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H),

6.28 (d, J = 7.9 Hz, 1H), 6.23 (t, J = 7.5 Hz, 1H), 6.11 (dd, J = 7.8, 1.7 Hz, 1H), 3.91 (q, J = 7.3 Hz, 1H),

2.70–2.60 (m, 1H), 2.41–2.30 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H), 1.19–1.07 (m, 1H). 13

C NMR (100 MHz,

CDCl3) δ 149.0, 146.6 (d, J = 2.7 Hz), 144.4 (d, J = 0.7 Hz), 140.4, 140.2 (d, J = 10.4 Hz), 139.6, 139.2,

138.9 (d, J = 7.7 Hz), 137.8, 135.7, 134.6, 133.7 (d, J = 22.0 Hz), 133.3 (d, J = 12.7 Hz), 132.7, 132.6,

132.5, 132.4, 132.0, 131.9, 131.7 (d, J = 2.8 Hz), 131.5 (d, J = 2.9 Hz), 131.4, 131.3, 129.4 (d, J = 4.0 Hz),

129.2, 128.6, 128.4, 128.3, 128.2, 127.6, 127.3, 127.0, 126.6, 126.5 (d, J = 13.2 Hz), 124.7, 124.4, 123.9,

119.5 (d, J = 8.0 Hz), 118.3, 35.6, 31.7, 29.9, 20.2. 19

F NMR (282 MHz, CDCl3) δ -75.86. 31

P NMR (162

MHz, CDCl3) δ 27.70. HRMS (ESI, m/z): calcd for C43H33F3O4PS [M+H]+: 733.1784, found: 733.1774.

An alternative procedure for phosphine oxide coupling previously reported98

was also successfully

tested, using bis-triflate (S,M,Ra)-3 (68 mg, 0.10 mmol), palladium(II) acetate (0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (0.2 equiv) as a catalyst, to yield product (S,M,Ra)-5 (35 mg,

0.05 mmol, 50%) in a lower yield. The rest of the methodology was equal in all other details to the one

described above.

2-((1R,7S)-2-(diphenylphosphino)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-tetrahydronaphthalen-1-

yl)phenyl trifluoromethanesulfonate (6).

Diphenylphosphine-triflate 6 was prepared from 5 by a modified procedure


A Schlenk tube was charged with diphenylphosphine oxide-

triflate (S,M,Ra)-5 (40 mg, 0.055 mmol) and equipped vacuum/nitrogen stopcock

and a magnetic stirring bar. The tube was evacuated and backfilled with nitrogen

three times. Dry and degassed toluene (2 mL), diisopropylethylamine (0.29 mL,

1.64 mmol, 30 equiv) and trichlorosilane (0.06 mL, 0.546 mmol, 10 equiv) were

injected in the tube. The mixture was heated with stirring at reflux over 3 d. After cooling to rt, the reaction

mixture was diluted with CH2Cl2 (10 mL), sat. aq. Na2CO3 (10 mL) was carefully added and the mixture

was stirred over 1 h at rt. The organic phase was separated and washed with water (10 mL), brine (10 mL),

dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. The product

was purified by column chromatography (SiO2, pentane:EtOAc = 10:1) to yield diphenylphosphine-triflate

(S,M,Ra)-6 (30 mg, 0.041 mmol, 75%) as a yellow foam. Rf: 0.20, pentane:EtOAc = 10:1. m.p. 218.6-219.3

°C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.5 Hz, 1H), 7.58–7.54 (m, 1H), 7.48 (d, J = 7.5 Hz, 1H),

7.45–7.39 (m, 5H), 7.36 (d, J = 7.8 Hz, 1H), 7.32–7.27 (m, 3H), 7.24 – 7.16 (m, 5H), 7.10–7.00 (m, 3H),

6.70 (t, J = 7.6 Hz, 1H), 6.44 (td, J = 7.6, 1.5 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 6.36 (d, J = 7.7 Hz, 1H),

3.93 (h, J = 7.1 Hz, 1H), 2.72 (dt, J = 14.1, 3.8 Hz, 1H), 2.49–2.30 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H), 1.38–

1.18 (m, 1H). 13

C NMR (100 MHz, CDCl3) δ 146.1, 145.5, 143.4, 140.5, 140.3, 140.2, 140.1, 139.4, 139.2,

138.5, 138.4, 138.3, 138.1, 137.5, 137.4, 137.3, 135.4, 134.9, 134.6, 133.7, 133.5, 129.5, 129.0, 128.7,

128.6, 128.5, 128.4, 128.2, 128.0, 127.3, 127.2, 126.8, 126.5, 125.3, 124.7, 124.1, 119.8, 119.5, 119.1, 36.1,

32.0, 29.4, 20.6. 19

F NMR (376 MHz, cdcl3) δ -74.78. 31

P NMR (162 MHz, CDCl3) δ -12.91. HRMS (ESI,

m/z): calcd for C43H33F3O3PS [M+H]+: 717.1835, found: 717.1829.

Alternative tested conditions for phosphine oxide reduction of 5 were conducted by modified procedures

previously reported, resulting in poor or no conversion towards the desired product.



287

Attempted synthesis of (2-((1R,7S)-2-(diphenylphosphino)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-

tetrahydronaphthalen-1-yl)phenyl)diphenylphosphine oxide (7)

The synthesis of diphenylphosphine-diphenylphosphine oxide 7 from 6 was

attempted by a modified procedure previously reported.98

A flame-dried Schlenk

tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. In

a glovebox, the Schlenk tube was charged with diphenylphosphine-triflate

(S,M,Ra)-6 (30 mg, 0.042 mmol), diphenylphosphine oxide (17 mg, 0.084 mmol,

2 equiv), palladium(II) acetate (1.9 mg, 8.4 µmol, 0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (3.6 mg, 8.4 µmol, 0.2 equiv). The Schlenk

tube was removed from the glovebox and attached to a nitrogen line. Dry dimethyl sulfoxide (0.5 mL) and

diisopropylethylamine (0.026 mL, 0.167 mmol, 4 equiv) were added by syringe. The mixture was heated

with stirring at 110 °C for 24 h. After being cooled to room temperature, the reaction mixture was

concentrated under reduced pressure to give a dark brown residue, which was diluted with EtOAc (10 mL).

The organic phase was washed with aq. 3M HCl (10 mL), brine (10 mL), dried over anhydrous MgSO4,

filtered and the solvent was removed under reduced pressure. The residue was purified by column

chromatography (SiO2, pentane:EtOAc = 5:1 to 2:1) to yield the oxidized substrate diphenylphosphine

oxide-triflate (S,M,Ra)-6 as major component. No trace of the expected diphenylphosphine-

diphenylphosphine oxide 7 was detected by 1H/

31P NMR analysis.

General Procedure for Ruthenium-Catalyzed Transformation of Aryl Triflates to Halides.

The synthesis of compounds 8 from 3, 9 and 10 from 5, and 11 from 6, respectively, was attempted by a



vacuum/nitrogen stopcock and a magnetic stirring bar. In a glovebox, the Schlenk tube was charged with a

magnetic stirring bar, LiBr (3.0 equiv) or NaI (1.5 equiv), [Cp*Ru(MeCN)3]1OTf (0.1 equiv), aryl triflate

3, 5 or 6 and 1,3-dimethyl-2-imidazolidinone (DMI, ca. 10 mL/mmol of triflate). The resulting mixture was

heated under stirring under the reported conditions (NaI: 100 °C over 24 h; LiBr: 120 °C over 72 h). After

the reaction mixture was poured into water and extracted with Et2O (3 x 10 mL), the combined organic

layer was washed with water (3 x 15 mL) and brine (15 mL), and dried over MgSO4. After filtration and

concentration, the crude mixture was analyzed by 1H/

19F/

31P NMR spectroscopy. The crude was then

subjected to column chromatography on silica gel. Bis-triflate (S,M,Ra)-3 was successfully converted to

what was assigned as triflate-bromide (S,M,Ra)-8 (full conversion, yield not determined), obtained by flash

column chromatography (SiO2, pentane:EtOAc = 25:1 to 10:1) together with large amount of not

removable DMI. 8: 1H NMR (300 MHz, CDCl3) δ 7.69–7.59 (m, 2H), 7.56–7.22 (m, 10H), 7.20–7.03

(m, 4H), 6.89 (td, J = 8.4, 7.9, 1.8 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H), 6.14 (t, J =

7.4 Hz, 2H), 6.00 (dd, J = 7.8, 1.7 Hz, 1H), 3.82 (h, J = 7.3 Hz, 1H), 2.82–2.51 (m, 1H), 2.32–2.19 (m, 2H),

1.11 (d, J = 7.0 Hz, 3H,) 1.10–0.95 (m, 1H). 19

F NMR (282 MHz, CDCl3) δ -76.01. Diphenylphosphine

oxide-triflate (S,M,Ra)-5 gave no conversion towards the corresponding diphenylphosphine oxide-bromide

(S,M,Ra)-9 or diphenylphosphine oxide-iodide (S,M,Ra)-10. Diphenylphosphine-triflate (S,M,Ra)-6 gave no

conversion towards the corresponding diphenylphosphine -iodide (S,M,Ra)-11.

