Alfons
Baiker
Department of Chemistry and Applied Biosciences, Institute of Chemical and Biochemical Engineering, ETH-Zurich, Hönggerberg, CH-8093 Zurich, Switzerland. E-mail: baiker@chem.ethz.ch
First published on 17th July 2015
In view of the importance of optically pure chiral products there is ample reason to develop methods that facilitate their efficient production. Compared to the mostly applied homogeneous catalysts based on transition metals coordinated to suitable chiral ligands, heterogeneous chiral catalysts could offer several features that are beneficial for practical application such as stability, ease of catalyst separation and regeneration as well as straightforward access to continuous process operation. Various strategies have been developed for imparting chirality to catalytic active surfaces, among which the chiral modification of active metal surfaces by adsorption of suitable chiral organic compounds has so far been among the most successful. In this tutorial review lessons learned from research on asymmetric hydrogenation on chirally modified noble metals will be presented. Key aspects for the design of such catalysts will be elucidated using chirally modified platinum catalysts for the asymmetric hydrogenation of α-activated ketones as an example.
Key learning points(1) Understanding the behavior of catalytic systems based on chirally modified metals requires that all (n − 1)n/2 interactions between (n) reaction components are considered.(2) Basic requirements for an efficient chiral modifier are proper anchoring on the noble metal surface, efficient enantiodifferentiation and structural stability under reaction conditions. (3) Subtle changes of the structure of the anchoring moiety as well as of the stereogenic center(s) of the modifier strongly influence enantioselection. (4) A transient surface complex formed via hydrogen bonding(s) between chiral modifier and prochiral substrate is at the origin of enantiodifferentiation. (5) Interaction of solvent with chiral modifier or substrate can alter the sense of enantiodifferentiation. |
The crystal structure of catalytically active metals is highly symmetrical and thus achiral. Therefore, various strategies have been developed for imparting chirality to catalytic active metal surfaces.2 Among these approaches the chiral modification by adsorption of chiral organic compounds, which is the focus of this tutorial review, belongs to the most successful. The concept of chiral modification has been applied primarily to platinum group metals and Ni used for the asymmetric hydrogenation of CO and CC bonds. The knowledge accumulated in these fields has been covered in various comprehensive reviews.3–5
The aim of this tutorial review is to provide a guide for the development of catalytic systems for asymmetric hydrogenation based on chirally modified metals. For illustrating the crucial aspects that have to be considered in the design of this kind of catalysts we will chose the best understood catalytic system, namely the platinum-catalyzed asymmetric hydrogenation of activated ketones (Scheme 1).
Scheme 1 Asymmetric hydrogenation of α-activated ketones over chirally modified Pt-catalysts. Percentages given for different ketone substrates indicate highest achieved enantiomeric excesses ee. |
rR = kRθ(CD–ketone)RθH; rS = kSθ(CD–ketone)SθH; rrac = kracθketoneθH |
This indicates that the ratio of the coverages of pro-(R) and pro-(S) surface complexes, (θ(CD–ketone)R/θ(CD–ketone)S), is a very influential factor determining the sense of enantiodifferentiation. This ratio can be roughly estimated by theoretical calculations of the structure and stability of the intermediate surface complexes using the relation:
θ(CD–ketone)R/θ(CD-ketone)S = exp[−ΔΔG0/RT] |
