Complex Systems from Simple Building Blocks via Subcomponent Self-Assembly

ACCOUNT A

Complex Systems from Simple Building Blocks via Subcomponent Self-AssemblySubcomponent Self-AssemblyVictoria E. Campbell, Jonathan R. Nitschke*The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKFax +44(1223)336362; E-mail: [email protected] 19 May 2008

SYNLETT 2008, No. x, pp 000A–000Nxx.xx.2008Advanced online publication: xx.xx.2008DOI: 10.1055/s-0028-1087361; Art ID: A49908ST© Georg Thieme Verlag Stuttgart · New York

Abstract: Subcomponent self-assembly allows for the constructionof complex architectures from simple building blocks via the simul-taneous, reversible formation of covalent and coordinative bonds.Complex structures may be rapidly built by taking advantage of thedifferent and complementary selectivities of covalent and coordina-tive bond-forming reactions. Because both kinds of bonds areformed under thermodynamic control, a wide variety of rearrange-ment reactions are possible involving substitution at both intrali-gand and metal–ligand bonds. Understanding the selectivities thatunderlie these reactions also allows one to pick out specific prod-ucts from among diverse dynamic combinatorial libraries of inter-converting structures.

1 Introduction2 Initial Work2.1 Aqueous Copper(I)-Templated Subcomponent Self-

Assembly3 Construction3.1 Dicopper and Tricopper Helicates3.2 Tetracopper(I) Grid3.3 Catenates and Macrocycles4 Rearrangements4.1 Cascade Reaction4.2 Electronic Effects5 Sorting5.1 Sorting Ligand Structures with Copper(I)5.2 Cooperative Selection by Iron and Copper5.3 Sorting within a Structure6 Systems Chemistry6.1 Deterministic Self-Sorting Systems of Subcomponents6.2 Interplay between Three Dynamic Equilibria7 Chiral Information Transfer7.1 Chirality Transfer from Carbon to Copper(I)7.2 Chiral Resolution during Crystallization8 Boron-Templated Self-Assembly8.1 Mononuclear Boron-Templated Structures8.2 More-Complex Structures8.3 Subcomponent Substitution Reactions within Imino-

boronate Ester Systems9 Conclusions

Key words: subcomponent self-assembly, dynamic combinatorialchemistry, systems chemistry, coordination chemistry, dynamic co-valent chemistry

1 Introduction

Physical laws can direct the flow of matter toward a more-organized state: This idea underlies a range of phenomenaobserved in many different scientific disciplines acrosswidely varying scales of length. Certain pathways of ma-terial self-organization have led to progressively increas-ing complexity.1 One particular strand of matter thatbegan to organize itself chemically over 3 billion yearsago2 started down the road to Darwinian evolution,3 re-cently leading to the emergence of multicellular organ-isms that might be capable of puzzling out details of theirown origins.4

In addition to potentially shedding light on basic questionsrelating to the origins of life, the study of chemical self-organization can open up new possibilities within the artof synthesis. Provided that the rules underlying a givensystem are understood, complex structures may be createdfrom simpler building blocks under thermodynamic, asopposed to kinetic, control in a process commonly re-ferred to as ‘self-assembly’.5,6 In recent years, self-assem-bly has been employed to synthesize new materials7 andprototypes of functional molecular machines;8,9 the use ofself-assembly as a construction technique is widely pre-dicted to play an essential role in coming generations ofnanotechnology.10

Our research program has dealt with the development andemployment of subcomponent self-assembly toward thecreation of increasingly more complex structures and sys-tems. This technique is a subset of metal-organic self-assembly11 and involves the simultaneous formation ofcovalent (carbon–heteroatom) and dative (metal–hetero-atom) bonds, thus bringing both ligand and complex intobeing at the same time. The roots of subcomponent self-assembly lie in the template synthesis of Busch.12 Beforeand after the start of our program, other researchers haveemployed this method to synthesize a wealth of structures,such as macrocyles,13 helicates,14,15 rotaxanes,16 catenanes,17

grids,18,19 and Borromean20 and Solomon21 links, to citejust a few examples. The reader is referred to a compre-hensive recent review by Stoddart et al.22 focusing uponstructures built up using thermodynamic synthesis involv-ing dynamic covalent6 imine bonds (C=N), which haveproven particularly useful in linking subcomponents to-gether.

