Urea substituted phosporamidite ligand complex as a catalyst in allylic substitution reactions 4 april 2013 – 26 july 2013 HomKat – Homogenous and Supramolecular Catalysis Rosa Kromhout 10003493 Supervisors: Yasemin Gümrükçü Date: Prof. dr. Joost H. Reek 31 Januari 2014 Second reviewer: Dr. N.R. Shiju
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Urea substituted phosporamidite ligand complex as a catalyst in allylic substitution reactions
4 april 2013 – 26 july 2013 HomKat – Homogenous and Supramolecular Catalysis
Rosa Kromhout
10003493
Supervisors: Yasemin Gümrükçü Date: Prof. dr. Joost H. Reek 31 Januari 2014 Second reviewer: Dr. N.R. Shiju
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CONTENTS
CHAPTER PAGE
1 Abstract 3
2 Populaire samenvatting 4
3 Introduction 5
4 Goal of research 8
5 Results and discussion 9
6 Conclusion 17
7 Prospects / Further investigation 17
8 Experimental data 18
9 References 21
3
1 ABSTRACT
Transition metal-catalyzed nucleophilic allylic substitutions reactions are useful methods for carbon-
carbon and carbon-heteroatom bond formation. The direct substitution of allylic alcohols results in
only water as a byproduct and is a progress for the more atom economical and environmentally
friendly transformations. Recently, a phosphoramidite palladium complex is developed as a catalyst
for this type of reactions. It has been found that an addition of catalytic amount of urea during the
catalysis improves the activity. A possible explanation for this improvement was that the hydrogen
bond interaction between allylic alcohol and the catalytic amount of urea additive assists in the
activation of the alcohol. The leaving ability of the hydroxyl group is promoted, resulting in better
conversions when compared to catalysis without additional urea. This interesting discovery raises the
question what role urea plays when it is substituted in a ligand. For this research the goal is to
determine the effect is of urea substituted phosphoramidite ligand in catalysis of direct activation of
allylic alcohols.
The new phosphoramidite ligand with an urea substituent is successfully synthesized and analyzed
with spectroscopic techniques. A palladium catalyst that is formed with this ligand is tested for
amination reaction of cinnamyl alcohol with N-methylaniline. The same reaction was pursued for
kinetic studies. The results of the kinectic studies were compared with previous catalyst that was
using urea as an additive. Also commercially available monophos, that has no possibility to form any
type of hydrogen bond with the substrate, was tested for this reaction. Based on those results we
conclude that the new complex is only active at 80⁰C where others are at room temperature and a
catalytic additional amount of free urea still assists in the catalysis. Furthermore is discovered that
the chirality of ligands also plays a role in the activity, chiral ligands carry out the reaction with higher
conversions. The lack of a chiral center in the new ligand could be one of the reasons of low activity.
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2 POPULAIRE SAMENVATTING
De overgangsmetaal gekatalyseerde nucleofiele allylische substitutie reactie is een handige en
effectieve manier om koolstof-koolstof of koolstof-hetero atoom verbindingen te maken. Allylische
alcoholen kunnen zonder voorbewerking van de hydroxygroep gekatalyseerd worden. De grote
voordelen hiervan zijn is dat de stoichiometrische hoeveelheden afval van de voorbewerking wegvalt
en alleen licht milieu belastende water wordt geproduceerd als bijproduct. Onlangs is er een
fosforamidiet-paladiumcomplex gesynthetiseerd dat deze reactie kan katalyseren. Ontdekt is dat de
waterstofbruginteractie tussen de alcohol en additionele urea voor een betere conversie tijdens de
katalyse zorgt in vergelijking met katalyses zonder additionele urea. Een mogelijke verklaring is dat
deze waterstofbrug de vertrekmogelijkheid van de hydroxygroep bevorderd. Deze waarneming leidt
tot de vraag wat voor effect een urea heeft wanneer deze is ingevoegd in het ligand. Het doel van dit
onderzoek is onderzoeken wat de effecten zijn van een urea gesubstituteerd ligand in de directe
katalysse.
Het nieuwe ligand is succesvol gesynthetiseerd en geanalyseerd met spectroscopische technieken.