As an example the complex formed in the hydrogenation of ketopantolactone (4,4-dimethyldihydrofuran-2,3-dione) on cinchonidine-modified Pt/Al2O3 is shown in Fig. 2. The theoretical calculations revealed some important features of the interaction of the ketone substrate with the cinchonidine-modified platinum. A surface complex is formed between the cinchona modifier and the reactant ketone via hydrogen bonding (N–H⋯O) between the quinuclidine N atom of the modifier and the oxygen atom of the keto carbonyl group. As a rough guide the structures of these complexes could be considered to resemble the structure of corresponding enantiodifferentiating transition states and thereby provide a helpful criterion for judging the potential of a chiral compound to act as a suitable modifier.6–9 Steric constraints can easily be inspected and energetic considerations allow identification of the more stable diastereomeric complex favoring one of the enantiomers. Limitations of this approach arise mainly from the fact that enantioselection is accompanied by small energetic differences of a few kJ mol−1 and accurate quantum chemical calculations of binding energies and structures of large complexes adsorbed on metal surfaces are still challenging. Furthermore, the assumption that enantiodifferentiation can be traced to different stability of the adsorbed diastereomeric surface complexes (thermodynamic control) needs to be proven and possible solvent influences complicate the theoretical prediction. Thus predictions for such complex systems are only reliable in conjunction with experimental verification of important boundary conditions (adsorption modes, conformations, solvent interaction etc.). Furthermore, note that minimum energy structures are compared whereas at the transition state, at least one of the degrees of freedom will be at a maximum and a choice has to be made as to the likely reaction pathway. Enantioselectivity is considered to come about by the different stability of the adsorbed diastereomeric modifier–substrate complexes, i.e. predictions of the sense of enantiodifferentiation will fail if kinetics of hydrogen addition are different for the diastereomeric pro-(R) and pro-(S) complexes affording the (R)- and (S)-products. Nevertheless, it is noteworthy that in spite of these critical points, the predictability of the sense of enantiodifferentiation by this approach seems to work reasonably in several cases.6–9
Fig. 2 Theoretically calculated intermediate enantiodifferentiating surface complexes (CD–ketopantolactone) of pro-(R) and pro-(S) cycles in the asymmetric hydrogenation of ketopantolactone over cinchonidine-modified Pt. The pro-(R) complex is favored by 2.2 kcal mol−1 which indicates an achievable ee > 90% to (R)-pantolactone if the reaction is thermodynamically controlled. Experimentally 94% ee to (R)-pantolactone are achieved (cf.Scheme 1). Adapted with permission from ref. 6. Copyright © 1997 Academic Press. |
Fig. 3 Structure sensitivity of the asymmetric hydrogenation of ketopantolactone over Pt nanoparticles of different shapes. Adapted with permission from ref. 13. Copyright, 2009 © American Chemical Society. |
Special attention has to be given to the pretreatment of the catalyst. Thermal pretreatment in hydrogen at ca. 400 °C (prereduction) proved to be essential with Pt-based catalysts to achieve optimal catalytic performance.12 The striking effect of reductive catalyst pretreatment was proposed to be due to cleaning of the surface from adsorbed impurities and/or change of size and shape of Pt particles. Another pretreatment, which enhances the catalytic performance, is ultrasonification of the prereduced catalyst in the presence of the chiral modifier, as demonstrated for the hydrogenation of ethyl pyruvate on cinchonidine-modified Pt/Al2O3 affording 97% ee.14
Beside the active noble metal, the support material has a crucial influence on the catalytic behavior. While originally almost exclusively carbon and sometimes alumina supports were used, later a variety of other supports, such as silica, titania, and zeolites were employed.3–5 Recently, the scope of supports has been extended by the application of carbon nanotubes (CNTs). The encapsulation of chirally modified Pt nanoparticles in CNT channels showed significantly enhanced activity and enantioselectivity in the asymmetric hydrogenation of α-ketoesters compared to similar catalysts where the Pt nanoparticles were deposited at the outside of the CNTs.15 The enhanced catalytic performance of the encapsulated Pt nanoparticles was attributed to enrichment of the chiral modifier and reactants inside the channels of the CNTs.
