Chiral Modification of Solid Surfaces: A Molecular View - The Journal

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J. Phys. Chem. C 2008, 112, 16196–16203

CENTENNIAL FEATURE ARTICLE Chiral Modification of Solid Surfaces: A Molecular View† Francisco Zaera* Department of Chemistry, UniVersity of California, RiVerside, California 92521 ReceiVed: May 23, 2008; ReVised Manuscript ReceiVed: August 6, 2008

Modification of solid surfaces using chiral agents is perhaps the most promising avenue for bestowing chirality onto heterogeneous catalysts, and with that developing cheap and clean processes for the synthesis of enantiopure compounds. Unfortunately, in spite of the ample interest in the pharmaceutical, agro, and finechemical industries, no viable chiral heterogeneous catalysts have been identified yet for use in practical applications. Chiral modification of surfaces has proven to depend in complex ways on a large number of parameters, a fact that makes the empirical development of enantioselective heterogeneous catalysts nearly impossible; a more comprehensive approach is needed to better navigate through such a multivariable field. To address this problem, several surface-science groups have recently focused on developing the basic molecular-level understanding of the chemistry involved. Here we present a brief state-of-the-art report of this research area, with emphasis on the advances made by our own group. 1. Introduction The concept of chirality in chemistry has a long history, going back to the realization by Louis Pasteur in 1848 that the crystals of sodium ammonium tartrate tetrahydrate exist in two distinguishable mirror forms.1 He noted that although most of the physical and chemical properties of both types of crystals are identical, they each give rise to light rotation in opposite (D, or dextrorotatory, from the Latin dexter, meaning right, and L, or levorotatory, from the Latin laeVus, meaning left) directions. Thanks to Pasteur’s observation, a molecular explanation for the optical activity of certain substances, as already reported by Jean-Baptiste Biot in 1812,2 was possible. Indeed, the existence of the two types of crystal was soon connected to the two possible ways of arranging four different substituents around a given tetrahedral carbon atom (R for rectus (right), and S for sinister (left)),3,4 and christened chirality by Lord Kelvin in 1904.5 The biological implications of the existence of two chiral forms of many organic compounds, what we now call enantiomers, became evident soon thereafter, when additional research by Pasteur revealed that tartaric acid from only one of his two types of crystals could be fed successfully to micro-organisms. He also recognized the tendency of living systems not to produce racemic (50:50) but rather enantiomerically pure (100:0) mixtures. This chiral preference is prevalent in biology, and manifests itself in many ways. Natural (L)-asparagine, for instance, is bitter, whereas artificial (D)-asparagine is sweet; (D)-limonene smells like oranges, but (L)-limonene has a piney, turpentine-like odor. † This year marks the Centennial of the American Chemical Society’s Division of Physical Chemistry. To celebrate and to highlight the field of physical chemistry from both historical and future perspectives, The Journal of Physical Chemistry is publishing a special series of Centennial Feature Articles. These articles are invited contributions from current and former officers and members of the Physical Chemistry Division Executive Committee and from J. Phys. Chem. Senior Editors. * E-mail: [email protected].

The origin of this enantiopreference in living organisms is still a matter of debate (and may have involved some chiral surface chemistry).6 What is clear is that it requires an enantioselective approach to the design of pharmaceuticals and agroproducts. This fact became evident in the fifties and sixties with the introduction of Thalidomide to control morning sickness in pregnant women.7 It was later found that while the (R) enantiomer of this molecule exhibits the desired therapeutic effects, the (S) counterpart causes severe birth defects; there were tens of thousands of reported cases of fetal malformations before the drug was retired from the market. Other examples of the importance of enantiopurity in drug manufacturing include Ethambutol, one enantiomer of which is used to treat tuberculosis (the other causes blindness), and Naproxen, one enantioisomer of which is used to treat arthritis pain (the other causes liver poisoning). At present, the business of making and marketing single enantiomers amounts to over $160 billion, accounts for close to half of the profits in sales of medicines worldwide, and includes such blockbusters as Lipitor, Zocor, Plavix, and Nexium.8,9 In 2006, 80% of the small-molecule drugs approved by the U.S. Food and Drug Administration were chiral, and 75% were single enantiomers.10 There are a number of procedures available for the manufacturing of enantiopure chemicals, including reactions with other chiral compounds10,11 and chromatographic separations of racemic mixtures.12,13 Among these, enantioselective catalysis is perhaps the more promising approach, because there stereochemistry is controlled by a small amount of catalyst, so the resulting processes can be quite cost-effective and environmentally friendly.14 At present homogeneous enantioselective catalysts, typically chiral metal complexes, are the most versatile for this application.15,16 Nevertheless, those bring about a number of problems related to the need for separation and recycling steps. It would be advantageous to use heterogeneous enantioselective catalysts instead. Unfortunately, the field of heterogeneous chiral catalysis has yet to rise to this challenge.