Attempted synthesis of ((1R,7S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-

tetrahydronaphthalen-2-yl)diphenylphosphine oxide (15) from 5

The synthesis of hydroxyl-diphenylphosphine oxide 15 from 5 was attempted

by a modified procedure previously reported.37

To a solution of

diphenylphosphine oxide-triflate (S,M,Ra)-5 (20 mg, 0.027 mmol) in a 2:1

mixture of l,4-dioxane and MeOH (0.2 mL) was added aq. 3N NaOH (0.1 mL,

0.33 mmol, 12 equiv) solution at ambient temperature. The reaction mixture

was stirred for 16 h, acidified (pH = 1) by addition of aq. 2N HCl, and then

extracted twice with EtOAc. The organic phase was dried over MgSO4 and

Chapter 8

288

concentrated under reduced pressure to give a pale brown residue. No conversion to the desired product 15

was observed as determined by NMR analysis of crude. Major decomposition of the switch functionality

occurred as determined by 1H NMR spectroscopy. Complete hydrolysis of the triflate substituent was

determined as observed by lack of any resonance peak in the 19

F NMR spectrum. Notably, two sets of

resonances with a ratio of 70:30 were observed in the 1H/

31P NMR spectra. Base-triggered addition of

lower hydroxyl substituent to the overcrowded alkene bond was proposed, affording a mixture of two

atropisomeric by-products 16 and 16’ (NMR resonances not assigned to corresponding isomer). 1H NMR

(400 MHz, CDCl3, A:B = 70:30 mixture of atropisomers) δ 8.90 (d, J = 8.0 Hz, 0.7H, A), 8.64 (dd, J = 7.9,

1.5 Hz, 0.3H, B), 7.94 (d, J = 6.9 Hz, 0.7H, A), 7.86–7.79 (m, 1.6H), 7.74–7.65 (m, 3H), 7.61 (d, J = 7.6

Hz, 0.7H, A), 7.55–7.40 (m, 6H), 7.41–7.29 (m, 6H), 7.28–7.08 (m, 3H), 7.07–7.01 (m, 1.6H), 6.96 (t, J =

6.8 Hz, 1H), 6.88 (t, J = 7.5 Hz, 0.7H, A), 6.81 (dd, J = 8.0, 1.4 Hz, 0.3H, B), 6.67–6.58 (m, 1.2H), 5.97 (d,

J = 7.7 Hz, 0.7H, A), 4.51 (s, 0.7H, A), 3.49 (s, 0.3H, B), 2.80 (t, J = 8.1 Hz, 0.7H, A), 2.69–2.60 (M,

0.9H), 2.35–2.22 (m, 1H), 2.15-2.09 (m, 0.8H), 1.35–1.20 (s, 3H), 1.11–1.02 (m, 1.2H), 0.97 (d, J = 6.9 Hz,

2H, A), 0.90–0.75 (s, 1.7H). 31

P NMR (162 MHz, CDCl3, A:B = 70:30 mixture of atropisomers) δ 29.80

(A), 29.18 (B).

(6S,6aR)-6a-(9H-fluoren-9-yl)-6-methyl-4,5,6,6a-tetrahydrobenzo[kl]xanthen-1-ol (19)

In a comparative experiment, the same procedure described for the attempted

hydrolysis of 5 to 15 was applied to the deprotonation of bisphenol 1 (30 mg,

0.072 mmol) and hydrolysis of bis-triflate 3 (25 mg, 0.037 mmol), affording

in either case the common species 19 (28 mg, 0.067 mmol, 94%, and 15 mg,

0.036 mmol, 97%, respectively) as a red-brown oil. A single set of absorptions

was observed in the 1H NMR spectrum. No resonance was observed in the

19F

NMR spectra from reaction with 3. 1H NMR (400 MHz, Chloroform-d) δ 8.54

(d, J = 8.0 Hz, 1H), 8.03 (d, J = 6.1 Hz, 1H), 7.79–7.67 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.43–7.35 (m,

2H), 7.35–7.26 (m, 3H), 7.20 (tt, J = 7.5, 0.9 Hz, 1H), 7.10–7.04 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.90 (td,

J = 7.6, 1.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.86 (d, J = 7.7 Hz, 1H), 4.67 (s, 1H), 3.70 (s, 1H), 2.57 (ddd,

J = 17.8, 11.0, 7.3 Hz, 1H), 2.15–1.98 (m, 2H), 1.08–1.00 (m, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.91–0.83 (m,

1H).

(1S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-tetrahydronaphthalen-2-yl

trifluoromethanesulfonate (20).


vacuum/nitrogen stopcock and a magnetic stirring bar. A

solution of 2,2‘-bisphenol derived switch (R,P)-1 (100 mg,

0.24 mmol) in dry CH2Cl2 (2.5 mL) was injected under

nitrogen. To this solution was added dry pyridine (29 µL,

0.36 mmol, 1.5 equiv), followed by triflic anhydride (45 µL,

0.27 mmol, 1.2 equiv) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, at which time TLC

indicated that the reaction was completed. The reaction mixture was diluted with CH2Cl2 (10 mL) and

washed subsequently with aq. 1 M HCl (10 mL), aq. 1 M NaHCO3 (10 mL), and brine (10 mL). The

organic phase was dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced

pressure. The product was purified by column chromatography (SiO2, pentane:EtOAc = 10:1) to yield

hydroxyl-triflate 20 (120 mg, 0.22 mmol, 91%) as a thick yellow oil. The mixture contains two stable

atropisomers which were assigned by 1H/

19F NMR spectroscpy to (R,P,Sa)-20 and (R,P,Ra)-20 in a A:B =

65:35 ratio, respectively. Rf: 0.20 and 0.15, pentane:EtOAc = 10:1. 1H NMR (400 MHz, CDCl3, A:B =

35:65 mixture of atropisomers) δ 7.82 (dd, J = 6.1, 2.8 Hz, 0.65H, B), 7.74 (d, J = 7.7 Hz, 0.35H, A), 7.68–

7.64 (m, 0.35H, A), 7.62 (d, J = 7.5 Hz, 0.35H, A), 7.60–7.56 (m, 0.65H, B), 7.49 (d, J = 7.5 Hz, 0.65H, B),

7.47–7.43 (m, 1.8H, A+B), 7.35–7.20 (m, 3H, A+B), 7.24 (s, 1H), 7.17–7.11 (m, 1.3H, B), 7.02 (td, J = 7.6,



289

1.2 Hz, 0.35H, A), 6.98–6.88 (m, 1.3H, B), 6.88–6.82 (m, 1H, A+B), 6.72 (d, J = 7.8 Hz, 0.65H, B), 6.64 (t,

J = 7.5 Hz, 1H, A+B), 6.52 (d, J = 7.9 Hz, 0.35H, A), 6.45–6.38 (m, 1H, A+B), 4.53 (s, 0.35H, A), 4.49 (s,

1H, 0.65B), 4.22–4.11 (h, J = 7.1 Hz, 0.65H, B), 4.05 (h, J = 7.1 Hz, 0.35H, A), 2.80–2.69 (m, 1H, A+B),

2.53–2.32 (m, 2H, A+B), 1.51 (d, J = 7.0 Hz, 2H, B), 1.31 (d, J = 7.0 Hz, 1H, A), 1.32–1.20 (m, 1H, A+B). 13

C NMR (100 MHz, CDCl3, A:B = 35:65 mixture of atropisomers) δ 155.3, 154.2, 154.0, 149.5, 149.3,

145.2, 145.0, 144.3, 143.0, 142.8, 142.3, 141.8, 141.6, 141.6, 141.1, 140.2, 140.1, 139.9, 139.8, 138.0,

137.9, 134.3, 134.1, 132.1, 131.9, 130.5, 130.0, 129.8, 129.8, 129.7, 129.1, 129.0, 128.6, 127.0, 126.9,

126.7, 126.3, 126.2, 123.6, 123.3, 123.1, 122.2, 121.8, 121.5, 121.3, 119.0, 118.8, 117.3, 37.3, 36.8, 33.9,

33.3, 31.5, 31.2, 24.1, 22.8. 19

F NMR (376 MHz, CDCl3, A:B = 35:65 mixture of atropisomers) δ -74.18

(A), -74.44 (B). HRMS (ESI, m/z): calcd for C31H24F3O4S [M+H]+: 549.1342, found: 549.1331. CSP-HPLC

analysis of the atropisomeric mixture (Chiralpak AD-H, heptane:2-propanol = 95:5, flow rate =

0.5 mL/min, column temperature = 40 °C, Rt: 16.5 min for (R,P,Sa)-20 (A, minor), 21.4 min for (R,P,Ra)-20

(B, major)) showed sharp elution peaks for both species, which suggests no interconversion between the

two isomers at the tested analytical condition. EXSY experiment at 55°C showed no evidence of exchange

between the two atropisomers.