Studies on the effect of acidic and basic supports indicated that both chemo- as well as enantioselectivity could strongly be influenced by tuning the acid–base properties of the support. This was demonstrated by comparing the catalytic behavior of Pt/Al2O3, Pt/Al2O3–SiO2, and Pt/Al2O3–Cs2O in the enantioselective hydrogenations of ketopantolactone (Fig. 4) and methyl benzoylformate over cinchonidine-modified catalysts.16 The acidic or basic properties of the Pt/Al2O3 catalyst were varied by gradual introduction of SiO2 and Cs2O, respectively. The gradual change of the acid–base properties of the support allowed to vary systematically the metal–support interaction and thus the electronic properties of the Pt particles, which were characterized by the bridged to linear (B/L) ratio of chemisorbed CO. The enantioselectivity in the hydrogenation of the above substrates was found to be correlated to the acid–base properties of the catalyst reflected by the B/L ratio of chemisorbed CO. Highest enantioselectivity was observed with acidic catalysts showing low B/L ratio. This behavior indicates that the acid–base properties of the support are crucial for optimizing the enantio-selectivity of these catalytic systems.
Fig. 4 Effect of the acidity and basicity of the support on the asymmetric hydrogenation of ketopantolactone over cinchonidine-modified Pt/Al2O3 doped with SiO2 (top and middle) and Cs2O (bottom), respectively. Adapted with permission from ref. 16. Copyright © 2010 Elsevier Inc. |
Another property of the support affecting the catalytic performance is its pore structure, it influences the intraparticle diffusion of reactants, modifier and product.17 The pore size has to be adapted to the size of the chiral modifier otherwise noble metal particles in pores are not accessible to chiral modification and racemic hydrogenation may prevail. For the most frequently used chiral modifiers, cinchona alkaloids, this means that the pore size should be bigger than about 1–2 nm.
Originally almost exclusively natural cinchona alkaloids, cinchonidine (CD), cinchonine (CN) as well as quinidine (QD) and quinine (QN) (Scheme 2) were applied as chiral modifiers for the Pt-catalyzed asymmetric hydrogenation of activated ketones and these modifiers are still most frequently used. Cinchona alkaloids show considerable conformational flexibility due to their structure comprising two rigid moieties (quinoline and quinuclidine), which are separated by single carbon–carbon bonds. Several conformations have been identified by NMR and theoretical calculations,19 which can be classified in “open” and “closed” conformation, that means conformations where the nitrogen atom of the quinuclidine points away from or towards the aromatic quinoline ring, respectively. Fig. 5 shows the three most stable conformations of cinchonidine. The population density of these conformers is influenced by the surrounding medium (solvent), temperature and possible interaction with co-adsorbed species. The open conformation of cinchonidine has been proposed to be most suitable for the interaction with the ketone in the intermediate enantiodifferentiating modifier–ketone complex and the population of this conformation is favored in apolar and protic solvents.19
Fig. 5 Most stable conformers of cinchonidine and their experimental and theoretically calculated populations in solvents of different permittivity. Adapted with permission from ref. 19. Copyright, 1998 © American Chemical Society. |
Systematic studies of the influence of structural changes of cinchona alkaloids on their enantiodifferentiating behavior and the hydrogenation reaction rate revealed some important structural features of the cinchona alkaloids, which are responsible for their unique behavior as chiral modifiers in Pt- and Pd-catalyzed asymmetric hydrogenations.3–5,20 With few exceptions, modifiers derived from cinchonidine lead to an excess of (R)-products, whereas cinchonine derivatives preferentially lead to the (S)-enantiomer. Important structural elements in the cinchona molecule, which affect ee and hydrogenation rate of activated ketones are:20 (i) the aromatic quinoline moiety; (ii) the substitution pattern of the quinuclidine; and, (iii) the substituents at C9. Strongest effects on ee have changes in the O–C9–C8–N part of the cinchona alkaloid and the partial or total hydrogenation of the quinoline moiety. The absolute configuration at C8 seems to be most influential in controlling the absolute configuration of the major product enantiomer (exceptions are large substituents at C9). The nature of substituents in the quinuclidine part has comparatively minor influence, except alkylation of the quinuclidine nitrogen, which leads to complete loss of ee.17,20 The amine function of the quinuclidine plays a crucial role in the formation of the transient enantio-differentiating surface complex between chiral modifier and reactant ketone. This 1:1 complex is formed via hydrogen bonding between the quinuclidine N atom and the O atom of the carbonyl group of the ketone substrate (N–H⋯O), as previously proposed based on theoretical calculations6–8 and later evidenced by ATR-IR spectroscopy studies.21 Recent operando ATR-IR studies corroborated the importance of this transient surface complex for the mechanism of the asymmetric hydrogenation.22 Based on all these studies,3–5 the following conclusions can be drawn about the effect of the various structural parts of cinchona alkaloids on their enantiodifferentiating ability: the aromatic ring system (quinoline) is important for adsorption (anchoring) of the modifier on the noble metal surface, the stereogenic center comprising C8 and C9, and the amine function adjacent to the stereogenic center are essential for enantiodifferentiation.