10.1021/jp804588v CCC: $40.75  2008 American Chemical Society Published on Web 09/27/2008

Centennial Feature Article Francisco Zaera is a Professor of Chemistry at the University of California, Riverside. He received his Licenciate degree in Chemistry in 1979 from the Simón Bolívar University in Caracas, Venezuela. After working there as a lecturer for another year, he recived his Ph.D. degree in Chemistry from the University of California, Berkeley in 1984. He then worked as an Assistant Chemist at the Brookhaven National Laboratory National Synchrotron Light Source, in a joint appointment with Exxon Research Laboratories, and moved to his present position in 1986. His research interests are in the areas of surface and materials chemistry and heterogenous catalysis, with particular emphasis on surface reaction kinetics and in-situ spectroscopic characterization of surface intermediates. Prof. Zaera has been awarded the 1994 and 1995 Union Carbide Innovation Recognition Program Award, the 2001 ACS George A. Olah Award in Hydrocarbon or Petroleum Chemistry, the 2003 Paul H. Emmett Award of the North American Catalysis Society, a 2004 Humboldt Research Award for Senior U.S. Scientist, and the 2008 ACS Arthur W. Adamson Award for Distinguished Service in the Advancement of Surface Chemistry. He is a Fellow of the American Vacuum Society and of the American Association for the Advancement of Science. He has held several editorial positions, including his present post as Senior Editor of The Journal of Physical Chemistry, and has organized 18 international conferences and symposia. He has also held several professional offices, including those of Treasurer (1997, 1998), Vice Chair (2005), Chair-Elect (2006) and Chair (2007) of the Colloids and Surface Chemistry Division of the American Chemical Society, and Treasurer-Secretary and President of the California Catalysis Society (19901992). Prof. Zaera has close to 250 publications in scientific journals, has presented over 150 invited talks, and has trained 14 graduate students, 30 postdocs, and 20 visiting scientists. More information about Prof. Zaera can be found at his web site, http://chem.ucr.edu/Zaera/lab.html.

Historically, the first attempts to carry out heterogeneous chiral catalysis involved the deposition of a catalytically active metal or metal oxide onto a chiral support such as quartz, cellulose, silk, or synthetic chiral polymers. However, none of those led to processes with acceptable enantioselectivities.17-19 Other ideas have included the anchoring of homogeneous catalysts on high-surface-area supports20,21 and the use of intrinsically chiral surfaces,22,23 but, again, those have not yet led to any successful examples of enantioselective catalysis. The most promising route so far has been the addition of a small amount of a chiral molecule (a chiral modifier) to the reaction mixture to bestow enantioselectivity on more traditional catalysts. This chiral modification approach has indeed proven successful in a pair of families of reactions, the hydrogenation of β-ketoesters on nickel catalysts modified by tartaric acid,24-26 and the hydrogenation of R-ketoesters on platinum-group metals modified by cinchona alkaloids.19,27-30 Unfortunately, neither family is of great use in practical applications. Moreover, because of the complexity of the known systems, their extension to other reactants or other catalysts has been limited; the successful cases are quite sensitive to changes in reactants, catalyst, modifier, solvent and/or reaction conditions in ways that are difficult to predict. A molecular-level understanding of how the chiral modification of catalytic surfaces occurs is needed to further advance this field and to be able to design new chiral catalytic processes from first principles. Acquisition of that knowledge has proven difficult, however, at least in part because mechanistic studies with chiral transition-metal complexes, enzymes, and other simpler models have only provided limited help. Fortunately, there has been an increased interest in the surface-science community recently to tackle this issue.19,31-35 We in particular have been working on the development of a fundamental understanding of the surface chemistry associated with chiral surface modification. In this article we provide a brief overview of the main conclusions reached from that research so far. 2. Chiral Templates on Surfaces Studies on the mechanism by which chiral modifiers bestow enantioselectivity on catalytic surfaces have led to the proposal