Initial proof-of-concept experiments in our laboratoriesestablished the utility of subcomponent self-assembly

B V. E. Campbell, J. R. Nitschke ACCOUNT

Synlett 2008, No. x, A–N © Thieme Stuttgart · New York

based upon copper(I) coordination and imine bond forma-tion.23 From there, we have built up our research programalong the main lines noted below. Construction: we haveinvestigated what kinds of structures may be synthesizedusing subcomponent self-assembly, seeking to push backthe limits of how much structural complexity may be gen-erated during the course of a single self-assembly reac-tion.15,19,24–26 Substitution and reconfiguration: we haveexplored the driving forces that allow these structures torearrange and reorganize in well-defined ways.15,26–28

Sorting: we have employed the techniques and ideas ofdynamic combinatorial chemistry6,29,30 to study the pa-rameters that allow complex dynamic combinatorial li-braries (DCLs), consisting of mixtures of structures thatinterconvert through the exchange of subcomponents, tobe sorted by taking advantage of the thermodynamic pref-erences of the system.24,27,30,31 Systems chemistry: we haveextended the ideas of reconfiguration and sorting to studythe interplay between separate reversible chemistries,32,33

allowing entry into the emerging area of systems chemis-try.32–35 Chiral communication: we have investigatedchiral information transfer within systems containing bothfixed (carbon stereocenters) and dynamic (metal stereo-centers) chirality;30,36 the possibility of exchanging chiralelements between structures provides additional complex-ity and interest. Finally, we have extended our methodol-ogy to bring into play new subcomponent motifs, such asiminoboronate esters,37,38 and we have investigated thedriving forces for substitution and reconfiguration in thesesystems.39

2 Initial Work

2.1 Aqueous Copper(I)-Templated Subcompo-nent Self-Assembly

Our initial study23 involving copper(I) and imines in aque-ous solution validated certain key ideas, as well as takinginitial steps in the directions of construction and substitu-tion.

In aqueous solution, copper(I) is frequently observed todisproportionate to copper(II) and copper metal. Whenamines and carbonyl compounds are mixed in water, im-ines are in most cases the minority species.40 However,this stability pattern reverses when imines and copper(I)are present together in aqueous solution. Imines are excel-lent ligands for copper(I), stabilizing the metal in this ox-idation state, and in turn metal coordination can preventimines from hydrolyzing. Utilizing the mutual stabiliza-tion of copper(I) and imines in aqueous solution, we wereable to prepare complex 1 from the precursors shown inScheme 1.23

Despite the thermodynamic stability of complex 1, it un-derwent covalent imine substitution in the presence of sul-fanilic acid to form complex 2 (Scheme 2).

This substitution reaction occurred with excellent selec-tivity (>95% yield), which can be understood in terms ofthe large difference in acidity between sulfanilic acid(pKa = 3.2) and taurine (pKa = 9.1). The protonated formof the weaker acid (taurine) is displaced from complex 1,

Victoria E. Campbell wasborn in 1981 in Turin, Italy.She received her bachelor’sdegree in chemistry fromthe New College of Florida,

USA, in 2003, and a mas-ter’s degree in materials sci-ence from the University ofWisconsin, Madison, in2005. She is currently pur-

suing a Ph.D. in chemistryat the University of Cam-bridge under the supervisionof Jonathan Nitschke.

Jonathan Nitschke wasborn in 1973 in Syracuse,New York, USA. He re-ceived his bachelor’s degreein chemistry cum laudefrom Williams College in1995, and his doctoratefrom the University of Cali-fornia, Berkeley, in 2001under the supervision of T.Don Tilley. He then under-took postdoctoral studieswith Jean-Marie Lehn in

Strasbourg, France, underthe auspices of a US Nation-al Science Foundation fel-lowship, and in 2003 hestarted his independent ca-reer as a maître-assistant inthe Organic Chemistry De-partment of the Universityof Geneva, Switzerland. Hewas the first recipient of theEuropean Young ChemistAward in August 2006, andbecame a Swiss National

Science Foundation assis-tant professor in August2007. In September 2007,he received the WernerPrize of the Swiss ChemicalSociety. Since November2007, he has held the posi-tion of University Lecturerand Walters-Kundert NextGeneration Fellow at theUniversity of Cambridge,UK.

Biographical Sketches

ACCOUNT Subcomponent Self-Assembly C


and the deprotonated form of the stronger acid (sulfanilicacid) is incorporated, thus forming complex 2.23

3 Construction

The bis(iminopyridine)copper(I) motif described in Sec-tion 2.1 proved versatile, serving as a starting point for thedesign and synthesis of a variety of assemblies of greaterstructural complexity. Some of the structures that we wereable to prepare are described below.

3.1 Dicopper and Tricopper Helicates

The reaction of deprotonated sulfanilic acid with a cop-per(I) source, such as copper(I) tetrafluoroborate, and1,10-phenanthroline-2,9-dicarbaldehyde in water gaveanionic double helicate 3 in quantitative yield(Scheme 3).15 A variety of different double-helical struc-tures, sharing the bis(diiminophenanthroline)dicoppercore of 3, could be prepared in a similar fashion from var-ious amine subcomponents. A set of ‘selection rules’ wereuncovered that allowed the prediction of whether a heli-cate might be generated from a given amine based uponsteric, solvent, pH, and charge effects.15

Using a modified version of the method used to preparedicopper helicate 3, a tricopper double helicate could alsobe synthesized. The reaction of copper(I), quinolin-8-ylamine, and 1,10-phenanthroline-2,9-dicarbaldehydegave helicate 4 as the unique product (Scheme 4).25