Various models have been proposed for the 1:1 interaction between the cinchona modifier and α-ketoester.3–5 A common feature is the crucial role of the N–H⋯O bond. Based on STM studies under UHV conditions Mc Breen and coworkers proposed that additionally to the N–H⋯O interaction, two aromatic H bonds of the quinoline may interact with the ester carbonyl O atom, however, whether this additional binding modes are relevant under reaction conditions has not been verified yet.23 Until recently, it was assumed that the hydroxyl group at C9 of the cinchona alkaloid is not involved in the modifier–substrate interactions. However, a comparison of the efficiency of cinchonidine, cinchonine, and 9-epi-cinchonidine (or 8-epi-cinchonine) revealed that the configuration at C9 does affect ee and rate, indicating that in some cases it may be involved in the substrate–modifier interaction.24 The involvement of the C9–OH group in the diastereomeric complex between CD and ketopantolactone has recently been evidenced by ATR-IR combined with modulation excitation spectroscopy performed with C9–OH (CD) and C9–OCH3 (O-methyl-CD).25 Whether the C9–OH is also involved in the asymmetric hydrogenation of other activated ketones can hitherto not be answered.
The lessons learned from the studies of the influence of structural modification of cinchona alkaloids on their enantiodifferentiating ability have triggered the development of new synthetic modifiers. The knowledge about the structural requirements of the chiral modifier gained by the experiments with cinchona alkaloids and their derivatives has been used for a modular built-up of simpler modifiers based on enantiomerically pure 2-hydroxy-2-arylethylamines,26 2-(1-pyrolidinyl)-1-(1-naphthyl)ethanol,27,28 and 1-(1-naphtyl)ethylamine.29,30 Various derivatives of these compounds (Scheme 2) showed good enantiodifferentiation in the hydrogenation of some ketones, but generally not exceeding that of cinchona alkaloids. A common feature of all efficient synthetic modifiers is the aromatic moiety acting as anchoring unit. Recently the potential of chiral imidazolidinone and proline-derived surface modifiers has been explored, however these synthetic modifiers showed inferior performance compared to cinchona alkaloids.31
Finally it should be stressed that the optimal choice of the modifier is strongly dependent on the structure of the substrate and the solvent used. This specificity renders it difficult to provide a general rule for the choice of the most suitable modifier for a particular ketone.
Fig. 6 Conformational behavior of ethyl pyruvate in media of different permittivity and in the presence of a hydrogen donator. Adapted with permission from ref. 33. Copyright 2000 © Royal Society of Chemistry. |
Whether the conformational changes of the substrate induced by the solvent have a bearing on the structure of the enantiodifferentiating modifier–ketone complex is not clear yet and needs to be clarified.