J. Phys. Chem. C, Vol. 112, No. 42, 2008 16197 of two distinct models. On the one hand, the suggestion has been made that perhaps the modifier adsorbs in a nonclosepacked but ordered arrangement that leaves uncovered chiral sites on the surface available for adsorption of the reactant.26,36 On the other, it may be possible for each individual modifier molecule to create a chiral environment for the reactant by itself, without the need of any ordering on the surface,37-40 in a way similar to that seen in homogeneous chiral systems.41 In thermodynamic terms, this dichotomy can crudely be expressed in terms of entropy versus enthalpy factors being dominant in the chiral modification process. We have been testing the validity of both hypotheses using a number of specific adsorption systems, and start below with a discussion of the first, “templating,” model. The idea of surface ordering within the adsorbed modifiers as a way to produce chiral sites in heterogeneous catalysts was initially proposed by Wells and co-workers to explain the catalytic behavior of cinchona-modified platinum.42 Their explanation was discredited soon thereafter because no ordering was ever observed with any cinchona alkaloids or related compounds adsorbed on platinum surfaces.31,43,44 However, it was later recognized that analogous models may still be able to explain the chiral modification induced by simpler molecules.26 This idea is certainly supported by reports from extensive surface-science and quantum-mechanical studies on the adsorption of enantiopure tartaric acid on Cu(110) singlecrystal surfaces, which clearly indicate the formation of extended supramolecular assemblies with lower symmetry than the underlying surface and the formation of chiral channels of exposed bare metal atoms.45-47 Analogous ordered surface structures have also been reported with a few aminoacids as well.48,49 Unfortunately, long-range order can not be achieved as easily on the more catalytically relevant nickel metal.50 On the other hand, comparable levels of complexity have been seen in the adsorption of tartaric acid on nickel versus copper surfaces, and there is some indication that ordered tartrate layers may form on Ni(111).51 The reported observations have been used to suggest that even if long-range surface ordering of the chiral modifier (the tartaric acid in these systems) does not occur, a chiral imprint may be obtained locally by bonding to the surface via two or more points within each molecule.26,36 Also, longrange order may not be required for the modifier alone, and may be cooperatively induced by interactions between the adsorbed tartrate and beta ketoester species.52 Inspired by the pioneering experiments of Tysoe et al.,53,54 we decided to test these possibilities indirectly, by probing the chemical effect that chiral modifier layers adsorbed on platinum have on the further adsorption of a second chiral reactant. The conceptual idea behind our experiments is illustrated schematically in Figure 1. The suggestion in this example is that Pt(111) surfaces covered with overlayers of (S)- and (R)-2-butoxide chiral modifying moieties display different behavior toward the adsorption of enantiopure (S)- (or (R)-) propylene oxide probing adsorbates. This is indeed confirmed by the experimental results. Figure 2 reports key temperature programmed desorption (TPD) and reflection absorption infrared spectroscopy (RAIRS) data indicating an enantiopreference for adsorption of the probe molecule (propylene oxide) on Pt(111) surfaces chirally modified with 2-butoxide moieties of the same chirality.55 Specifically, it is seen that the surface modified with (S)-butoxide moieties ((S)ButO), prepared via thermal activation of adsorbed (S)-butanol ((S)-ButOH), is capable of adsorbing approximately 35% more (S)-propylene oxide ((S)-ProO) than an identical surface modi-

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Figure 1. Schematic illustration of the chiral-site titration procedure reported in the text. In this example a Pt(111) single-crystal surface is first chirally modified by adsorbing a well-defined submonolayer of either (S)- (left) or (R)- (right) 2-butoxide ((S)- or (R)-2-ButO, prepared via thermal activation of the corresponding 2-butanols, 2-ButOH). That surface is then exposed to (S)-propylene oxide ((S)-ProO) to saturate the chiral sites formed. A comparative quantitative measurement of the uptake of the ProO probe molecule on both surfaces, by temperature programmed desorption (TPD) or by reflection absorption infrared spectroscopy (RAIRS), is used to evaluate the extent of the enantioselectivity bestowed on the surface by the chiral modification.