Attempted synthesis of ((1R,7S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-

tetrahydronaphthalen-2-yl)diphenylphosphine oxide (15) from 20

The synthesis of hydroxyl-diphenylphosphine oxide 15 from 20 was attempted

by a modified procedure previously reported.98

A flame-dried Schlenk tube was

equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. In a

glovebox, the Schlenk tube was charged with diphenylphosphine oxide-triflate

(S,M,Ra)-5 (100 mg, 0.18 mmol), diphenylphosphine oxide (74 mg, 0.370 mmol,

2 equiv), palladium(II) acetate (8.1 mg, 36 µmol, 0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (14.4 mg, 36 µmol, 0.2 equiv). The Schlenk tube was removed from

the glovebox and attached to a nitrogen line. Dry dimethyl sulfoxide (2 mL) and diisopropylethylamine

(0.104 mL, 0.72 mmol, 4 equiv) were added by syringe. The mixture was heated with stirring at 110 °C for

24 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced

pressure to give a dark brown residue, which was diluted with EtOAc (10 mL). The organic phase was

washed with aq. 3M HCl (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and the solvent

was removed under reduced pressure. The residue was purified by column chromatography (SiO2,

pentane:EtOAc = 20:1 to 3:1) to yield five distinct fractions that were anaysed by 1H/

19F/

31P NMR

spectroscopy. No conversion to the desired product 15 was observed; instead decomposition of the

overcrowded alkene functionality was observed from the 1H NMR spectra.

8.5 References

(1) Eliel, E. L. (Ernest L.; Wilen, S. H. Stereochemistry of organic compounds; Wiley: New York, 1994.

(2) Yamamoto, H.; Carreira, E. M. Comprehensive chirality; Elsevier Science, 2012.

(3) Blackmond, D. G. Cold Spring Harbor perspectives in biology. Cold Spring Harbor Laboratory Press,

2010.

(4) Bentley, R. Encyclopedia of Molecular Cell Biology and Molecular Medicine; Wiley-VCH Verlag GmbH

& Co. KGaA: Weinheim, Germany, 2006.

(5) Timsit, Y.; Youri. Int. J. Mol. Sci. 2013, 14, 8252–8270.

(6) Boyer, P. D. Nature 1999, 402, 247–249.

(7) Goto, H.; Yashima, E. J. Am. Chem. Soc. 2002, 124, 7943–7949.

(8) Hofacker, A. L.; Parquette, J. R. Angew. Chemie Int. Ed. 2005, 44, 1053–1057.

(9) Maurizot, V.; Dolain, C.; Huc, I. European J. Org. Chem. 2005, 2005, 1293–1301.

(10) de Jong, J. J. D.; van Rijn, P.; Tiemersma-Wegeman, T. D.; Lucas, L. N.; Browne, W. R.; Kellogg, R. M.;

Uchida, K.; van Esch, J. H.; Feringa, B. L. Tetrahedron 2008, 64, 8324–8335.

(11) Ribó, J. M.; Crusats, J.; Sagués, F.; Claret, J.; Rubires, R. Science,. 2001, 292, 2063–2066.

(12) Feringa, B. L. Science, 2001, 292, 2021–2022.

Chapter 8

290

(13) Prins, L. J.; Timmerman, P.; Reinhoudt, D. N. J. Am. Chem. Soc. 2001, 123, 10153–10163.

(14) Prins, L. J.; Verhage, J. J.; de Jong, F.; Timmerman, P.; Reinhoudt, D. N. Chem. - A Eur. J. 2002, 8,

2302–2313.

(15) Ishi-i, T.; Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.; Shinkai, S. J. Am. Chem. Soc. 2002, 124,

14631–14641.

(16) Iamsaard, S.; Aßhoff, S. J.; Matt, B.; Kudernac, T.; Cornelissen, J. J. L. M.; Fletcher, S. P.; Katsonis, N.

Nat. Chem. 2014, 6, 229–235.

(17) Feringa, B. L.; van Delden, R. A. Angew. Chemie Int. Ed. 1999, 38, 3418–3438.

(18) Eelkema, R.; Feringa, B. L. Org. Biomol. Chem. 2006, 4, 3729–3745.

(19) Crassous, J. Chem. Commun. 2012, 48, 9687–9695.

(20) Zahn, S. Science, 2000, 288, 1404–1407.

(21) Lauceri, R.; Raudino, A.; Scolaro, L. M.; Micali, N.; Purrello, R. J. Am. Chem. Soc. 2002, 124, 894–895.

(22) Lauceri, R.; Purrello, R. Supramol. Chem. 2005, 17, 61–66.

(23) Mazet, C.; Gade, L. H. Chem. - A Eur. J. 2002, 8, 4308–4318.

(24) Purrello, R. Nat. Mater. 2003, 2, 216–217.

(25) Ziegler, M.; Davis, A. V.; Johnson, D. W.; Raymond, K. N. Angew. Chemie Int. Ed. 2003, 42, 665–668.

(26) Tashiro, R.; Sugiyama, H. J. Am. Chem. Soc. 2005, 127, 2094–2097.

(27) Werner, A. Chem. Ber. 1911, 44, 1887–1899.

(28) Zelewsky, V. A. von. Stereochemistry of Coordination Compounds.; Wiley: Chichester, UK, 1996.

(29) Amabilino, D. B.; Stoddart, J. F. Chem. Rev. 1995, 95, 2725–2828.

(30) Sauvage, J.-P.; Dietrich-Buchenecker, C. Molecular Catenanes, Rotaxanes and Knots: A Journey

Through the World of Molecular Topology; WILEY‐VCH Verlag: Weinheim, Germany, 1999.

(31) Caulder, D. L.; Raymond, K. N. J. Chem. Soc. Dalt. Trans. 1999, No. 8, 1185–1200.

(32) Hamilton, T. D.; MacGillivray, L. R. Cryst. Growth Des. 2004, 4, 419–430.

(33) Jacobsen, N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis I–III; Springer: Berlin,

2000.


(35) Brussee, J.; Jansen, A. C. A. Tetrahedron Lett. 1983, 24, 3261–3262.

(36) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc.

1980, 102, 7932–7934.

(37) Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945–1948.

(38) Ngo, H. L.; Lin, W. J. Org. Chem. 2005, 70, 1177–1187.

(39) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem. Soc. 2009, 131, 12882–12883.

(40) Mikami, K.; Aikawa, K.; Yamanaka, M. Pure Appl. Chem. 2004, 76, 537–540.

(41) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chemie Int. Ed. 2005, 44, 7257–7260.

(42) Aikawa, K.; Mikami, K. Angew. Chemie Int. Ed. 2003, 42, 5455–5458.

(43) Aikawa, K.; Mikami, K. Angew. Chemie Int. Ed. 2003, 42, 5458–5461.

(44) Mikami, K.; Aikawa, K. Org. Lett. 2002, 4, 99–101.

(45) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801–2803.

(46) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802–1803.

(47) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929–

6941.

(48) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3, 2161–2164.

(49) Ueki, M.; Matsumoto, Y.; Jodry, J. J.; Mikami, K. Synlett 2001, 2001, 1889–1892.

(50) Wolf, C. Dynamic Stereochemistry of Chiral Compounds: Principles and Applications; RSC Publishing:

Cambridge, 2007.

(51) Watson, A. A.; Willis, A. C.; Wild, S. B. J. Organomet. Chem. 1993, 445, 71–78.

(52) Gladiali, S.; Dore, A.; Fabbri, D.; De Lucchi, O.; Valle, G. J. Org. Chem. 1994, 59, 6363–6371.

(53) Bringmann, G.; Schöner, B.; Peters, K.; Peters, E.-M.; von Schnering, H. G. Liebigs Ann. der Chemie

1994, 1994, 439–444.

(54) Fritsch, R.; Hartmann, E.; Brandl, G.; Mannschreck, A. Tetrahedron: Asymmetry 1993, 4, 433–455.

(55) Bringmann, G.; Keller, P. A.; Rölfing, K. Synlett 1994, 1994, 423–424.

(56) Bringmann, G.; Busse, H.; Dauer, U.; Güssregen, S.; Stahl, M. Tetrahedron 1995, 51, 3149–3158.

(57) Bringmann, G.; Breuning, M.; Endress, H.; Vitt, D.; Peters, K.; Peters, E.-M. Tetrahedron 1998, 54,

10677–10690.

(58) Ohmori, K.; Kitamura, M.; Suzuki, K. Angew. Chemie Int. Ed. 1999, 38, 1226–1229.

(59) Bringmann, G.; Heubes, M.; Breuning, M.; Göbel, L.; Ochse, M.; Schöner, B.; Schupp, O. J. Org. Chem.

2000, 65, 722–728.

(60) Mislow, K.; Hyden, S.; Schaefer, H. J. Am. Chem. Soc. 1962, 84, 1449–1455.



291

(61) Tichy, M.; Ridvan, L.; Holy, P.; Zavada, J.; Cisaova, I.; Podlaha, J. Tetrahedron: Asymmetry 1998, 9,

227–234.

(62) Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.; Rosini, C. Angew. Chemie Int. Ed. 2001, 40, 451–454.

(63) Hatsuda, M.; Hiramatsu, H.; Yamada, S.; Shimizu, T.; Seki, M. J. Org. Chem. 2001, 66, 4437–4439.

(64) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, No. 10, 1561–1578.

(65) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345–7348.