At this point it should be stressed that there is a fundamental difference between the effect of acidic supports (see Section 2.2) and acid solvents. The support acidity affects the electronic state of Pt (metal–support interaction), which in turn influences the enantioselectivity and reaction rate. In contrast acid solvents, such as acetic acid and trifluoroacetic acid, protonate the basic N atoms of the cinchona alkaloid modifier and can form various linear or cyclic H-bonded complexes with the alkaloid and the ketone and these chemical changes in turn can influence the catalytic performance.34 An example, illustrating this difference is the enantioselective hydrogenation of ketopantolactone, where the acidic support improves the enantioselectivity, whereas the use of acetic acid as solvent diminishes it.35 The strong effect the solvent can have is particularly evident by examples of hydrogenations where the sense of enantiodifferentiation is switched if the solvent is changed. A striking example is the enantioselective hydrogenation of ethyl pyruvate on Pt modified with β-isocinchonine, an ether derivative with C8–C9 configuration identical to cinchonine. In acetic acid the expected (S)-ethyl lactate is the major enantiomer produced, whereas in toluene the sense of enantiodifferentiation changes to (R)-ethyl lactate.36
Finally, the solvent can also coadsorb on the surface and affect the surface coverages of reactants and modifier and thus the reaction kinetics.
Normally reactions are performed in the pressure range 0.1–2 MPa, but pressures up to 10 MPa have also been used. While for most substrates (e.g. α-ketoesters, α-ketolactons, cyclic imidoketones) operation of the reactor in the kinetic regime at high hydrogen partial pressure (resulting in higher surface coverage of hydrogen) proved to be favorable, low pressure and mass-transfer limited conditions were found advantageous for some trifluoromethyl ketones and α-ketoacetals.37
Catalyst reuse is an important issue particularly for industrial production in a batch reactor. Beside the common reasons for catalyst deactivation (poisoning by impurities, structural and chemical changes) there is an additional point, which has to be considered for keeping the original catalytic performance of chirally modified noble metals. In spite of strong adsorption, some loss by desorption of the chiral modifier during multiple recycles can occur which may lead to some decrease of enantiodifferentiation and/or activity. This loss of modifier and the accompanying decrease in catalytic performance can easily be compensated by addition of some additional modifier to the reaction solution. Immobilization of the modifier by grafting, tethering or encapsulation are possible strategies to avoid loss of modifier upon reuse of the catalyst. However, so far only encapsulation15 afforded catalysts with promising catalytic performance.
Other relevant side reactions arise from interactions of amino- and hydroxyl groups of the modifier with some commonly used solvents. The most prominent are base-catalyzed aldol type reactions of ketones with enhanced reactivity (acidity of α-hydrogen), as first observed in the hydrogenation of ethyl pyruvate over CD-modified Pt/alumina.
Depending on the solvent (aprotic or protic) the quinuclidine N atom can either act as a nucleophile or an electrophile. Modifiers with a primary amino group such as naphthylethylamine can react with the ketone substrate providing the corresponding hemiaminal. After elimination of water and subsequent hydrogenation of the intermediate imine a secondary amine can be formed, which then acts as the actual modifier (cf.Scheme 3). This reaction can be utilized for the modular built-up of a suitable chiral modifier starting from commercially available simple napthylethylamine as mentioned in Section 2.3. If the diastereoselectivity of the reduction of the imine intermediate is high, as in the case of the hydrogenation of ethyl pyruvate and other α-activated ketones over napthylethylamine-modified Pt, high enantioselectivity can be achieved in spite of the transformation of the original modifier. Tertiary amine modifiers such as the cinchona alkaloids cannot undergo similar reductive alkylation reactions. The intermediate possessing the quaternary N atom is unstable and the reaction reverts, except for some amino-aldehydes where the intramolecular nucleophilic attack leads to a cyclic ionic adduct.
A side reaction, which can bias the proper functioning of the noble metal catalyst is the destructive adsorption of alcohols (solvent) as well as reactant ketones. This degradation can lead to the formation of CO and strongly adsorbed CxHyOz fragments, which poison the catalyst surface. Destructive adsorption is suppressed in the presence of hydrogen, which implies that these compounds should only be brought in contact with the noble metal catalysts in the presence of hydrogen. Disregard of this rule can lead to poor catalytic performance and false interpretation of mechanistic studies.