3.2 Tetracopper(I) Grid

The reaction of a water-soluble m-phenylenediamine andpyridine-2-carbaldehyde in deuterium oxide solution gavea complex DCL of ligands, as observed by NMR spectros-copy. Upon the addition of copper(I) tetrafluoroborate tothis solution, the library condensed to give only one prod-uct, tetracopper(I) grid 5, in near quantitative yield(Scheme 5).19

Tetracopper(I) grid 5 was formed in water uniquelyamong all the different solvents tried. If the grid was syn-thesized in water, isolated, and subsequently dissolved inanother solvent, it was observed to decompose. Interest-ingly, the crystal structure of the grid suggested the pres-ence of strain, as indicated by a distorted geometry. Wehypothesized that the hydrophobic effect provides an es-sential driving force for the synthesis and stability of thegrid. By adopting the observed geometry, the ligands andthe metal ions are wrapped together in a compact structurein which the hydrophobic ligand surfaces are minimallyexposed to the aqueous environment. A ‘diffuse pressure’applied by the hydrophobic effect would thus compensatefor the structure’s strain. We envisage extending this strat-egy to the synthesis of other strained architectures becausestrained structures have been observed to have unusualand potentially technologically interesting properties.41

3.3 Catenates and Macrocycles

The reaction of the short diamine 2,2¢-(ethylene-dioxy)bis(ethylamine) with phenanthrolinedicarbalde-

Scheme 1 Mutual stabilization of copper(I) and imines in aqueoussolution

½ CuCl2

½ Cu0CuI

1

N

N

SO3–

N

N

SO3–

Cu+N

N

SO3–

H2N

SO3–

N

O

2

2D2O

2

D2O

Scheme 2 Acidity-driven subcomponent substitution

2

NH3+

SO3–

D2O

+ 2

1

N

N

SO3–

N

N

–O3S

Cu+N

N

N

N

Cu+

–O3S

SO3–

+H3N

SO3–

2

Scheme 3 Construction of dicopper double helicate 3

N

N

2

O

O

N

N

–O3S SO3–

SO3–

N

NN

NN

–O3S

NCu+

Cu+

3

NH2

SO3–

2

2 CuI

D2O

Scheme 4 Preparation of tricopper double helicate 4

NCu+

N N

N

N

N

N

NCu+

N

N

N

NCu+

N

NH2

4

4

N

N

2

O

O3 CuI

D2O

D V. E. Campbell, J. R. Nitschke ACCOUNT


hyde and copper(I) yielded macrocycle 6 as the uniqueproduct (Scheme 6).26 The diamine substrate is only longenough to give a single twisted macrocyclic topology oncyclization, as confirmed by X-ray crystallography.

The incorporation of a longer diamine containing rigidphenylene spacer groups produced interlocked structure 7(Scheme 6). The orientation of the phenylene groups al-lowed the flexible chains to bridge across the backs of thephenanthroline units, but rendered the formation of a mac-rocyclic topology similar to that of 6 thermodynamicallyunfavorable. Structure 7 was thus selected as the only ob-served product. Thus, it was possible to choose the topol-ogy of the product through careful attention to the lengthand flexibility of the subcomponent starting materials.

4 Rearrangements

Many of the structures synthesized using subcomponentself-assembly underwent rearrangement and substitution

reactions, which may occur both at covalent and coordina-tive linkages. We particularly focused on investigating re-actions that cleanly transformed one structure intoanother. The driving forces for such substitutions includedthe chelate effect, use of pKa differentials, relief of stericencumbrance, and substitution of an electron-poor sub-component for an electron-rich one.

4.1 Cascade Reaction

Bis(diimine) complexes, such as 8 (Scheme 7), were ob-served to have a rich substitution chemistry.27 As was thecase for the systems shown in Scheme 2, pKa-driven im-ine exchange reactions favored the displacement of theprotonated form of the weaker acid and the incorporationof the deprotonated form of a stronger one.23,15 As shownin Scheme 7, complex 8 reacted with o-phenylenediaminedihydrochloride in aqueous solution to give 9, which inturn reacted with bis(biquinoline)copper(I) complex 10 togive the mixed-ligand species, i.e. complex 11, as the

Scheme 5 Synthesis of [2 × 2] grid 5

N

N

N

N

R

N

N

N

N

R

N NNN

R

N NN N

R

Cu+

Cu+ Cu+

Cu+

N

O

H2N NH2

2

5

OHN

OH

CuI

only in H2O 99%

R = CONH(CH2)2OH

Scheme 6 Synthesis of macrocycle 6 and catenane 7

N

N

N

NN

NN

NCu+

Cu+

N

N2

NH2

OO

H2N

2

OO

O O

6

O

O

O O

NH HN

NH2NH2

2

N N

HN

HN HN

N

N

N

N

N

NH

N+CuCu+

7

O O

O O

2 CuI

2 CuI

ACCOUNT Subcomponent Self-Assembly E


thermodynamic product.42 The ligand exchange appearsto be driven by steric effects. The substitution of one ofthe diimine ligands for a less sterically hindered biquino-line provided the driving force for this reaction.43

Interestingly, complex 8 was unreactive toward ligand ex-change with complex 10, possibly as a result of the differ-ent steric properties of the two complexes. This lack ofreactivity opened the door to a new kind of cascade reac-tion that operates at both covalent and coordinative levels.Imine (covalent) exchange was followed by ligand (coor-dinative) exchange between copper complexes 9 and 10,resulting in the mixed-ligand complex 11 as the uniqueproduct.