(66) Korenaga, T.; Aikawa, K.; Terada, M.; Kawauchi, S.; Mikami, K. Adv. Synth. Catal. 2001, 343, 284–288.



(69) Vlatkovic, M.; Collins, B. S. L.; Feringa, B. L. Chemistry - A European Journal. September 2016, pp

17080–17111.

(70) Yamamoto, T.; Yamada, T.; Nagata, Y.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 7899–7901.






(76) Eigen, M.; Wilkins, R. G. In Mechanisms of Inorganic Reactions; 1965; pp 55–80.

(77) Otsuki, J.; Akasaka, T.; Araki, K. Coordination Chemistry Reviews. 2008, pp 32–56.

(78) Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 12005–

12006.


(80) Schliwa, M. Molecular Motors; Wiley-VCH Verlag GmbH, 2006.

(81) Sud, D.; Norsten, T. B.; Branda, N. R. Angew. Chemie - Int. Ed. 2005, 44, 2019–2021.

(82) Sud, D.; McDonald, R.; Branda, N. R. Inorg. Chem. 2005, 44, 5960–5962.

(83) Kean, Z. S.; Akbulatov, S.; Tian, Y.; Widenhoefer, R. A.; Boulatov, R.; Craig, S. L. Angew. Chemie

2014, 126, 14736–14739.


(85) Miyake, H.; Tsukube, H. Chem. Soc. Rev. 2012, 41, 6977–6991.

(86) Shinoda, S. Chem. Soc. Rev. 2013, 42, 1825–1835.

(87) Boiocchi, M.; Fabbrizzi, L. Chem. Soc. Rev. 2014, 43, 1835–1847.


(89) Ousaka, N.; Takeyama, Y.; Iida, H.; Yashima, E. Nat. Chem. 2011, 3, 856–861.



(92) Cai, D.; Payack, J.; Bender, D.; Hughes, D.; Verhoeven, T.; Reider, P. Org. Synth. 1999, 76, 6.

(93) Goto, M.; Konishi, T.; Kawaguchi, S.; Yamada, M.; Nagata, T.; Yamano, M. Org. Process Res. Dev.

2011, 15, 1178–1184.

(94) Gladiali, S.; Taras, R.; Ceder, R. M.; Rocamora, M.; Muller, G.; Solans, X.; Font-Bardia, M. Tetrahedron

Asymmetry 2004, 15, 1477–1485.

(95) Botman, P. N. M.; Fraanje, J.; Goubitz, K.; Peschar, R.; Verhoeven, J. W.; van Maarseveen, J. H.;

Hiemstra, H. Adv. Synth. Catal. 2004, 346, 743–754.

(96) Wang, S.; Li, J.; Miao, T.; Wu, W.; Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org. Lett. 2012, 14, 1966–1969.

(97) Yuan, W.-C.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Tetrahedron Lett. 2005, 46, 509–512.

(98) Mikami, K.; Aikawa, K.; Korenaga, T. Org. Lett. 2001, 3, 243–245.

(99) Hérault, D.; Nguyen, D. H.; Nuel, D.; Buono, G. Chem. Soc. Rev. 2015, 44, 2508–2528.

(100) Chen, W.-H. unpublished results, University of Groningen.

(101) Li, Y.; Lu, L.-Q.; Das, S.; Pisiewicz, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2012, 134, 18325–

18329.

(102) Wu, H. C.; Yu, J. Q.; Spencer, J. B. Org. Lett. 2004, 6, 4675–4678.

(103) Bonnafoux, L.; Gramage-Doria, R.; Colobert, F.; Leroux, F. R. Chem. - A Eur. J. 2011, 17, 11008–11016.

(104) Yu, R.; Chen, X.; Wang, Z. Tetrahedron Lett. 2016, 57, 3404–3406.

(105) Uehara, A.; Bailar, J. C. J. Organomet. Chem. 1982, 239, 1–10.

(106) Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63, 2597–2600.

(107) Schmid, R.; Cereghetti, M.; Heiser, B.; Schönholzer, P.; Hansen, H.-J. Helv. Chim. Acta 1988, 71, 897–

929.

(108) Pihko, P. M. Angew. Chemie Int. Ed. 2004, 43, 2062–2064.


(110) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146–146.

Chapter 8

292

(111) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758.

(112) Terada, M. Chem. Commun. 2008, No. 35, 4097–4112.

(113) Meng, X.; Huang, Y.; Chen, R. Chem. - A Eur. J. 2008, 14, 6852–6856.

(114) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790–3800.

(115) Liu, Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348, 973–979.

(116) Cheon, C. H.; Imahori, T.; Yamamoto, H. Chem. Commun. 2010, 46, 6980–6982.

(117) Hayashi, T. Acc. Chem. Res. 2000, 33, 354–362.

(118) Imazaki, Y.; Shirakawa, E.; Ueno, R.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 14760–14763.

293

Summary

Chirality is a fundamental aspect of modern organic chemistry. Many biologically active compounds,

ranging from pharmaceuticals to agrochemicals, flavor, fragrances and nutrients are chiral. During the last

century, scientists have jointly built a strong and multifaceted knowledge of stereochemistry, which led to

the development of a plethora of stereoselective synthetic methodologies and analytical techniques. While

static stereochemistry deals with the spatial arrangement of atoms in molecules and the corresponding

chemical and physical properties, dynamic stereochemistry emphasizes structural change and comprises

asymmetric reactions as well as interconversion of configurational and conformational isomers. Dynamic

stereochemistry plays a fundamental role across the chemical sciences, ranging from asymmetric synthesis

to drug discovery and nanomaterials. The unique stereodynamics of chiral compounds have paved the way

to artificial machines and other molecular devices that lie at the interface of chemistry, engineering,

physics, and molecular biology. The stereospecific interaction between fixed and dynamic chirality of

molecular and supramolecular systems has given access to a playground full of remarkable nanomachines

capable of displaying controllable transfer and amplification of chirality. Among the several approaches

exploited to achieve control over responsive molecular systems, the use of light as an external stimulus is

characterized by its non-invasive nature, high spatio-temporal resolution, and selectable wavelength –

hence energy – of radiation, which provides asymmetric responses by photoisomerization of chiral

molecular switches or motors. Most remarkable examples for application of light-driven systems are based

on sterically overcrowded alkenes, azobenzenes and dithienylethenes derivatives (Scheme 1), which confer

helix inversion and motion capabilities to nanovehicles, liquid crystals, polymers, gelators, catalysts, and

biological derivatives.

Scheme 1. Most popular light-responsive molecular switches: a) azobenzenes; b) dithienylethenes; c)

molecular motors.

The work described in this thesis explores how of second generation molecular motors/switches can be

tuned, modified and applied in photoswitchable catalysis. The final aim is to develop alternative designs of

switchable catalysts which could display improved thermal stability and more advanced catalytic

performance when compared with previously described systems based on first generation molecular

motors. We envisioned these novel responsive scaffolds to be tailored for applications via multiple modes

of catalytic activity (e.g. metal-catalysis, organocatalysis, activity control, dual stereocontrol) and in wider

range of reaction conditions (e.g. temperature, reaction time).

Summary

294

Chapter 1 provides an introduction to the concept of photo-controlled dynamic transfer of chirality. The

most popular types of photoresponsive switches and related isomerization mechanisms are presented.

Subsequently, relevant examples of applications of molecular switches and motors to achieve dynamic

transfer of chirality are discussed. Main fields of application include: molecular motion, control over

supramolecular, liquid crystal or polymer morphology, stereoselective catalysis, chiral recognition, and

control of biological derivatives. The aim is hereby to draw the attention on how the light-responsive

dynamic chirality of such systems is used to selectively induce a reversible and reproducible asymmetrical

response for smart applications in functional materials.

Chapter 2 describes the synthesis and experimental and computational investigation of four overcrowded

alkenes 2.1-2.4 featuring scaffolds analogous to second generation molecular motors (Scheme 2).

Irradiation with UV light allowed for high yielding E-Z isomerizations providing metastable

diastereoisomers. Kinetic studies on metastable isomers using CD and HPLC identified two pathways at

high temperatures for thermal isomerization. All the metastable isomers displayed unprecedented high

energy barriers for thermal helix inversion, thus making the alternative thermal E-Z isomerization the

predominant relaxation process. In order to show the value of these overcrowded alkenes as bistable

switches, photochemical switching cycles were performed which proved the alkenes to be excellent

switches displaying good reversible selectivity and fatigue-resistance. The switch featuring a phenanthrenyl

upper-half 2.1 showed the best performance as reversible photochromic selector, while the

benzo[f]thiochromene derivative 2.4 excelled in thermal stability, both exhibiting highly selective

isomerizations. These favorable switching properties offer attractive prospects towards the design of novel

photoresponsive bistable catalysts.

Scheme 2. Schematic representation and isomerization pathways of overcrowded alkenes 2.1-2.4 discussed

in Chapter 2.