Met het palldiumcomplex zijn katalytische reacties tussen cinnamyl alcohol en N-methylaniline
uitgevoerd en de kinetiek van de reacties is bestudeerd. De verkregen resultaten zijn vergeleken met
de resultaten van afgelopen onderzoeken waarin urea is berbuikt als additief. Een monophos ligand,
dat geen waterstofbrug kan vormen met het substraat, is ook onderzocht. Uit de resultaten bleek dat
het nieuwe palladiumcomplax actiever is op 80⁰C, waar andere katalysotoren actief zijn op kamer
temperatuur en dat een additieve hoeveelheid urea nog steeds assisteert tijdens de katalytische
reactie. Daarnaast bleek chiraliteit van het ligand ook invloed te hebben op de activiteit van een
katalysator. Een katalysator dat chiraliteit bevat voert dezelfde reactie met hogere conversies uit. Het
urea gesubstitueerde ligand mist deze chiraliteit, wat een van de oorzaken kan zijn waardoor de
conversie lager is dan de eerder onderzochte liganden.
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3 INTRODUCTION
In the last century the modern pharmaceutical industries have made remarkable achievements in the
organic chemistry. However, most of the unveiled syntheses were developed without taking the
sustainability and waste ratio in consideration. The discovery of the ability of transition metal
complexes to lower the energy barrier of reactions has played a major part in the improvements. In
the last few decades many other improvements were made on the field of sustainability and atom
economy. Reactions which at first were unable to be performed under extreme reaction conditions,
can now be carried out at mild reaction conditions. Many reactions were reviewed again and with
the developments new catalytic pathways were discovered.
In this research we focused on the nucleophilic substitution reactions, that are used in formation of
carbon-carbon and carbon-heteroatom bonds.1 Using allylic alcohols for this reaction is interesting
for the cleaner process. However, the hydroxyl group has poor leaving abilities and it needs to be
activated in order to pursue the catalysis. One of the solutions is the substitution of allylic alcohols
with good leaving groups, such as halogens, esters or phosphates.2 The stoichiometric amounts of
waste was formed end of the reaction. The pre-activation step and the formation of stoichiometric
amounts of waste were the major disadvantages of this type of nucleophilic reaction. (Figure 1)
Figure 1: Two reaction paths for the nucleophilic allylic substitution reaction. The upper reaction pathway requires the
pre-activation step of the alcohol, afterwards the nucleophilic attack takes place. The lower reaction pathway describes the direct activation of allylic alcohol, were water is the only side product.
However, the nucleophilic substitution reaction can be a very promising reaction when the allylic
alcohol is directly used in catalysis without pre-activation.3 This will eliminate the stoichiometric
amounts of waste and water is the only side product. Water has a lower hazard quotient (Q) than
halides and phosphates, which makes it a more environment friendly waste product.4 The hazard
quotient indicates quantitatively what is the impact of the type of compound on the environment.
Absolute Q-values are difficult to assign, because the effects of waste differ according to location and
type. Also, with the direct catalysis the E-factor, kg of waste over kg of produced product, is lower
than the reactions with the pre-activation step. By multiplying Q and the E-factor a better measure is
given of the impact on the environment than these factors alone. The EQ of water as a sole waste
product is significantly lower compared to the EQ-value of the stoichiometric amounts of waste.
Researchers have performed the direct amination of allylic alcohols with various transition metal
catalysts. Ruthenium, Iridium and platinum catalysts were developed by various research groups.5, 7
Though, palladium is the most used transition metal used in allylic amination substitution reactions.
Since 1964 various palladium complexes were reported, these complexes often contained small
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ligands which had no particular participation in the selectivity of the substitution.6 To increase the
selectivity, and also the activity, additional additives were added. Researchers have reported organic
additives, such as CO2 gasses under high pressure, and inorganic additives, such as transition metal
oxides.7 These additives were added in catalytic or stoichiometric amounts to activate the C-O bond
and promote the leaving ability of the hydroxyl group.
Unfortunately these additives make the entire substitution reaction less atom economical. However,
in the last decade, several palladium catalyst were reported which perform the allylic substitution
reaction without any additives. Mono- or bidentate phosphine ligands were used in the catalysis of
amination of allylic alcohols. The research groups of Le Floch8 and Breit9 have studied a range of
palladium complexes for the amination of different types of allylic alcohols. These catalysts can
activate the allylic alcohol directly and that increases the atom economy. Therefore, palladium based
catalyst are of interest in this study.
The catalysts studied by Le Floch and Breit often involved, next to the ligands, a η3-π-allyl compound,
which structure is very similar to allylic alcohols. During the catalysis the η3-π-allyl compound gets
replaced by the allylic alcohol. The catalyst promotes the hydroxyl group leaving ability of the
substrate and a nucleophile will be able to attack. An attack of the nucleophile can result in two
isomeric products, one linear product and one branched product, and the sole byproduct, water.