4.2 Electronic Effects

The electronic nature of each amine incorporated intothese complexes plays an important role in determiningthe complexes’ stabilities. We have shown that the elec-tronic effects of the para-substituent of an aniline, as mea-sured by the Hammett spara parameter,44,45 may be used to

drive subcomponent substitution reactions of copper(I)complexes.28 We were able to utilize the Hammett equa-tion to predict product identities and yields, and ultimatelyit was possible to design a three-step transformation of aseries of copper(I)-containing structures, as shown inScheme 8. The outcome of each step in the sequence waspredictable based upon the Hammett s parameters of theentering and leaving anilines. We were able to change thetopology of the complex at each step. Starting from mono-nuclear complex 12, we obtained dicopper macrocycle13.46 The mononuclear topology could be recovered bythe addition of an electron-rich aniline to yield 14. Finally,the addition of an aliphatic diamine led to the synthesis ofmononuclear macrocycle 15. The driving force for thislast substitution is entropic in nature and can be thought ofas a special case of the chelate effect.

5 Sorting

The reversible character of the self-assembly process atboth covalent and coordinative levels allows one to envis-

Scheme 7 Cascade reaction in which covalent (imine) exchange induced coordinative (ligand) exchange

8 11

10N

NCu+

SO3–

SO3–

SO3–

SO3–

OO

N

N

OO

+NH2Cl–

+NH2Cl–

O

O+NH2Cl–

+NH2Cl–

N

NCu+

SO3–

SO3–

SO3–

SO3–

N

N

–O2C

–O2C

Cu+

N

NN

N

CO2–

CO2–

N

N

SO3–

SO3–

–O2C

–O2C

Cu+

N

N

9

Scheme 8 One-pot series of transformations combining substituent electronic effects and the chelate effect to provide driving forces for imineexchange

N

N

N

N

Cu+

O

NH2

NH2

O

N

N

N

NCu+

N

N

N

NCu+

N

N

N

N

Cu+

NMe2

Me2N

O O

H2N NH2N

N

N

N

Cu+

O

O

99.5% 97% 93%predicted:

97.6%predicted:

97.5%

1512

1413

NMe2

NH2

F V. E. Campbell, J. R. Nitschke ACCOUNT


age systems where DCLs of subcomponents could be sort-ed into a limited number of structures using theselectivities imposed by metal ions. We have investigateda number of systems in which individual subcomponentsare guided to specific locations within collections of struc-tures.

5.1 Sorting Ligand Structures with Copper(I)

Initial investigations demonstrated that complexes con-taining different imine ligands could be synthesized ineach other’s presence. The mixture of 2,2¢-(ethylene-dioxy)bis(ethylamine), pyridine-2-carbaldehyde, and 2-formylbenzenesulfonate in water gave a library of ligandsin dynamic equilibrium with the starting materials. Uponthe addition of copper(I), the library collapsed eliminatingall but two of these ligands during the formation of com-plexes 8 and 15 (Scheme 9).27

The simultaneous formation of 8 and 15 from the libraryresults in a situation in which all the copper ions are tetra-coordinate and each nitrogen atom is bound to one copperion. Any other possible products would be complexeswith either more than one metal center (entropically disfa-vored) or unsatisfied valences at either the metal or ligand(enthalpically disfavored).

5.2 Cooperative Selection by Iron and Copper

We have examined a larger self-sorting system in whichiron(II) and copper(I) act together to sort a more-complexdynamic library of ligand subcomponents, as shown inScheme 10.27

When pyridine-2-carbaldehyde and 6-methylpyridine-2-carbaldehyde were mixed with 2-aminoethanol and tris(2-aminoethyl)amine in aqueous solution, a dynamic libraryof imines formed in equilibrium with these starting mate-rials (Scheme 10). When copper(I) tetrafluoroborate andiron(II) sulfate were added, the library was observed to

collapse leaving compounds 16 and 17 as the sole prod-ucts.

During the course of our study, we identified the impor-tant thermodynamic driving forces behind this selectivity,such as the template effect, the chelate effect, and, mostinterestingly, a ‘spin-selection’ phenomenon. Pseudo-octahedral complex 17 contains iron(II) in the diamagnet-ic low-spin state,47 with short, strong iron–nitrogen bonds.Analogous complexes incorporating 2-methylpyridineresidues possess some high-spin character with corre-spondingly longer iron–nitrogen bonds. The formation ofthe stronger metal–ligand bonds of 17 provided an impor-tant driving force for the incorporation of the nonmeth-ylated pyridine residues.