Chapter 3 describes the design and synthesis of two photoresponsive bifunctionalized catalysts 3.1 and 3.2

(Scheme 3a) based on corresponding overcrowded alkene cores 2.1 and 2.2 investigated in Chapter 2. Each

motor half is equipped with a catalytically active group, with the aim of obtaining bifunctional switches

whose catalytic activity could be turned ON and OFF by light-induced configurational isomerization

(Scheme 3b). The compounds show switching upon irradiation with 312 nm light, forming the

corresponding metastable states with high photostationary state ratios. Interestingly, they do not exhibit

reversible switching upon irradiation at longer wavelength. Based on comparative results with differently

functionalized derivatives, the dimethylamine group was hypothesized to have a detrimental influence on

the reversibility of the switching processes. Switches St-(E)-3.1 and St-(Z)-3.2 display properties of

photoswitchable catalytic activity control in the Michael addition reaction between (E)-3-bromo-β-

nitrostyrene and 2,4-pentanedione (Scheme 3c). From the experimental results, both isomers displayed a

decrease in catalytic activity upon irradiation to the metastable state. As opposed to our initial assumption

295

of controlling the activity of the thiourea moiety by steric hindrance or hydrogen bonding interactions, both

E- and Z-isomers behave comparably as ON/OFF catalytic switches upon photoisomerization with clear

changes in reaction rate and turnover frequency, regardless of the catalyst geometry. Therefore, such

behavior does not seem predominantly regulated by the steric hindrance exerted by the amine substituent

around the thiourea moiety.

Scheme 3. a) Schematic representation of catalytically active bifunctionalized overcrowded alkenes

discussed in Chapter 3. b) Proposed designs of bifucntionalized overcrowded alkenes for light-assisted

control of catalytic activity. c) Light-assisted control of catalytic activity in organocatalyzed Michael

addition.

Chapter 4 describes the study towards a trifunctionalized molecular photoswitch based on an overcrowded

alkene for light–assisted tandem catalytic processes (Scheme 4a). We proposed a two-step sequence of

Morita–Baylis–Hillman (MBH) reaction and enamine catalyzed aldol reaction catalyzed by merging two

pairs of orthogonal bifunctional catalytic groups. Preliminary tests on the catalytic performance in MBH

reaction of bifunctional molecular switches 3.1 and 3.2 described in Chapter 3 were discouraging.

Alternative designs, featuring thiourea and tertiary amine or phosphines groups and aimed to improve the

catalytic activity in the MBH reaction, and respective attempted syntheses are presented (Scheme 4b).

Lastly, we explored other organocatalyzed reactions that could be mediated by the initially proposed

photoswitchable catalysts design (e.g. conjugated addition; alkylation via benzyl transfer; decarboxylative

protonation; alcoholysis). In all instances, the screening tests described herein were performed by using

compound 4.5 as a model catalyst, due to its inherent similarity with the Z-isomers of 3.1 and 3.2. As

opposed to our initial assumption, no activity was observed in any case. As demonstrated in this work, an

aromatic amine substituent was shown to be a poorly active catalytic moiety.

Summary

296

Scheme 4. a) Proposed design of a trifunctionalized light-responsive organocatalyst for ‗one-pot‘ assisted

tandem catalysis. b) Proposed alternative designs of bifunctionalized overcrowded alkenes derivatives 4.1-

4.4 and binaphthyl-derivative 4.5 used as model catalyst discussed in Chapter 4.

Chapter 5 describes the synthesis and study of a photoresponsive molecular switch 5.1, featuring a versatile

2,2‘-biphenol motif in which chirality is transferred across three stereochemical elements has been designed

and successfully executed. The design of 5.1 was based on parent compound 2.3 described in Chapter 2 to

achieved good photoresponsive properties and thermal stability. The comparison of experimental and

computational data confirmed the proposed model of coupled central-to-helical-to-axial transfer of

chirality, demonstrating the most favored conformation of the lower aryl substituent to be parallel to the

fluorenyl lower half of the switch core. Investigation with CD and UV-vis absorption spectroscopy, 1H NMR spectroscopy and chiral HPLC analysis proved the reversible photoswitchability of 1. However,

compared with the forward photoisomerization at 365 nm, the reverse process induced by irradiation at 420

nm was shown be less selective, yielding an equimolar mixture of isomers of 5.1 with opposite helicities.

The dynamic central-to-helical-to-axial-to-central transfer of chirality was successfully applied to creation

of another stereogenic element, as demonstrated by using (R)-5.1 as photoswitchable stereoselective

catalyst in the enantioselective addition of diethylzinc to benzaldehydes. Clear reversal of enantioselectivity

was accomplished for each substrate, with ee‘s of secondary alcohols up to 68% and ∆ee‘s up to 113%.

297

Scheme 5. a) Schematic representation of photoswitchable 2,2‘-biphenol-substituted overcrowded alkene

5.1 and relative photochemical isomerization described described in Chapter 5. b) Light-assisted control of

stereoselectivity in enantioselective addition of organozinc to aromatic aldehydes.

Chapter 6 describes the synthesis and study of five photoresponsive chiral phosphoramidite-molecular

switch derivatives L, obtained from parent compound 5.1, in which chirality is dynamically transferred

across from five to seven stereochemical elements (Scheme 6a). The unique combination of a light-

triggered molecular switch featuring a bridged biaryl-derived monodentate ligand moiety allows reversible

photo-switching between two stereochemical forms with distinct ligand properties. The ligands were used

to alter the activity and invert the stereoselectivity of the copper–catalyzed conjugate addition of

diethylzinc to 2-cyclohexen-1-one (Scheme 6b). Catalysis results supported by kinetic experiments suggest

that each diastereoisomer of the ligand provides a distinctive activity and opposite stereoselectivity in the

asymmetric catalytic event. This results in an elegant balance of two competing diasteroisomeric catalysts

(Scheme 6c), of which complementary catalytic performance is tunable upon photoisomerization due to the

reversible matched-mismatched interaction between the dynamic chirality of the switch unit and the fixed

chirality of the phosphoramidite ligand site.

Scheme 6. a) Schematic representation of chiral photoresponsive phosphoramidite ligands L and relative

photochemical isomerization described in Chapter 6. b) Light-assisted control of activity and

stereoselectivity in enantioselective copper-catalyzed addition of diethylzinc to 2-cyclohexen-1-one. c)

Schematic top-down view of Cu-L complexes: for each (S,SP)- or (S,RP)-diastereoisomer two metal-ligand

complexes with opposite coupled helicity (M or P) can be selectively addressed by irradiation with UV-

light.

Chapter 7 describes the synthesis and study of a photoresponsive chiral phosphoric acid 7.1, obtained from

parent compound 5.1, in which chirality is dynamically transferred from the switch core to the biaryl motif

(Scheme 7a). The established concept of coupled helical-to-axial transfer of chirality described in Chapters

5-6 is further extended to a non-P-stereogenic phosphoric acid functionality for application in

Summary

298

organocatalysis. Experimental analysis by UV-vis absorption, CD and 1H NMR spectroscopy proved the

reversible photoswitching properties of 7.2. Its applicability as a switchable stereoselective organocatalyst

was investigated in a selection of previously reported Brønsted acid-catalyzed transformations.

Unfortunately, slow reaction rates and no asymmetric induction were observed in each case. In attempt to

increase catalytic efficiency and asymmetric induction, a more complex design of a 3,3‘-biaryl substituted

phosphoric acid switch derivative 7.2 was proposed (Scheme 7a) and an attempt towards its synthesis is

described.

Scheme 7. a) Schematic representation of chiral photoresponsive phosphoric acid derivative 7.1 and

relative photochemical isomerization described in Chapter 7. b) Proposed alternative design of phosphoric

acid 7.2 featuring a 3,3‘-disubstituted-biaryl switch core.

Chapter 8 describes the study towards a bidentate biaryl bis(diphenylphosphine) ligand 8.1 based on an

overcrowded alkene for photoswitchable asymmetric homogeneous metal-catalyzed transformation

(Scheme 8a). Unlike the designs previously described in Chapters 5-6-7, hereby an efficient coupled

motion with effective inversion of the local chirality surrounding the coordinated metal center is envisioned

to occur only in the bidentate metal-ligand complex MLn-8.1. The proposed synthetic route started with

derivatization of 2,2‘-bisphenol functionalized molecular switch 5.1 to provide the corresponding bis-

triflate 8.2 (Scheme 8b). Palladium-catalyzed phosphorylation and phosphine oxide reduction yielded the

monophosphine-derivative 8.3. Various procedures to synthesize the bis-phosphine derivative 8.1 failed,

supposedly due to the high steric hindrance that impedes the metal-catalyzed phosphination mechanism. An

attempt to redirect the goal of the project to the development of a chiral photoswitchable Brønsted acid

catalyst 8.4, featuring diphenylphosphine and phenol functionalities on the biphenyl unit, is described.

Scheme 8. a) Schematic representation of proposed metal complexes MLn-(S)-8.1 and relative

photochemical isomerization described in Chapter 8. b) Attempted synthetic route stating from 5.1 towards

bis(diphenylphosphine)-derivative 8.1 and hydroxy-diphenylphosphine-derivative 8.4.

299

Samenvatting

Chiraliteit is een fundamenteel aspect van de moderne organische chemie. Veel biologisch actieve stoffen,

van medicijnen en agrochemikalieën bestanddelen, tot smaak, geur en voedingsstoffen zijn chiraal.