Figure 2. Propylene oxide TPD (58 amu, left) and RAIRS (right) data from titration experiments of Pt(111) surfaces chirally modified with 2-butoxide layers using enantiopure propylene oxide.55 Chiral 2-ButO layers were first prepared by dosing 0.4 L of either (R)- or (S)-2-ButOH on Pt(111) at 170 K, and the surface then saturated with 2.0 L of either (S)- (in the TPD experiments) or (R)- (in RAIRS) ProO at 100 K, The differences in ProO TPD yield and RAIRS signal intensity for the 822 cm-1 peak (due to the ring deformation of the ProO directly adsorbed on the platinum surface) clearly indicate some enantioselectivity in the adsorption on these chirally modified surfaces.

fied with the (R)-ButO enantiomer. Similarly, the (R)-modified surface displays a peak for the ring deformation vibrational mode of adsorbed (R)-ProO approximately three times as intense as that seen on the (S)-modified surface. This latter result is not as straightforward to quantify because it reflects changes in both coverage and adsorption geometry, but does point to the same general conclusion: that chirally modified surfaces show a preference for the uptake of one enantiomer of the probe molecule over the other. It should also be noted that no significant intermolecular interactions between the 2-butoxide and propylene oxide adsorbates could be identified in this case by the RAIRS data. The effect described above has proven fairly general, having been observed with 2-butanol53,56 and 2-amino butanoic acid53 on Pd(111), and with 2-butanol55 and 2-methyl butanoic aci57 on Pt(111). On the other hand, no chiral effect was detected in studies with 2-methyl butanoic acid on Pd(111);53 it seems that

Zaera

Figure 3. Propylene oxide TPD titration data for a Pt(111) surface chirally modified with (S)-2-methyl butanoate.57 The left panel displays raw TPD traces for selected coverages of (S)-2MBA to illustrate the different peak shapes obtained with (S)- vs (R)-ProO, while the right panel summarizes the key data from those experiments in the form of peak temperature maxima and ProO yields as a function of (S)-2MBA initial exposure. Enantioselectivity at intermediate (S)-2MBA coverages is manifested both by higher yields and by higher desorption temperatures for the (S)-ProO enantiomer. For reference, 2MBA monolayer saturation on clean Pt(111) occurs after exposures of about 3.0 L.

the nature of the surface is one of the key parameter that defines this enantioselectivity. Enantiospecificity in adsorption has also been identified on Pd(111) surfaces modified with a number of aminoacids.58 Complementing these studies, Monte Carlo simulations have shown how the experimental results are consistent with a surface templating model, and also with the requirement of multiple adsorption points for the chiral modification.59 The coverage dependence of the chiral effect being discussed here, which shows optimum behavior at coverages of the modifier somewhere between one and two-thirds of saturation, is also explained by these simulations,60 and has become one of the central arguments in support of the chiral supramolecular surface templating explanation. Our study of surface templating with 2-methyl butanoic acid (2MBA) on Pt(111) revealed additional subtleties in these systems.57 Like in the other cases, a significant change in the uptake of the chiral probe was observed when switching from homochiral to heterochiral modifier-probe pairs, with a maximum in enantioselectivity taking place at intermediate coverages (Figure 3). In addition, though, it was seen that the shape of the traces for the thermal desorption of the propylene oxide is also different in the two cases (Figure 3). This points to a level of interaction between the two molecules on the surface, stronger in the case of the homochiral pair (the (S)-2MBA/(S)-ProO combination in the example of Figure 3). A clear split in the TPD trace is observed even at coverages below those where the difference in yields is observed, suggesting that adsorption of propylene oxide at a site adjacent to a 2-methyl butanoic acid moiety involves different energetics than on the clean Pt(111). Perhaps not only entropic but also energetic factors contribute to the enantioselectivity seen in this system. A more pronounced effect has been recently seen by us when using 1-(1-naphthyl)ethylamine (NEA) as the surface modifier.61 Indeed, ProO TPD titrations of NEA-modified Pt(111) surfaces point again to a relative enhancement in the adsorption of one enantiomer over the other at intermediate coverages (Figure 4),