(Figure 2)
Figure 2: a. Palladium metal complex b. Reaction scheme of nucleophilic allylic substitution reaction with intermediate
Remarkable, ligands that contain phosphor, sulfur or nitrogen have the most influence on the
conversion in the substitution reactions. Most likely this is caused by their property to donate
electrons into the orbitals of the transition metals. The high electron density on the metal is probably
needed for the stabilization of the substrate-catalyst intermediate. When a free allyl coordinates
with the catalyst there forms a sigma donation from the π system at the allyl to the pz orbital metal
or other suitable orbitals.10 (Figure 3) This is the lowest π orbital energy level, the next orbital is a
non-bonding orbital. Depending to the electron distribution the allyl will act as a donor or acceptor,
mostly this is a filled donor orbital. The suitable orbitals of the metal are py and dyz orbitals. The last
and highest orbital acts as a acceptor for the π-back donation from the dxz op px orbital of the metal.
If a substrate coordinates the electron distribution will likely be different such that the non-bonding
is not a donor but an acceptor. The hydroxyl group on the substrate is an electron withdrawing
group, causing an empty non-bonding orbital. The electron density on the metal is increased by the
electron donating ligands and probably donates electrons into the non-bonding orbital of the allyl.
These electron exchanges cause the coordination and stabilization of the catalyst-substrate
complexes. With various ligands various electronic properties can be obtained.
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Figure 3: Coordination of η3-allyl compound and a metal by sigma donation and π-back donation.10
In previous studies various ligands were screened for their selectivity in amination reactions as
shown in figure 2b. The used reaction during the screening is the allylic amination reaction of
cinnamyl alcohol and N-methylaniline. (Figure 4) Discovered was that phosophoramidite ligands have
great selectivity towards the linear product. The best performing phosphoramidite (1) contained an
amino acid attached to the backbone. (Figure 5)
Figure 4: Amination reaction with cinnamyl alcohol and N-methylaniline
Figure 5: a. Ligand 1 with descriptions of the backbone and amino acid section b. Complex structure of a 2:1 ligand: palladium ratio.
During the same screening process also is discovered that an addition of a catalytic amount of urea
improves the activity of the catalyst in amination of allylic alcohols. Most likely it is the effect of
hydrogen bond formation between the hydroxyl group and the urea. This bond formation is helping
to activate the C-O bond and promoting the leaving ability. (Figure 6) However, the addition of urea
makes the overall substitution reaction less atom economical. Therefore, it is interesting to
investigate whether the urea substituted ligand has any effect on the selectivity and activity of the
catalyst which is applied for the substitution reaction. The main idea was that the inserted urea to
the phosphoramidite ligand will increase the selectivity compared to ligands without urea inserted. In
this case the urea substituent might be closer to the hydroxyl group and therefore this ligand might
help to increase the activity of the catalyst compared to non-substituted phosphotamidite ligands.
Figure 6: Transition state with hydrogen interaction between cinnamyl alcohol and urea
8
First, we prepared a new urea substituted phosphoramitide ligand and analyzed its structure with
analytical spectroscopic measurements. Then the palladium complex of this ligand is prepared with
(Pd-allyl(COD))BF4 precursor. Kinetic studies were performed in presence and absence of additional
free urea to determine whether the free urea effects the results of the catalysis.
4 GOAL OF RESEARCH
The goal is to determine the influence of urea substituted phosphoramidite ligand complexes in the
allylic nucleophilic substitution reaction of cinnamyl alcohol and N-methylaniline and compare the
results to earlier studied ligands.
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5 RESULTS AND DISCUSSION
Ligand synthesis
The synthesis of urea substituted ligand, 2, was completed in three steps.
Figure 7: Ligand 2
First the backbone of the ligand is synthesized. This diol is synthesized with a commercial available
alcohol, 3-tert-butyl-4-hydroxyanisole, potassium ferricyanide (K3Fe(CN)6) and KOH. (Figure 8)
Figure 8: Reaction scheme of the synthesis of the diol backbone
The urea part of the ligand was synthesized separately with the straight formed reaction of
commercial available ethylenediamine and phenyl isocyanate. (Figure 9)
Figure 9: Reaction scheme of the synthesis of the urea amine
The P-Cl backbone of 2 was synthesized with the diol and PCl3. The addition of urea amine resulted in
the phosphoramidite ligand (2) successfully.
Figure 10: Reaction scheme of the synthesis of ligand 2
The characterization of ligand 2 was done by 1H-NMR is reported here for the first time. The peaks
are assigned to the corresponding protons with the help of 2D-cosy experiments.
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Figure 11: Ligand 2
Figure 12: 1H-NMR spectrum of the ligand 2
Table 1: Data set of 1H NMR (300 MHz, CD2Cl2) from ligand 2