Fig. 7 Top: Chemical structures of the cinchona-alkaloid modifiers; the main submolecular moieties, the absolute configurations at C8 and C9, and the torsional angles τ1 and τ2 are indicated. Bottom: Two views of a stable conformer of PhOCD adsorbed on platinum; in addition to τ and τ2, the two degrees of freedom associated with the phenyl ring, torsional angles τ3 and τ4, are also indicated; Pt gray, C orange, H white, N blue, O red; the carbon atoms of the quinuclidine (left) and of the phenyl moieties (right) have been darkened. Adapted with permission from ref. 38. Copyright 2007 © John Wiley and Sons. |
Fig. 8 Inversion of enantioselectivity through competitive adsorption of chiral modifiers. (A) Structure of cinchonidine (CD) and O-phenyl-cinchonidine (PhOCD) show similar absolute configuration at the stereogenic centers C8 and C9 but induce different enantiodifferentiation. (B) Nonlinear behavior of CD–PhOCD mixture due to higher strength of adsorption of CD. Adapted with permission from ref. 39. Copyright 2003 © Elsevier Ltd. |
An interesting aspect, which has received considerable attention is the use of modifier mixtures whose individual components give rise to opposite enantio-differentiation, that is opposite product enantiomers. Such mixtures can show significant nonlinearity in their enantiodifferentiating behavior, that means the stereochemical outcome of the reaction is not predictable based on the expected individual contributions of the modifiers and their concentrations. A representative example of such a nonlinear behavior is shown in Fig. 8B. The enantioselectivity in the hydrogenation of ketopantolactone on Pt/Al2O3 originally modified with PhOCD is switched by simply adding CD to the reaction solution. This is explained by the higher adsorption strength of CD compared to PhOCD, leading to successive replacement of the latter on the surface.40 In most cases the main reason for the nonlinear behavior is the different adsorption strength of the modifiers resulting in a significant enrichment of the modifier with higher adsorption strength on the surface and thus higher number of the correspondingly modified surface sites. However, a mutual interaction of the co-adsorbed modifiers and influence on their adsorption modes cannot be ruled out and may in some cases also contribute to the nonlinearity of the behavior of modifier mixtures. Note that this type of nonlinear effect distinguishes considerably from the nonlinear behavior observed in homogeneous catalysis, where it is traced to molecular interactions (associations) between two enantiomers of the auxiliary or ligand.
Fig. 10 Interactions which have to be considered in the design of catalytic systems based on modified noble metals. |
For a deeper understanding that helps in the design of these catalytic systems all interactions need to be considered. Depending on the complexity of the catalyst system, this task can be very demanding. In a first step we may therefore sort out interactions that are likely to be of little significance such as e.g. the adsorption of solvent on metal particles and support. For hydrogenation reactions the catalyst is typically a supported metal that means one has to consider the interaction of the different reaction components with the active metal as well as with the support material, except the latter is inert. For the type of reactions considered here the catalyst is typically Pt/Al2O3. In the following we focus on some important interactions occurring in this catalytic system.
Fig. 11 Adsorption modes of cinchonidine determined by ATR-IR spectroscopy. Adapted with permission from ref. 42. Copyright 2001© American Chemical Society. |
Time-lapsed scanning tunneling microscopy on Pt(111) surfaces at room temperature (normal reaction temperature) revealed that the adsorbed cinchona alkaloids possess considerable mobility, which increases with hydrogen pressure.44 Furthermore, interconversion between parallel and tilted adsorbed cinchona alkaloids was observed. The high mobility of adsorbed cinchona alkaloids may somewhat be suppressed in the liquid phase, where the asymmetric hydrogenations are normally carried out. Studies with modifiers where the anchoring group was varied indicated that extended aromatic ring systems such as quinoline, naphthalene or anthracene are suitable anchoring groups for chiral modifiers.20,26–30
The adsorption modes observed for a single component (substrate, modifier, product) may alter significantly depending on the conditions applied and information collected at conditions far from those governing during reaction, though valuable on its own, has to be interpreted with caution for understanding the surface processes occurring under reaction conditions. Consequently, adsorption studies of substrates or modifiers alone are not very conclusive for helping in the evaluation of optimal modifier–substrate pairs for enantioselective hydrogenation. What is needed are spectroscopic investigations of co-adsorbed modifier–substrate pairs under reaction conditions, which is however a demanding task and still barely found in the literature.