5.3 Sorting within a Structure

The preparation of structure 18, shown in Scheme 11, re-quired a different kind of selectivity in the choice ofligand subcomponents. Whereas during the simultaneousformation of the mononuclear complexes of Scheme 9 allmixed ligands were eliminated from the initially formeddynamic library, in the system of Scheme 11, the mixedligands formed the unique structure selected during equil-ibration.24

This differential selectivity results from the differingnumbers of donor atoms offered by the aldehydes uponwhich these structures are based. The two aldehydes ofScheme 9 readily lend themselves to the construction of aset of homoligands bearing a number of donor atoms di-visible by four, matching the coordination preference ofcopper(I). In contrast, pyridine-2,6-dicarbaldehyde mustmake homoligands incorporating an odd number of donorsites. To generate ligand sets bearing a number of donorsites divisible by four, heteroligands are necessary. Fol-lowing this principle, the formation of heteroligand-con-taining structure 18 is selected from the componentsshown in Scheme 11.

Scheme 9 Formation of complexes 8 and 15 from a dynamic library of ligands

SO3–

NH2H2N

O O2

D2O

N

N

SO3–

N

SO3–

N

N

N

N

N

NN

SO3–

N

O

SO3–

2

2

OO

OOO O

O

H2N

N

N

O

O

H2N

2 CuI

N

NCu+

SO3–

SO3–

SO3–

SO3–

OO

N

N

OO

N

NN

N

Cu+

OO

O

O

8

15

ACCOUNT Subcomponent Self-Assembly G


The special stability of compound 18 was demonstratedby the fact that it could also be generated by mixing to-gether the two homoligand-containing complexes 19 and20. Although both of these complexes are thermodynam-ically stable, 19 contains only three donor atoms per cop-per, whereas 20 contains five such donors. The possibilityof achieving coordinative saturation thus drives an iminemetathesis reaction, redistributing the subcomponents togive structure 18 as the uniquely observed product.

The preparation of 18 demonstrates the use of subcompo-nent self-assembly to address an old synthetic problem:how to induce each of the formyl groups of a symmetricalsubstrate, e.g. pyridine-2,6-dicarbaldehyde, to react with adifferent amine without obtaining statistical mixtures ofproducts. Although the dynamic nature of the imine bondsof 18 played an essential role in its thermodynamic syn-thesis, it is useful to be able to ‘turn off’ the possibility ofdynamic exchange in order to create a structure that per-sists even in the absence of the metal templates. This goalwas readily attained by treating 18 with sodiumborohydride48 to reduce the imine bonds to secondaryamines, followed by potassium cyanide to remove themetal ions49 (Scheme 12). The ability to convert 18 into21 brings this methodology into the realm of organic syn-thesis, allowing ready access to a product that could bedifficult to prepare using other methods.

6 Systems Chemistry

Building upon the idea of sorting simple dynamic librar-ies, we have started investigating systems where multipleproducts are formed during the course of a single self-assembly reaction, in common with those systems inves-tigated by Klekota and Miller,50 and Lehn,51 Meijer,34,52

and von Kiedrowski53 and co-workers.

6.1 Deterministic Self-Sorting Systems of Sub-components

We have prepared the self-sorting system shown inScheme 1333 for which the rules that govern the self-assembly process have been deciphered. When the twoamines were mixed with the three aldehydes shown, nu-merous intermediate imine structures were possible, andone could imagine that each intermediate might react withcopper(I) in a variety of ways. However, only four prod-ucts were observed following thermodynamic equilibra-tion. Copper(I) ions thus exerted a strong template effect54

upon the dynamic library. As described in previous sys-tems, this selectivity may be encapsulated as a ‘rule of va-lence satisfaction’:24 the smallest possible structures willbe formed in which all copper(I) ions are tetracoordinateand all nitrogen atoms are bound to a copper(I) ion.

Scheme 10 Formation of a dynamic library of ligands, and the collapse of this library following the addition of copper(I) and iron(II)

1.5 CuI

FeII

N

N

O

O

H2NOH

3

3

H2NN H2N

N

N

NN N

N

N NN

H2NN N

N

N N

H2NN H2N

N

NN

N N

N

N NN

H2NN N

N

N N

H2NN N

N

N N

NN N

N

N NN

N

NN N

N

N N

N

N

N

N

H2O

NH2 H2N

NNH2

OH

OH

N

N

N

N

Cu+

OH

HO

1.5

N

N

N

N

N

N

NFe

2+

317

16

H V. E. Campbell, J. R. Nitschke ACCOUNT


By controlling the stoichiometry of the five starting sub-components, any arbitrary subset of the four productstructures 22–25, in any relative proportions, may be pre-pared. The self-assembly rules governing this system are,thus, deterministic and may be used as programming in-structions for the selection of ‘output’ structures basedupon ‘input’ chemical species.