Wetenschappers hebben gedurende de laatste eeuw gewerkt aan het opbouwen van de basiskennis van

stereochemie, iets wat op zijn beurt heeft geleid tot een breed inzetbare kennis en kunde in de

stereoselectieve synthese, en de analyse van deze moleculen. Waar statische stereochemie zich bezighoudt

met de ruimtelijke schikking van atomen in moleculen en de bijbehorende eigenschappen, richt het

vakgebied van dynamische stereochemie zich meer op veranderingen in chiraliteit, asymmetrische reacties

en de evenwichten tussen configurationele en conformationele isomeren. Dynamische stereochemie speelt

een fundamentele rol in de verschillende vakgebieden van de scheikunde, van asymmetrische synthese tot

de ontdekking van medicijnen en nanomaterialen. De unieke stereodynamica van chirale moleculen heeft

de deur geopend naar kunstmatige moleculaire machines en andere moleculaire systemen waarbij de

grenzen tussen de chemie, techniek, natuurkunde en biologie vervagen. De stereospecifieke interactie

tussen statische en dynamische chiraliteit van chirale supramoleculaire systemen heeft ons de mogelijkheid

gegeven te kunnen spelen met de opmerkelijke eigenschappen van nanomachines die op hun beurt de

gecontroleerde overdracht naar amplificatie in chiraliteit hebben bewerkstelligd. Er zijn meerdere manieren

beschreven om controle over deze zogenaamde ―responsive materials‖ uit te kunnen oefenen. Het gebruik

van licht as externe bron heeft als eigenschappen dat deze niet invasief hoeft te zijn. Andere kenmerken zijn

een grote nauwkeurigheid van de dosis, golflengte (en dus energie) en intensiteit die een asymmetrische

respons tewerkstellen bij de fotoisomerisatie van chirale moleculaire motoren en schakelaars. De meeste

voorbeelden van door licht beïnvloede moleculaire systemen zijn gebaseerd op sterisch gehinderde alkenen,

azobenzenen en dithienyletheen verbindingen, die op hun beurt helix conversie en beweging induceren

bijvoorbeeld bij nanovoertuigen, vloeibare kristallen, polymeren, gel-vormende componenten,

katalysatoren en biologische moleculen.

Schema 1. Populaire, licht gevoelige moleculaire schakelaren en motoren a) azobenenen b) dithienyl-

ethenen c) moleculaire motoren.

Het werk beschreven in dit proefschrift onderzoekt hoe van de tweede generatie moleculaire motoren /

schakelaars kunnen worden afgestemd, aangepast en toegepast in fotowisselbare katalyse. Het uiteindelijke

doel is om alternatieve ontwerpen van schakelbare katalysatoren te ontwikkelen die een verbeterde

thermische stabiliteit en meer geavanceerde katalytische prestaties zouden kunnen vertonen in vergelijking

Samenvatting

300

met eerder beschreven systemen op basis van eerste generatie moleculaire motoren. We voorzagen dat deze

nieuwe responsieve scaffolds op maat werden gemaakt voor toepassingen via meerdere wijzen van

katalytische activiteit (bijvoorbeeld metaalkatalyse, organokatalyse, activiteitscontrole, dubbele

stereocontrole) en in een breder bereik van reactieomstandigheden (bijvoorbeeld temperatuur, reactietijd).

Hoofdstuk 1 geeft een introductie op het concept van licht-geïnduceerde dynamische overdracht van

chiraliteit. De meest voorkomende types van lichtgevoelige schakelaren en gerelateerde isomerisatie

mechanismes zijn hierin beschreven. Enkele relevante voorbeelden van applicaties van moleculaire

schakelaars en motoren voor de controle van dynamische overdracht van chiraliteit worden hierna

besproken. Toepassingen zijn gevonden in : moleculaire bewegingen, controle van supramoleculaire

vloeibare kristallen of polymeren, stereoselectieve katalyse, chirale herkenning en de controle van

biohybride moleculen. Het doel van deze studies is om na te gaan hoe de dynamische chiraliteit van deze

systemen benut kan worden om een betrouwbaar en reversibel asymmetrisch effect te hebben op

functionele materialen.

Hoofdstuk 2 beschrijft de synthese en het experimentele en computationele onderzoek van een viertal

gehinderde alkenen 2.1-2.4 die structurele overeenkomsten hebben met de tweede generatie moleculaire

motor (Schema 2). Bestraling met UV licht resulteerde in een E-Z isomerisatie naar het instabiele

diastereoisomeer met een hoge opbrengst . Kinetische studies met het instabiele isomeer met behulp van

CD en HPLC identificeerde twee routes bij hoge temperaturen voor de thermische isomerisatie. Alle

instabiele isomeren vertoonden een significant hogere energetische barrière voor de thermische isomerisatie

in vergelijking met vorige verwante structuren. Dit maakt de alternatieve E-Z isomerisatie het dominante

relaxatie proces. Daarnaast werden photochemische schakelings-cycli uitgevoerd. Deze toonden aan dat de

alkenen uitstekende schakelaars met goede reversibiliteit zijn, die bovendien goed bestand zijn tegen

degradatie.De schakelaar met het phenanthryl motief in bovenste helft 2.1 vertoont de beste resultaten als

reversibele photochromische schakelaar, terwijl de benzo[f]thiochromeen afgeleide 2.4 uitblinkt in

thermische stabiliteit. Beide motoren ondergaan de isomerisatie met hoge selectiviteit. Deze gunstige

schakel-eigenschappen bieden interessante vooruitzichten voor het ontwerp van nieuwe lichtgevoelige bi-

stabiele katalysatoren.

Schema 2. Schematische representatie en isomerisatiepaden van alkenen 2.1-2.4 besproken in hoofdstuk 2.

Hoofdstuk 3 beschrijft het ontwerp en de synthese van twee lichtgevoelige bifunctionele katalysatoren 3.1

en 3.2 gebaseerd op de verwante gehinderde alkenen 2.1 en 2.2 die beschreven zijn in hoofdstuk 2. Beide

motor helften hebben een katalytisch actieve groep met het doel een bifunctionele schakelaar te creëren

wiens katalytische activiteit AAN en UIT geschakeld kan worden met behulp van een licht . (Schema 3b).

De moleculen vertonen de gewenste schakeling na het bestralen met 312 nm licht, en nemen de instabiele

301

vorm aan met een hoge ―photostationary state‖ ratio. Opvallend is de afwezigheid van reversibele

schakeling met licht van een langere golflengte. Gebaseerd op vergelijkbare resultaten met verschillende

gefunctionalizeerde analoge verbindingen blijkt de dimethylamine groep een sterk negatieve uitwerking te

hebben op de reversibiliteit van het schakelproces. Schakelaars st-(E)-3.1 en st-(Z)-3.2 vertonen

eigenschappen van licht-schakelbare katalytische controle in de Michael additie tussen (E)-3-bromo-β-

nitrostyreen en 2,4-pentadione (Schema 3c). Uit de experimentele data bleek dat beide isomeren een

vermindering van katalytische activiteit vertonen, na blootstelling aan bestraling en conversie naar de

metastabiele toestand. In tegenstelling tot onze initiële doelstelling van het controleren van de activiteit van

de thiourea functionaliteit door sterische hinder of waterstofbrug interacties, bleken zowel de E als de Z

isomeren vergelijkbaar als AAN/UIT katalysator te functioneren, met duidelijke verschillen in

reactiesnelheden ongeacht de geometrie van de katalysator. De eigenschappen van de motor lijken dus in

mindere mate beïnvloed te worden door de sterische hinder die veroorzaakt wordt door de substituent op

het amine van de thiourea groep.

Schema 3. a) Schematische representatie van katalytisch actieve bifunctionele gehinderde alkenen

besproken in hoofdstuk 3. b) Voorgestelde ontwerp van de bifunctionele gehinderde alkenen. c) Light

geïnduceerde controle van katalytische activiteit in de organokatalytische Michael reactie.

Hoofdstuk 4 omschrijft de studie naar een trifunctionele moleculaire schakelaar gebaseerd op een gehinderd

alkeen voor licht geassisteerde katalytische processen. Het voorstel was om een twee-staps proces van een

Mortita-Baylis-Hillman (MBH) reactie en een enamine gekatalyseerde aldol reactie te katalyseren door het

samenvoegen van twee paren van orthogonale bifunctionele katalytische groepen. Initiële testen m.b.t. de

katalytische functie in de MBH reactie van de bifunctionele moleculaire schakelaars 3.1 en 3.2 die zijn

beschreven in Hoofdstuk 3 waren ontmoedigend. Alternatieve ontwerpen met thiourea en tertaire amines of

fosfine groepen voor de verbetering in de MBH reactie zijn beschreven in Schema 4b. Tot slot hebben we

ook gekeken naar andere organo-gekatalyseerde reacties die konden worden versneld door het initiële

ontwerp hierboven beschreven (bijvoorbeeld geconjugeerde addities, alkyleringen via een benzyl

overdracht, decarboxylatieve protonering of alcoholyse). Motor 4.5 is gebruikt voor alle tests, gezien de

overeenkomsten met de Z isomeren 3.1 en 3.2. In tegenstelling tot onze eerste aanname was er geen

Samenvatting

302

meetbare katalytische activiteit. In deze studie kwam naar voren dat een aromatische amine substituent een

slechte activerende groep is voor deze reacties.