Centennial Feature Article

Figure 4. Propylene oxide TPD titration data for a Pt(111) surface chirally modified with (S)-1-(1-naphthyl)ethylamine.57 The main panel displays raw TPD traces for the titration of 1.0 L of (S)-NEA with either (S)- or (R)-ProO to highlight the existence of two desorption states for the ProO, at ∼185 and 210 K with the (S) enantiomer and at 180 and 205 K with the (R) counterpart. The insets display the yield ratios obtained with the (S)-ProO vs (R)-ProO enantiomers (SS/SR) for each of the TPD peaks as a function of initial NEA exposure. A significant enantioselectivity is seen here, as in the other cases, but mainly in the high-temperature state.

the behavior expected from the templating mechanism. In this case the overall ProO adsorption yield ratio between homochiral versus heterochiral modifier-probe pairs reaches a value of approximately 2.2, and occurs at NEA coverages between half and two-thirds of monolayer saturation. In addition, though, two clearly separated molecular desorption states are evident in these data, at ∼180-185 and 205-210 K, respectively. It is interesting to note that with NEA not only the split between the two states is quite clear, with the high-temperature ProO desorption state appearing at temperatures roughly 25 K higher than those of the regular monolayer peak, but also a small but consistent difference in the peak temperatures of all the desorption peaks between the experiments with (S)- vs (R)-ProO is evident: the former always desorbs at ∼5 K higher temperatures with (S)NEA (and at lower temperatures with (R)-NEA) than the latter. Two more conclusions were derived from the studies with NEA: (1) the enantioselectivity is mostly seen in the hightemperature ProO desorption peak, which reaches an enantioselectivity ratio of more than a factor of 4 (Figure 4), and (2) with the homochiral pair the ProO yield increases in absolute terms in the intermediate range where the enantioselectivity is observed. The first observation strongly suggests that this enantioselectivity is associated, at least in part, with a strong individual modifier-probe interaction, and the second that there may be a synergy by which the uptake of the probe induces a rearrangement of the modifier on the surface to open more adsorption sites. 3. Chiral Modification via Complex Formation This brings us to the discussion of the other model put forward to explain these chiral modifications of solid surfaces, that of a direct one-to-one interaction between individual chiral modifier molecules and the reactant. This second model has been mostly associated with the ability of larger molecules, cinchona alkaloids in particular, to promote chiral hydrogenations on platinum and palladium catalysts. Cinchona alkaloids have in

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Figure 5. Schematic representation of a cinchona alkaloid adsorbed on a platinum surface and interacting with a carbonyl-containing reactant. This structural depiction highlights the three main functionalities believed to define their performance as chiral promoters in catalysis: (1) a quinoline aromatic ring, believed to help anchor the modifier to the surface, (2) a quinuclidine tertiary amine ring, capable of interacting with the reactant via the electron lone pair of the nitrogen atom, and (3) a chiral alcohol linker that creates a chiral pocket for the reactant and helps favor the preferential hydrogenation of one of the two sides of the carbonyl plane. Free rotation around the C-C bonds in the alcohol linker create a dynamic environment around the reaction site that can be influenced not only by the solvent used and the presence of solid surfaces, but also by the nature of the peripheral R1 and R2 groups within these molecules. For cinchonidine, R1 ) H and R2 ) CHdCH2.

fact also found many chiral applications in homogeneous catalysis,62,63 so they clearly possess all the molecular features required for the promotion of enantioselectivity in catalysis. Three key functionalities have been identified in cinchona alkaloid molecules (Figure 5):19 (1) an aromatic ring, which in heterogeneous catalysis with metals appears to help with the adsorption of the modifier on the surface, (2) an amine group, with a basic nitrogen atom capable of binding to acidic centers in the reactant, and (3) a chiral linker to define the chiral pocket between the aromatic and amine moieties that promotes enantioselectivity. Note that simpler versions of all these three functionalities are already present in the NEA modifier discussed in the previous section. In fact, NEA has also been shown to impart chirality to R-ketoester hydrogenation catalysts, albeit with lower enantioselectivity than cinchona alkaloids.64,65 It appears that these may be the ingredients required for the energetics of reactant-modifier interactions to play a relevant role in chiral modification in catalysis. On the other hand, it is also apparent that even small changes in any of those functionalities may lead to vastly different performances in chiral modification of catalysts. The details of how this happens are still not fully understood. Our work in this area has centered around the characterization of the adsorption of cinchona alkaloids from solution onto platinum surfaces in situ using infrared spectroscopy.66,67 Our initial results have indicated that, in fact, the details of the adsorption are central to the ability of the cinchona to chirally modify the surface of the metal catalyst. Figure 6 summarizes the results from our studies on the effect of three different parameters on the adsorption of cinchonidine, a typical cinchona alkaloid, to illustrate this point. The left panel displays the correlation encountered between the adsorption geometry of the quinoline ring of the cinchona on the Pt surface68,69 and the degree of enantioselectivity seen in catalysis.70 It appears that it is the flat-lying geometry seen at intermediate solution concentrations that favors high chiral selectivity.71-73 The middle panel reports on the evolution of cinchonidine adsorption as a function of the time of exposure of the surface to hydrogen.74 An initial reducing period is required to condition the surface before the cinchona uptake and chiral catalytic effect start, but prolonged hydrogen exposures also lead to the hydrogenation of the cinchona and the consequent loss of enantioselectivity.75-78