6.2 Interplay between Three Dynamic Equilibria

In the systems of Schemes 14 and 15, three distinct kindsof linkages, i.e. disulfide (S–S), imine (C=N), and coordi-native (N→M, M = metal), were shown to be capable ofsimultaneous dynamic exchange.32 Equilibria between thehomo- and hetero-disulfide subcomponents of this systemcould be perturbed by more than two orders of magnitudevia changes at the coordinative and imine linkages.

Of the three product states shown in Scheme 14, the oneon the left was strongly preferred, even though the samenumber of covalent and coordinative bonds are present ineach of the different mixtures. We suspect that this selec-tivity is primarily entropic in nature: the number of parti-cles in the system is maximized when the subcomponentsare combined so as to generate one equivalent of 26 andtwo equivalents of 27. The system may, thus, be said toproduce complex structure 26 by expelling spectator com-pound 27, which is not able to participate in metal–ligandinteractions.

Similarly, we were able to synthesize the correspondingDCL incorporating hexacoordinate iron(II) in place of tet-racoordinate copper(I) (Scheme 15). In this system, thehomo-disulfide library members were favored even morestrongly, by a factor of 179 to what was observed in thecase of the free disulfides. As in the copper(I) system, thisselectivity appeared to be entropic in nature: the numberof particles present in the system were maximized towardthe left of the equilibria (Scheme 15).

The reversible nature of the imine and coordinative bondsof the systems of Schemes 14 and 15 allowed the equilib-ria of these systems to be readily manipulated. We wereable to address both coordinative (N→M) and covalent(C=N) linkages independently.

First, transmetalation was used to alter the equilibrium be-tween the homo- and hetero-disulfides. The addition ofiron(II) tetrafluoroborate to copper-containing 26 resultedin the quantitative transformation of 26 into 30(Scheme 16). When this transformation was carried out inthe presence of disulfide 27, the system’s ratio of homo-to hetero-disulfide residues could, thus, be altered from avalue associated with 26 (measured ratio = 1.4) to one im-posed by 27 (measured ratio = 83). Second, covalent im-ine exchange could also be used to perturb the equilibriumbetween the disulfides. The addition of chelating amine34 to complex 30 resulted in the quantitative formation ofmononuclear complex 17 (Scheme 16). Following libera-tion from 30, the two disulfides became free to re-estab-lish their initial equilibrium, settling upon an equilibriumratio of 0.43, identical to the value observed in the absenceof metal ions.

These complex systems of equilibria are reminiscent ofbiological signaling mechanisms. The presence of copperor iron in the system results in an increase in the equilib-rium concentration of a disulfide, with the amount liberat-ed being linked to the identity and quantity of the metal

Scheme 11 Preparation of structure 18 from a mixture of ligand sub-components (top) and through the covalent comproportionation ofsubcomponents from preformed structures 19 and 20 (bottom)

N

N

N

N

N

N

NCu+

Cu+N

N

NH2

O O

N

O

O

2 CuI

MeCN2

O O

NH2H2N

2

N

N

N N

NCu+

N

Cu+

O O

OO

19

N

N

N

NCu+

N

N

N

NCu+

20

18

½½ N

Scheme 12 Hydrogenation and demetalation of complex 18 to pro-duce compound 21

1) NaBH4 MeOH–MeCN

2) KCN, MeOH

18 21

N

NH

HN

N

O

N

HN

NH

N

O

N

N

N

N

N

N

NCu+

Cu+N

O O

ACCOUNT Subcomponent Self-Assembly I


ion present. Such systems might be harnessed as metal-ion sensors,55 and may lead to an improved understandingof the organizational principles of chemical and biologicalnetworks, and of self-sorting systems in general.

7 Chiral Information Transfer

7.1 Chirality Transfer from Carbon to Copper(I)

The use of chiral (S)-3-aminopropane-1,2-diol as a sub-component allowed the preparation of complex 35 in

quantitative yield (Scheme 17).36 Both NMR spectrosco-py and circular dichroism indicated that the M-diastereo-mer was present in 20% excess when the synthesis wascarried out in dimethyl sulfoxide (DMSO). However,when complex 35 was synthesized in dichloromethane,the only observed product was the P-diastereomer.