Schema 4. a) Ontwerp van een trifunctioneel ligtgevoelige organokatalysator voor ―one pot‖ tandem

katalyse. b) Alternatieve ontwerpen voor bifunctionele gehinderde alkeen afgeleiden 4.1 en 4.4 en

binaphthyl afgeleide 4.5 gebruikt als model katalysator zoals beschreven in Hoofdstuk 4.

Hoofdstuk 5 beschrijft de synthese en het bestuderen van een lichtgevoelige moleculaire schakelaar 5.1,

met een veelzijdig 2,2-bifenol motief waarin de chiraliteit van de motor wordt doorgegeven. Het ontwerp

van 5.1 was gebaseerd op analoog 2.3 uit Hoofdstuk 2 om goede lichtgevoeligheid en thermische stabiliteit

te verkrijgen. De vergelijking tussen experimentele en berekende data bevestigden de voorspelde

overbrenging van chiraliteit van centraal-naar-helisch-naar-axiaal. Hiermee is gedemonstreerd dat de meest

gunstige conformatie van de onderste aryl substituent parallel aan die van de fluorenyl kern zal zijn. Verder

onderzoek met CD en UV-vis-absorptie spectroscopie, 1H NMR spectroscopie en chirale HPLC analyse

gaven bewijs voor het reversibele schakelen van schakelaar 1. Echter, vergeleken met de voorwaartse

photo-isomerisatie bij 365 nm, is het teruggaande proces door bestraling met licht van 420 nm minder

selectief, en geeft het een equimolair mengsel van isomeren van 5.1 met tegengestelde heliciteiten. Het via

dynamische centraal-naar-helisch-naar-axiaal-naar-centraal overbrengen van chiraliteit is succesvol

toegepast in het creëren van een extra chiraal element. Dit is gedemonstreerd door (R)-5.1 als lichtgevoelige

schakelaar toe te passen in de enantioselectieve additie van di-ethylzink aan aldehydes. Een duidelijke

omkeer in enantioselectiviteit werd behaald voor ieder substraat, met een enantiomere overmaat(ee) tot

68% en een ∆ee tot 113 %

303

Schema 5. a) Schematische weergave van 2,2‘biphenol gesubstitueerde lichtgevoelige schakelaar 5.1 en de

relatieve photochemische isomerisatie beschreven in hoofdstuk 5. b) De photochemisch gecontroleerde

enantioselectieve additie van organozinc aan aromatische aldehydes.

Hoofdstruk 6 omschrijft de synthese en de studie van vijf lightgevoelige chirale fosforamidiet-moleculaire

schakelaar afgeleiden L, verkregen vanuit gemeenschappelijk startmateriaal 5.1, waarin de chiraliteit

dynamisch is doorgegeven door vijf tot zeven stereochemische elementen (Schema 6a). De combinatie van

een lichtgevoelige moleculaire schakelaar met hieraan een gekoppeld biaryl, geeft de mogelijkheid tot twee

vormen van een stereochemische groep met bijbehorende karakteristieke ligand eigenschappen. De

liganden zijn toegepast om de activiteit en daarmee de stereoselectiviteit van de koper gekatalyseerde

geconjugeerde additie van diethylzinc aan 2-cyclohexene-1-one te beinvloeden.

De resultaten van de katalyse, samen met kinetische experimenten suggereren dat ieder diastereomeer van

het ligand een eigen activiteit met tegenovergestelde stereoselectiviteit heeft in het deel van de reactie waar

de stereocontrole plaatsvindt. Dit resulteert in een subtiele balans tussen de twee diastereomeren van de

katalysator die met elkaar in competitie zijn. De verdere katalytische eigenschappen zijn te beïnvloeden

door de fotoisomerisatie, en zijn afhankelijke van matched en mis-matched interacties tussen de

dynamische chiraliteit van de schakelaar en de vaste chiraliteit van het fosforamidiet ligand.

Schema 6. a) Schematische weergave van de chirale lightgevoelige fosforamidiet ligand in L, en relatieve

fotochemische isomerisatie beschreven in hoofdstuk 6. b) Door licht beïnvloede activiteit en

stereoselectiviteit in de enantioselectieve koper gekatalyseerde additie van diethylzinc aan 2-cyclohexene-

1-one. c) Schematische weergave van bovenaf van Cu-L complexen : voor ieder (S,SP)- of (S,RP)-

diastereomeer, zijn er twee metaal-ligand complexen met tegenovergestelde heliciteit (M of P) die selectief

gevormd kunnen worden onder invloed van UV licht.

Hoofdstuk 7 beschrijft de synthese en de studie van een lichtgevoelig chiraal fosforzuur 7.1, verkregen uit

structuur 5.1, waarin de chiraliteit dynamisch wordt overgedragen van de moleculaire schakelaar naar het

biaryl gedeelte (Schema 7a). Het eerder beschreven concept van gekoppelde helische-naar-axiale

Samenvatting

304

overdracht van chiraliteit beschreven in hoofdstuk 5 en 6 is verder uitgebreid naar een niet chiraal fosfor

atoom in een fosforzuur voor de toepassing in organokatalyse. Experimentele analyse met UV-vis-

absorptie, CD en 1H NMR spectroscopie bevestigden de reversibele schakelaar eigenschappen van 7.2 De

toepassing als schakelbare katalysator is onderzocht in een aantal reeds bekende Brønsted-zuur

gekatalyseerde transformaties. Langzame reacties en de afwezigheid van enige asymmetrische inductie

waren helaas de uitkomst van 7.2 in iedere geteste reactie. Om de katalytische eigenschappen mogelijk te

verbeteren is een poging gedaan om analoge verbinding 7.2 te synthetiseren (Schema 7a).

Schema 7. a) Schematische weergave van de chirale lichtgevoelige fosforzuur afgeleide 7.1 en de relatieve

fotochemische isomeriatie zoals beschreven in hoofdstuk 7. b) Voorstel voor een alternatief ontwerp voor

fosforzuur 7.2, inclusief een 3,3‘gesubstitueerde biaryl-kern.

Hoofdstuk 8 beschrijft de studie van een bidentate biaryl bis(difenylfosfine) ligand 8.1 gebasseerd op een

overgehinderd alkeen voor licht-schakelbare asymmetrische homogene metaal gekatalyseerde tansformaties

(Schema 8a). In tegenstelling tot de ontwerpen uit hoofdstukken 5, 6 en 7, wordt in dit hoofdstuk

omschreven hoe een gekoppelde beweging leidt tot een effectieve inversie van de lokale chiraliteit rond het

gecoördineerde metaal. De voorgestelde synthetische route begint met de omzetting van een 2,2‘bisfenol

moleculaire motor 5.1 naar het bijbehorende bis-triflaat 8.2 (Schema 8b). Een palladium gekatalyseerde

fosforylering, en de reductie van het fosfine-oxide gaf het monofosfine 8.3. Verscheidene procedures om

het bisfosfine te synthetiseren mislukten, waarschijnlijk door de hoge mate van sterische hinder. Een

verdere poging om het doel van het project bij te stellen naar een chiraal licht-schakelbare Bronsted-zuur

katalysator 8.4, waarin een difenylfosfine alsmede een fenol aanwezig zijn, is beschreven in dit hoofdstuk.

Schema 8. a) Schematische weergave van voorgestelde metaal complexen MLn-(S)-8.1 en de relatieve

photochemische isomeriatie zoals omschreven in hoofdstuk 8. b) Weergave van de gepoogde synthese van

bis(difenylfosfine)-derrivaat 8.1 en hydroxy-difenylfosfine-derrivaat 8.4, uitgaande van 5.1.