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Zaera

Figure 6. Examples of the central role that the adsorption of cinchonidine plays on its ability to chirally modify the performance of platinum catalysts. (Left) Correlation between the adsorption geometry of the quinoline ring, determined by RAIRS, and the resulting enantioselectivity during R-ketoester hydrogenation: the chiral effect appears to be maximum with a flat-lying adsorption, which is only available at intermediate concentrations.68 (Center) Cinchonidine uptake as a function of hydrogen exposure highlighting both the need of H2 pretreatments for adsorption (and chiral modification in catalysis) and the reduction in coverage (and enantioselectivity) seen at longer times because of cinchona hydrogenation.74 (Right) Correlation between the solubility of cinchonidine in different solvents and the reversible nature of its adsorption (measured by the amount of solvent required to remove half a monolayer).79 In general, solvents in which cinchonidine can dissolve more easily are better for catalysis.

Finally, the right panel of Figure 6 shows the correlation between the solubility of cinchonidine in different solvents and the reversible character of its adsorption.79 Cinchonidine solubility was in turn determined to depend strongly on the polarity and dielectric constant of the solvent, as does enantioselectivity in catalysis.80-83 The latter example highlights the importance of choosing the appropriate solvent to optimize the performance of these catalytic systems. It has become quite clear that the adsorption properties of cinchona alkaloids,84-86 and with that their ability to bestow chirality on surfaces,81,83,87 depends in great measure on the nature of the solvent used. Nevertheless, it is also apparent that this effect is mainly related to the molecular details of the chiral modifiers themselves, not to those of the solvent, because similar trends are observed with different cinchona as a function of the solvent used. For instance, although the solubilities of both cinchonidine and cinchonine change by several orders of magnitude when switching from good solvents such as acetic acid, chloroform or methanol to poor solvents like cyclohexane or water, they do so in roughly the same way: cinchonine is always ∼1 order of magnitude less soluble that cinchonidine (Figure 7, left top).79 It is our hypothesis that the trends observed in connection with solvent effects are mostly related to the rotational conformation space available to the chiral molecules because of the presence of several carbon-carbon single bonds.86 Those appear to be affected differently by different solvents,86 and may also be partially hindered by bonding to solid surfaces. The rotations around the two bonds in the alcohol linker of cinchonidine have been characterized extensively both theoretically88-90 and experimentally,88,91 and have been determined to involve energy barriers of only a few kcal/mol (Figure 8).86 What is still missing is a comparative study of this rotational behavior across a family of closely related cinchona alkaloids in order to better understand its role in defining the differences observed in adsorption properties and chiral modification abilities. This is an approach we have taken recently in our laboratory. It is our premise that the variations in solubility,

Figure 7. Results from comparative studies on the chiral modification of Pt catalysts with cinchonidine (Cd) vs cinchonine (Cn), two nearenantiomer cinchona alkaloids. These promote the production of opposite enantiomers in catalytic hydrogenation reactions with R-ketoesters, as expected, but display different enantioselectivities (right).94 The difference is accounted for by a combination of two key fundamental properties of these cinchona, their solubility79 (left, top) and their adsorption equilibrium on the Pt surface (left, bottom).85 The more restricted rotational conformation space available to cinchonine, as indicated by 2D NMR results, appears to be responsible for most of these changes, and may also affect the bonding mode of these modifiers on the surface.