The adsorption of the alcohol products can also significantly affect the surface processes and thus the overall kinetics of the hydrogenation because it may block active sites or interact with the modifier in a way that its interaction with the reactant ketone is disturbed.48
Fig. 12 Origin of hydrogen in the N–H⋯O interaction between cinchonidine and ketone. Time domain ATR-IR spectra during hydrogenation and deuteration over cinchonidine-modified Pt and proposed H addition mechanism. Adapted with permission from ref. 22. Copyright 2014 © John Wiley and Sons. |
The influence of the configuration at the stereogenic centers at C8 and C9 positions of cinchona alkaloids on the stereochemical outcome of the asymmetric hydrogenations has been a matter of debate for a long time. The traditional, widely held notion was that the configuration at C8 is determining the stereochemical outcome, while that at C9 is less influential. However, this scenario has recently been questioned by comparative catalytic and theoretical studies of the action of cinchonidine (CD), cinchonine (CN), and 9-epi-cinchonidine (ECD) as chiral modifiers of supported Pt and Pd catalysts.24 The study revealed that in the hydrogenation of various activated ketones on Pt, a change in the absolute configuration at C9 did not affect the absolute configuration of the main product, however, the enantiomeric excesses were lowered by up to 30% and the reaction rate dropped by about an order of magnitude. In the Pd-catalyzed hydrogenation of different α-functionalized olefins, application of ECD – the C9 epimer of CD and C8 epimer of CN – led to a dramatic drop in enantioselectivity and reaction rate.24 This observation indicates that a subtle combination of both the C8 and C9 configurations is responsible for enantioselection on Pd. Furthermore calculations of the adsorption strength confirmed that the very low activity of ECD-modified noble metals cannot be related to the considerably different adsorption strength of ECD relative to CD or CN. The study indicated that for the hydrogenation of ketones on Pt both stereogenic centers are involved in the enantioselection. The Pd-catalyzed hydrogenation of olefins is even more demanding in the sense that only the right combination of the C8 and C9 configurations leads to effective chiral modifiers.24
The knowledge of the stability and structure of the adsorbed diastereomeric complex formed between substrate and modifier can give valuable information about the possible structure of the transition state and thus pave the way to a rationally guided design of new efficient chiral modifiers.8
Fig. 13 Schematic representation of three parallel reaction cycles occurring in the hydrogenation of trifluoroacetophenone (TFAP) in H2-saturated toluene on unmodified Pt Sites (red), CD-modified Pt sites (blue) and CD-modified Pt sites interfering with the product alcohol PTFE (violet) highlighting their dependence on liquid-phase concentrations and their contribution to enantioselection. Liquid-phase concentration of TFAP, product alcohol (P), CD, and H2 are indicated in square brackets and adsorbed species by θ. Equilibrium adsorption constants are indicated by K and hydrogenation rate constants by k. For the sake of simplicity only one of the enantioselective cycles is shown and the addition of hydrogenation on the surface is presented as one step. Adapted with permission from ref. 49. Copyright 2014 © American Chemical Society. |
In some cases the solvent or additive can even be part of the modifier–substrate complex forming a modifier–acid–ketone complex as demonstrated for hydrogenation of methyl-, ethyl- and isopropyl-4,4,4-trifluoroacetoacetate in the presence and absence of carboxylic acids (acetic acid, trifluoroacetic acid (TFA)).34 The involvement of the carboxylic acids in the enantiodifferentiating surface complex strongly altered the enantioselectivity and rate of the hydrogenations. More recently, the addition of small amounts of TFA in the asymmetric hydrogenation of trifluoroacetophenone over cinchonidine-modified Pt/Al2O3 was shown to strongly enhance the enantioselectivity. In order to elucidate the reason for this beneficial effect of TFA, the reaction system has been investigated by in situ ATR-IR combined with modulation excitation spectroscopy.50 Crucial molecular interactions between the chiral modifier (CD), acid additive (TFA) and the reactant trifluoroacetophenone at the catalyst surface were elucidated under reaction conditions. Evidence was provided that it is a monodentate acid–base adduct in which the carboxylate of TFA resides at the quinuclidine N-atom of CD. Two possible molecular structures of the enantiodifferentiating surface complex were proposed, which can explain the beneficial effect of TFA addition on enantioselectivity. These complexes are shown in Fig. 14. Note that the role of the acid in these complexes is different. In the complex “CD–TFA–ketone 1” TFA serves as a linker between the basic amine function of CD and the oxygen of the keto-carbonyl group, which provides a better fixation of the substrate on the surface and also facilitates a second interaction between the OH and the CF3 functions. In the complex “CD–TFA–ketone 2” the role of TFA is mainly the stabilization of the open conformation of the CD modifier thereby facilitating improved access to the C9–OH of CD.