305

Abbreviations and Acronyms

APCI atmospheric pressure chemical ionization

BINAM 1,1′-Bi(2-naphthylamine)

BINOL 1,1′-Bi(2-naphthol)

BIPHEP 2,2‘-bis(diarylphosphino)biphenyl

CD Circular Dichroism

CIP Cahn-Ingold-Prelog

CLA chiral Lewis acid

cod 1,5-cyclooctadiene

Conv conversion

COSY NMR correlation spectroscopy

CSP chiral stationary phase

DABCO 1,4-diazabicyclo[2.2.2]octane

DBS dibenzosuberane

DFT density functional theory

DHPLC Dynamic HPLC

DMA N,N’-dimethylaniline

DMI N,N’-dimethylimidazolinone

DMRG density matrix renormalization group

dr diastereoisomeric ratio

(E) entgegen, denotes relative configuration

ee enantiomeric excess

er enantiomeric ratio

EDG electron donating group

EI electron ionization

ESI electrospray ionization

EXSY NMR exchange spectroscopy

EWG electron withdrawing group

GC gas chromatography

GC-MS gas chromatography-mass spectrometry

HOMO highest occupied molecular orbital

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

IR infra-red

LUMO lowest unoccupied molecular orbital

(M) denotes left-handed helicity

(Ma) denotes left-handed axial helicity

(M=) denotes left-handed overcrowded alkene helicity

MAP N-methylaminopyridine

MBH Morita–Baylis–Hillman

MS or M metastable

NMR nuclear magnetic resonance

NOESY nuclear Overhauser effect spectroscopy

(P) denotes right-handed helicity

(Pa) denotes right-handed axial helicity

(P=) denotes right-handed overcrowded alkene helicity

PET photoinduced electron transfer

PSS photostationary state

Abbreviations and Acronyms

306

(R) rectus, denotes absolute configuration

(Ra) rectus, denotes absolute axial configuration

(RP) rectus, denotes absolute configuration of phosphorus center

RC rotaxane catalyst

RCL responsive coordination ligand

ROC responsive organocatalyst

rt room temperature

(S) sinister, denotes absolute configuration

(Sa) sinister, denotes absolute axial configuration

(SP) sinister, denotes absolute configuration of phosphorus center

St or S stable

TD time-dependent

TEZI thermal E-Z isomerization

TLC thin layer chromatography

TOF turnover frequency

THI thermal helix inversion

UV-vis Ultraviolet-visible

(Z) zusammen, denotes relative configuration

307

Acknowledgements

The work described in this thesis is the product of the collaboration and joint effort provided by colleagues,

friends and family. Five years have passed since the start of my adventure as a PhD student and as a

‗Groninger‘. Many are the happy smiles I met and warm hugs I shared along the way. In this final salute, I

would like to thank all the wonderful people that made this period so memorable.

First of all, my promotor Ben. Thank you so much for accepting me as a member of your group, first as a

visiting student for my Master thesis‘ project in catalysis, and later as PhD student joining the molecular

motor group. You always impressed me with your enthusiasm and true passion for science and discovery,

which constantly attracts young bright minds willing to follow your lead towards the next level of chemical

control. Moreover, the richness and precision of details of your old-time stories during borrells and your

aggressive play in our football matches possibly amazed me even more. I am very grateful for the optimism

and support you always provided, even during the most stressful moments. Congratulations once more for

the Nobel Prize award: you truly deserved it and I feel much honored to have been part of your team in

such an unforeseen and unique event.

The members of the assessment committee, Prof. S. Harutyunyan, Prof. H. Hiemstra, and Prof. J.G. de

Vries are greatly acknowledged for correcting and approving the manuscript. In addition, I would like to

thank Prof. A. Minnaard, Prof. W. Browne, and Prof. E. Otten or the very helpful discussions,

collaborations and support with non-conventional measurements throughout my research activity.

Massimo and Martin, your supervision during my initial MS internship was a wonderful experience. Your

hot-blooded Latin spirit made my jump to the cold Netherlands less abrupt and definitely funnier than I

could had ever expected. You first taught me how to conduct high level research, hold effective

presentations, face daily life away from home and show on the field how Latins play football and

basketball. I would happily start all over again just to enjoy those moments once more. Thank you so much.

Dorus, I feel much honored to have become your friend during the past years. Your honesty, kindness,

charisma and generosity make you one of the best companions I have found so far. My daily routine in the

lab could not start without your signature salute: ―Che Pizzo! Che pasta! Che pollo!!!‖ Thank you so much

for your cheerful smiles, all our dinners, the motorbike rides in the wild countryside of Groningen, the

freezing cold nights in the Dutch forests, the crucial push you gave me to just leave and visit Norway on my

first solo road trip, the support provided as paranymph, and most of all thank you for teaching me to follow

my dreams and desires in order to maintain identity as the happy Pizzo.

Peter, right at the beginning of my PhD you became my reference in the lab. Despite being only few

months older than me, by then you had already built such a strong experience and skills as a synthetic

chemist. As Jos once said: ―If a reaction doesn‘t work in Peter‘s hands, it is simply chemically impossible.‖

Furthermore, you proved to achieve what others had for long tried in vain. The successful synthesis of the

fluoromotors is a perfect example. During four years we shared many precious moments: generous laughs

in the lab, intense hockey matches, beautiful sunsets in San Francisco, crazy reactions and glorious

revelations from on-point experiments. Our joint efforts and bright ideas led us to our most successful

projects described in this thesis in Chapter 5 and 6. I wish you and Lenka all the best luck for the

continuation of your journey in academia. If destiny had a different picture for you, we may as well resume

our back-up plan of intensive pineapple production as we suggested many times. Thank you.

Jos, your solid ego and unique outspokenness make you one of the most interesting, sharpest and funniest

people I have ever met. You were always open for intense and long discussions, not all necessarily related

to Chemistry, nor always sober in tone or subject. After you left for Australia, the C-wing definitely lost its

spark. Thank you very much for all your help, included the fundamental inputs and contribution to my

projects and thesis. I wish you and Heather the best luck and happy life.

Acknowledgements

308

Tom, I really enjoyed sharing the lab and collaborating with you in various projects. Your excellent

knowledge of theoretical Chemistry, sense of humor and great taste for music made my days in many

occasions. I‘ll remember you as the only true white gangsta, always howling ―Chemistry!‖ whenever most

need, whether for good luck or for mere boredom. Thank you so much for your help and support, especially

from abroad during the correction process of my thesis. Very much good luck with your post-doc in Spain.

Dear Matea and Raquel, I had so much fun organizing the group retreat in Strasbourg and strolling around

Ghent for the preparation of the Bonteavond. Your cheerful smiles have often brightened my days and will

always remain in my heart. Thanks to you, too.

I would also like to thank all the post-docs that helped me and enriched my experience in Ben‘s group:

Viktor, Sander, Valentin, Carlos, Thomas, Depeng, Michael, Adele and Krzysztof. Dear Beatrice, you

deserve a special thanks: not only for collaborating on the project described in Chapters 3 and 4, but mainly

for being a prime example of complete, resourceful and optimistic researcher; and a beautiful person, too. I

look forward to attend one of your lectures as full professor in the short future. Hug you soon!

Next I would like to thank all the wonderful colleagues with whom I shared labs, coffee rooms, borrells,

parties, climbing sessions, football subgroups and flunkyball matches: Anouk, Wojciech, Jort, Jana, Jeffrey,

Jochem, Filippo, Kuang-Yen, Weh-Hao, Henrieke, Romain, Diederik, Will, Thom, Jingling, Jiawen,

Yuchen, Chen, Petra, Claudia, Dusan, Mickel, Michael, Adi, Ashoka, Niek, Beatriz, Peter, Anne, Suresh,

Erik, Piotr, Vittorio, Francesca, Johnny, Antonio, Ana, Alaric, Rik, Nop, Francesco, Simone, Tilde, Pablo,

Ravi, Juan, Romina, Mu-Chieh, Marco, Francesca, Ivana, Massimo, Sambika, Cora, Giovanni, and Yan.

Our capable team of technicians is also greatly acknowledged. Pieter, Theodora, Monique, Wim and Hans:

your daily assistance with the lab equipment and instruments was fundamental for the smooth developing

of my projects. Thank you very much.

Thanks also to all the secretaries of our department for their support: Hilda, Alphons, Cristina, Annette and

Maud. A special thank is dedicated of course to Tineke. Behind an unordinary professor like Ben, there has

to be an extraordinary secretary like you. During the past four years you have constantly impressed me with

your professionalism, kindness, loyalty and versatility. You faced every situation – even my several stress

crises (I am truly sorry for those!) – with firm attitude and a tenacious smile. Thank you for all. I wish you

and your family the best luck.

It is important as well to recognize the contribute of all the great friends from outside the university that

kept me happy and mentally healthy throughout my PhD.

First of all my housemates and best friends Tim, Carina, Amanda, Timon, Arielle and Cezar. We shared so

much during our talks, dinners, trips, movie nights, BBQs, beer pong matches and parties. In many

occasions we felt like brothers and sister, in few critical others we were each other‘s guardian angels. Each

of you would deserve many more words than I can dedicate to you here. I‘ll make sure to compensate face-

to-face during my last farewell party. Thank you from the deep of my heart.

A big hug to my Arubian pals Ray, Jino, Guido, Nayif and Solo. We randomly met due to our common

passion for Smash, and you immediately welcomed me to enjoy much more throughout my entire last year

in G-town. I deeply enjoyed chatting, laughing, playing, dreaming, and cooking pasteechi with you during

our multiple chilling sessions. Masha danki.

I would like to dedicate my last words to my wife Susanna. Il nostro rapporto è nato dalla leggerezza e

spensieratezza di tre giorni magici, appena prima che la mia vita volgesse altrove per quattro lunghissimi

anni. Tutte le premesse erano contro ciò che si è poi rivelato un solido e intenso legame amore. Lontani,

indipendenti, tenaci, e ciò nonostante così bisognosi l‘uno dell‘altra. Ti ringrazio per tutto il sostegno che

mi hai costantemente fornito, dai primi mesi di lontananza agli ultimi faticosi giorni di scrittura. Come dice

saggiamente Tim, la parte migliore della nostra vita è iniziata il giorno in cui ci siamo sposati. Ora non resta

solo che viverla al pieno delle nostre energie e passioni. Ti amo profondamente, amore mio. Grazie ♥

Dynamic transfer of chirality in photoresponsive systems

Documents