adsorption, and catalytic performance seen between near enantiomer pairs such as cinchonidine vs cinchonine or quinine vs quinidine are caused by the nature and position of the peripheral groups, denoted R1 and R2 in Figure 5. Figure 7 highlights two key manifestations of such differences between cinchonine and cinchonidine, which display opposite chirality in the two carbons of the alcohol linker (usually denoted C8 and C9) but the same chirality in the quinuclidine ring. That places the outside vinyl moiety (R2 in Figure 5) at a different position in each molecule relative to the quinoline ring. As indicated in Figure 7, the effects of this subtle difference are profound, both in solution and on surfaces. In terms of the behavior of the molecules in solution, 2D NMR experiments

Centennial Feature Article

Figure 8. Ab-initio quantum-mechanical calculations of the energy barriers required for rotations around the alcohol chiral linker in cinchonidine.86 Although barriers as high as 15 kcal/mol are seen in some instances, many rotational conformations of the molecule display energetics within only a few kcal/mol of each other. This means that cinchona molecules exhibit a great degree of rotational freedom, and exist in many interchanging conformations, at least in solution. The relative populations of the possible rotational conformers, especially when adsorbed on metal surfaces, may play an important role in determining the effectiveness of cinchona alkaloids as chiral modifiers.

indicate a somewhat more restricted rotational conformation space for cinchonine than for cinchonidine.92 As a consequence, cinchonidine and cinchonine promote the production of opposite R-hydroxoesters enantiomers during the catalytic hydrogenation of R-ketoesters, as expected, but with different enantioselectivities; cinchonidine is often more enantioselective than cinchonine (Figure 7, right).93-95 Protonation of cinchonidine also significantly restricts its rotational conformation space,96 and severely affects its catalytic performance accordingly.97-99 In addition, differences in molecular conformation in these cinchona alkaloids also affect their adsorption equilibria: the equilibrium constant for cinchonine adsorption from carbon tetrachloride solutions is approximately five times larger than that for cinchonidine (Figure 7, left bottom, and Figure 9, left).85 Interestingly, it is cinchonidine that can displace cinchonine from Pt surfaces rather than the other way around (Figure 9, right).100,101 This is the reason why chiral promotion with cinchonidine + cinchonine mixtures typically display behavior similar to that seen with cinchonidine alone.44,94 Not only the solubility of the cinchona alkaloids but also their bonding mode to the surface contributes to these equilibrium constants for adsorption. Indeed, our infrared spectroscopy studies have provided direct evidence for such bonding differences: cinchonidine binds to the Pt substrate with the aromatic ring tilted along its long axis to optimize π-π intermolecular interactions, whereas cinchonine does it by tilting the ring along the short axis for better overlap with the lone electron pair of the nitrogen atom (at least at high surface coverages).85,86 This difference presumably arises from a balance between energetic (bonding, π-π stacking) and entropic (conformation) factors. In summary, the chiral modification of metal catalysts by cinchona alkaloids may be due mainly to interactions of individual modifier molecules with the reactant, as proposed in the past. However, the performance of these systems is also affected by a subtle balance between energetic factors, in particular bonding to the surface, and entropic contributions due to the availability of several rotational conformations. These

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Figure 9. (Left) Adsorption uptake for cinchonine (Cn) and cinchonidine (Cd) from CCl4 solutions onto Pt surfaces as a function of concentration, as followed by using the infrared absorption intensities of key in-plane quinoline ring stretching peaks.85 The experimental data are shown by the indicated symbols, while fits to Langmuir adsorption kinetics, used to estimate adsorption equilibrium constants, are displayed by the associated lines. (Right) In-situ RAIRS from experiments where a platinum surface was exposed sequentially to CCl4 solutions of (from top to bottom) Cn, Cd, and back to Cn.100 Those data indicate that while cinchonidine can displace cinchonine from the surface, the opposite is not possible. Such a trend is in apparent contradiction with the higher adsorption equilibrium constant seen for Cn, but is explained by its lower solubility in the CCl4 solvent.