We attributed this phenomenon to the ability of DMSO toact as a hydrogen bond acceptor, whereas dichlo-romethane cannot. In dichloromethane, the hydroxygroups appeared to be strongly associated with each other,making the structure more rigid and leading to efficientchiral induction. In contrast, DMSO would interact

Scheme 13 A complex self-sorting system

NH2

NH2

N

N

N

O

O

N

O

O

N

O

N

N

N

N

Cu+

22

N Cu+

Cu+ NN

N

N

NN

N

NCu+

N N

N

N

N

N

NCu+

N

N

N

NCu+

23

N

N

N

N

NCu

CuN

NCu

N

+

+

2425

8 CuI

8

8

2

4

2

N

DMSOMeCN

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

Scheme 14 Dynamic combinatorial library formed via equilibration between complex 26 and disulfide 27

S S

N

N

N

NCu

N

N

N

NCu

S S

2+

26

+S S

N

N

N

NCu

N

N

N

NCu

S

2+

27

29

S

OMe

OMe

S2 +

S

OMe

N

N

NCu

S

2+

28

OMe

S

OMe

2

27

S

OMe

OMe

S

S

MeO

N

S

SS

J V. E. Campbell, J. R. Nitschke ACCOUNT


strongly with the hydroxy groups of the complex, pullingthem out into the solvent medium. For a series of differentsolvents, a linear free energy relationship was uncovered

linking the solvent’s hydrogen bond acceptor strength tothe diastereomeric excess observed for the P-isomer.36

Scheme 15 Dynamic combinatorial library of iron(II) complexes incorporating both homo- and hetero-disulfides

230

+

S S

N

N

N

NFe

N

N

N

NFe

S

4+

31

27

3

33

S

OMe

S

N

N

N

N

N

N

Fe

SSS

N

N

N

N

N

N

Fe

SS

4+

2

S S

N

N

N

NFe

N

N

N

NFe

SS

4+

32

S

MeO

S

OMe

S

OMe MeOMeO

SS

S

N

N

N

N

N

N

Fe

SS

2+

2S

S

MeO

S

OMe

OMe

S +

27

2S

OMe

OMe

S +

27

S

OMe

OMe

S

Scheme 16 Transmetalation to convert 26 into 30, followed by the formation of mononuclear complex 17

S

N

S S

N

N

N

NCu

N

N

N

NCu

S S

N

N

N

N

N

Fe

SSS

N

N

N

N

N

N

Fe

SS

4+2+

26 30

MeCN

6 CuI

23

17

N

N

N

N

N

N

NFe

2+

NH2

NH2

N

NH2

S

S

NH2

H2N

2

SS

OMe

OMe

S

S

OMe

H2N

S

S

OMe

MeO

2

273

3

3

S

S

OMe

MeO3

+ 3

27

34

4 FeII

ACCOUNT Subcomponent Self-Assembly K


7.2 Chiral Resolution during Crystallization

When helicate 36 was synthesized using racemic 3-amino-propane-1,2-diol as a subcomponent, one could expect theformation of six diastereomeric pairs of enantiomers(Scheme 18). The NMR spectra of the solution were con-sistent with the presence of numerous diastereomers, andcould not have come from two or fewer diastereomers.

When helicate 36 was synthesized in methanol, X-rayquality crystals were observed to form from the reactionsolution. Single-crystal and powder diffraction datashowed the formation of only one enantiomeric pair ofdiastereomers of helicate 36, i.e. 4S-L and 4R-D. The oth-er diastereomers, capable of exchanging subcomponentamines, and thus forming a DCL of diastereomers, weretransformed into this single pair of enantiomers as theycrystallized out of solution. This system, thus, representsa novel example of complex chiral resolution during crys-tallization within a dynamic covalent6 system.30,56

8 Boron-Templated Self-Assembly

Another system we have investigated that extends theconcept of subcomponent self-assembly is based upon animinoboronate ester motif. Equimolar amounts of a diol,an amine, and 2-formylphenylboronic acid react via re-versible boron–oxygen and imine (C=N) bond formationto generate an iminoboronate ester (Scheme 19), as hasbeen reported by James et al.37 This reaction is inherentlymulticomponent in nature, uniting three distinct buildingblocks in a well-defined fashion: a diol subcomponent isheld at 90° to an amine subcomponent around a central,pseudo-tetrahedral boron atom.

Scheme 19 Self-assembly of an iminoboronate ester

8.1 Mononuclear Boron-Templated Structures

To investigate the scope and limitations of the iminobor-onate ester formation outlined in Scheme 19 in the contextof subcomponent self-assembly, we first prepared a seriesof mononuclear structures incorporating a variety of dif-ferent diol and amine subcomponents (Table 1).

Certain trends became clear from the data presented inTable 1. For example, more-electron-rich amines formedmore-stable iminoboronate esters, as did less-electron-rich diols, such as catechol.