Fig. 14 Enantiodifferentiating intermediate surface complexes between co-adsorbed ketone (TFAP) and chiral modifier CD in presence of a carboxylic acid (TFA). Conformation of adsorbed CD and N–H⋯O interaction between the quinuclidine N atom and the carbonyl group of the ketone adsorbed with its Re face allow for a second attractive interaction between OH and CF3. Adapted with permission from ref. 50. Copyright 2014 © John Wiley and Sons. |
Finally, it should be stressed that in the presence of carboxylic acids at least two different types of catalytic cycles may be operative: a cycle involving simply the modifier–ketone complex and cycles involving modifier–carboxylic acid–ketone complexes. Depending on the concentration of the carboxylic acid additive, the former or the later type of cycle may be predominant and control the enantioselectivity.
A key component of these catalytic systems is the chiral modifier. Cinchona alkaloids originally applied by Orito and coworkers, still are the most versatile chiral modifiers. Systematic studies of structural changes of cinchona alkaloids and their effect on rate and enantioselectivity have revealed important structural requirements of efficient modifiers. These are an aromatic moiety that anchors the modifier on the noble metal surface and a stereogenic region adjacent to an amine function, which forms a N–H⋯O hydrogen bond with the O atom of the keto carbonyl group of the substrate. The latter is crucial for the formation of an enantiodifferentiating surface complex between the substrate and chiral modifier. The knowledge of the structure–enantiodifferentiation relationship has triggered the search of various new synthetic modifiers that are more suitable for a synthetic modular built-up than cinchona alkaloids. However, the experience gathered so far indicates that it is difficult to compete with the efficiency and versatility of the classical cinchona alkaloids. Nevertheless, some of the synthetic modifiers indicate that a rational structural tailoring of chiral modifiers for a specific substrate may be possible if the molecular interactions of the different components of the catalytic system are better understood. An important step towards this aim is the application of in situ and operando spectroscopic techniques, which allow characterizing the catalytic system under working conditions.
An inherent problem in the design of catalytic systems based on chirally modified noble metals is their high specificity. Depending on the structure of the substrate and modifier as well as on the solvent used different interactions seem to control their functioning rendering it difficult to give general guidelines for the design of chiral modifiers for a specific substrate. Theoretical studies together with experimental validation tests may help in finding suitable modifier–substrate combinations. However, their rational design needs a broader research effort, which embraces fundamental studies on the reaction mechanism and knowledge of the various interactions occurring in these systems. Without this deeper fundamental understanding the search for new catalytic system will remain in the realm of empiricism. Another future challenge is the broadening of the scope of reactions, where the concept of chirally modified active surfaces can be applied. Efforts towards these aims could be rewarding considering the inherent technical advantages such heterogeneous catalytic systems could offer.
Finally, improvement of the stability of the chiral modification could lead to catalysts, which do not need any further modification when used in many repetitive applications. Recently, encapsulation of the modifier in carbon nanotubes15 has been demonstrated to have some potential to achieve this goal.
This journal is © The Royal Society of Chemistry 2015 |