factors affect the behavior of the cinchona both in solution and on the solid surface. As in the case of the chiral templating of surfaces with simple molecules such as tartaric acid, the extreme models initially proposed to explain chiral modification with cinchona alkaloids do not fully account for the physical chemistry behavior observed. 4. Conclusions and Future Outlook In this brief and personal review we have shown how in spite of the long history and great importance of chirality in chemistry and biology, chirality on surfaces is still quite poorly understood and has only recently become an active area of research. Here we have focused on a specific subset within this field dealing with the adsorption of chiral molecules to bestow enantioselectivity on metal-based catalysts, the area of interest in our own research group. In this, empirical observations related to surface chiral modification have preceded studies on the fundamental physical chemistry behind the desired effects. In fact, as mentioned above, effective heterogeneous enantioselective catalysts were already identified several decades ago. On the other hand, only two somewhat disconnected families of reactions, the hydrogenation of β-ketoesters using nickel and tartaric acid and the hydrogenation of R-ketoesters with platinum (and palladium) and cinchona alkaloids, have been advanced since. Unfortunately, these systems are quite demanding, and only operate efficiently under very specific conditions and for a small family of reactants and modifiers. Their complexity has hindered their empirical extension to a broader chemistry range. Clearly, what is needed is a better molecular-level understanding of the surface chemistry involved. As evidenced by our review, studies in this direction are still in their infancy. Two quite different and apparently disconnected mechanisms, surface templating and one-to-one reactant-modifier complexation, had been initially advanced to explain the two known families of chiral catalytic reactions. This has been, in our opinion, a somewhat negative development that has perhaps

16202 J. Phys. Chem. C, Vol. 112, No. 42, 2008 made the generalization of chiral modification effects more difficult, because it has suggested that each case is unique and requires its own set of criteria for optimization. By contrast, we in this review argue that both those models share some common features, and should be considered concurrently when studying any chiral modification system. This make the future of chiral catalysis more promising, but still does not take away the fact that additional work is needed to finally pinpoint the key parameters that control the surface chemistry behind chiral modification in catalytic processes so a better educated and more directed approach may be taken toward the design of new chiral catalysis. That will require a much more intense effort than that currently ongoing in this area. Perhaps the complexity of these systems has discouraged researchers from tackling the problem, but that can also be viewed as a great opportunity to contribute to an area with such potential impact in industrial applications. At least two shortcomings can be identified as hindering the present progress in the understanding of surface chiral modification. The first is a limitation in the analytical techniques available for the study of these systems. The main difficulty here is that the reactions of interest involve relatively complex molecules, and often occur at solid-liquid interfaces. The latter rules out the use of many of the modern ultrahigh vacuum surfacesensitive techniques that have proven so useful in the study of so many other catalytic and materials-science problems.102-104 Some valuable advances have been made recently in the implementation of electrochemistry,105-107 microscopy,105,106,108 and vibrational spectroscopy66,67,69,109 for the in situ detection of adsorbates in such solid-liquid interfaces, but more is needed. Perhaps other spectroscopies, including solid-state NMR, may be incorporated in the future. The ability to perform quantummechanical calculations on surfaces is also progressing quite rapidly, and may help here too.38,110 The second limitation is synthetic. Cinchona alkaloids in particular are fairly complex organic molecules extracted from natural products, and their systematic modification, to add substituents in specific positions as needed to engineer better chiral modifiers, represents a significant synthetic challenge.41,62 In addition, it is necessary to identify entirely new and different chiral modifiers, something that has been pursued only to a very limited extent so far.19,29,111 One probable starting point in this direction may be the chiral compounds used in homogeneous catalysis and in chiral organic synthesis.15,63,112 It is interesting to note that certain families of chiral compounds, sometimes called “privileged”,113 promote many seemingly unrelated homogeneous chiral conversions; the same molecules may find applications in heterogeneous chiral catalysis as well. From a fundamental point of view, different families of modifiers could be used to identify the particular functional groups associated with specific functions in surface chiral modification. Some conclusions have already been reached in this direction, as discussed above (2- or 3-point interactions between modifiers and surfaces, amines or carboxylic groups as interacting moieties to hold on to the reactant, aromatic rings for adsorption), but comparative studies with larger and more diverse sets of molecules would go a long way in this effort. Overall, the field of chirality on solid surfaces is still fairly undeveloped, and open to new discoveries. Besides chiral modification, chiral homogeneous catalysts may be grafted on surfaces,20,21 and intrinsically chiral or chirally imprinted surfaces,22,33 including those of nanoparticles,114,115 and highsurface-area oxides,116,117 may be used as catalysts themselves. These areas are being tackled by other research groups already, but progress has also been limited. There is ample room for

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