Scheme 17 Synthesis of diastereomers of complex 35

NN

N

Cu+

OH

HO

N

NOH

HO

O

2

NH2

OHHO

CuI

N

N

Cu+

HO

OH

N

NHO

OHMeOH

35-(M) 35-(P)

Solvent de(P), %MeOD 0CD2Cl2 100DMSO –20

2

Scheme 18 Synthesis of a mixture of six diastereomers of helicate 36 (each has an enantiomer not shown), and the sorting of this mixture intoone diastereomer (shown with its enantiomer) during crystallization

N

N

2

4 H2NOH

OH

+/–

R

N

N

R

N

R

N

R

N N

N N

Cu

Cu

R

N

N

S

N

R

N

R

N N

N N

Cu

Cu

R

N

N

S

N

R

N

S

N N

N N

Cu

Cu

R

N

N

S

N

S

N

R

N N

N N

Cu

Cu

S

N

N

S

N

R

N

R

N N

N N

Cu

Cu

R

N

N

S

N

S

N

S

N N

N N

Cu

Cu

NCu+

Cu+N N

N

N

NN

N

HO

OH

HOOH OH

HO

HO

OH

HOOH

NN Cu+

Cu+ NN

N

N

N

OH

HOOH

HO

N

OHHO

36 (4S-Λ)

36 (4R-∆)

crystallization

MeOHO

O

2 CuI

O N

R

B

HO

HO

OO

NH2

R

BOHOH

L V. E. Campbell, J. R. Nitschke ACCOUNT


8.2 More Complex Structures

Having clarified the rules that govern iminoboronate esterformation, we went on to investigate how greater com-plexity might be created using this methodology. We rea-soned that the use of multitopic diol or aminesubcomponents, capable of bridging two or more boroncenters, could provide a route to more-complex structures.

We were able to synthesize such structures, e.g. macrocy-cle 37 (Scheme 20) and cage 38 (Scheme 21), by selectingsubcomponents with the correct geometries and connec-tion properties. The iminoboronate ester motif, thus,serves as an excellent structural motif for the creation ofnew architectures via subcomponent self-assembly.

Scheme 20 Synthesis of macrocycle 37

Scheme 21 Synthesis of cage 38

8.3 Subcomponent Substitution Reactions with-in Iminoboronate Ester Systems

Within structures containing copper(I)-templated imineligands, we have shown that electron-rich amines maydisplace electron-poor amine residues,28 as noted in Sec-tion 4.2. The same driving force may be harnessed forsubstitution within iminoboronate-containing structuresas shown in Scheme 22, allowing the clean transformationof one structure into another.

In addition to their dynamic covalent imine bonds, the la-bile boron–oxygen bonds of iminoboronate esters mayserve as points of reassembly as shown in Scheme 23. Adifferent set of selection rules is followed in this case,with the more-electron-poor diol being the favored sub-component for incorporation. Substitution carried out atthese bonds may occur independently of substitutions in-volving the imine bonds.

Table 1 Amines and Diols Investigated in the Iminoboronate-Forming Reactiona

Amine Diol

100%100%

92%92%

92%85%

100%100%

96%95%

91%88%

100%100%

99%98%

90%83%

100%100%

89%87%

88%82%

100%100%

84%80%

67%50%

100%100%

90%81%

80%72%

97%96%

77%75%

68%70%

93%93%

78%55%

57%50%

82%86%

– –

insoluble insoluble insoluble

100%100%

100%100%

100%100%




a Values given in bold denote yields for imine condensation, those in italic are for boronic ester formation.

OH

OH OH

OH

OH

OH

N NH2

O NH2

NH2

S NH2

I NH2

Cl NH2

NH2

O

EtO

NH2

O

O2N NH2

–O3S NH3+

ONH2

N+

NH3+ 2 Cl–

–O3SNH3

+

–HO3PNH3

+

O

B(OH)2

NH2

4

DMF

BNN

B

O O

O

BN N

B

O OO

O O

NH2

OH

OHHO

OH

37

2

2

B(OH)2

6

HO OH

OH

OHHO

HO

OO

OO

OO

NB

B

NB

O O

O O

OO

NB

B

NB

NH2

NH2

2

3

38

DMF

r.t.

O

ACCOUNT Subcomponent Self-Assembly M


9 Conclusions

Subcomponent self-assembly has proven to be a usefultool to rapidly build up complexity within synthetic archi-tectures.17,20 Systems of related structures may be pre-pared in parallel, and structures made by this method maybe induced to reassemble in well-defined ways using a va-riety of driving forces. Our efforts are currently focusedupon using this technique to create functional materials,such as metal-containing polymers, as well as molecularmachines9,10,57 wherein reversible rearrangement reac-tions may serve to move different parts of a larger struc-ture relative to one another.

Acknowledgment

This work is supported by the Walters-Kundert Trust, the ERA-Chemistry Network, and the Royal Society. We acknowledge ge-nerous past support from the Swiss National Science Foundation.

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Scheme 22 Amine substitution reactions within the iminoboronatemotif

N NH2

NH2

ONH2

N

B OO

O

N

B OO

N

B OO

NH2

N

Scheme 23 Diol substitution reactions within iminoboronate esters

HO

2 MeOH

OH

OH

OHHO

OH

HOOH

NN

BOO

N

B OO

N

BOO

B OO

OHHO

N V. E. Campbell, J. R. Nitschke ACCOUNT


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Complex Systems from Simple Building Blocks via Subcomponent Self-Assembly

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