Chiral Recognition on Catalytic Surfaces: Theoretical Insight in a

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Chiral Recognition on Catalytic Surfaces: Theoretical Insight in a Biomimetic Heterogeneous Catalytic System Angelo Vargas,† Gianluca Santarossa,† Marcella Iannuzzi,‡ and Alfons Baiker*,† Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Ho¨nggerberg, HCI, 8093 Zurich, Switzerland, and Laboratory for Reactor Physics and System BehaVior, Paul Scherrer Institut, CH-5232 Villigen, Switzerland ReceiVed: February 15, 2008

Docking of molecules to surface chiral sites generated by adsorbed chiral organic modifiers is a fundamental step in heterogeneous metal-catalyzed asymmetric hydrogenation. The understanding of such docking events is nonetheless limited by the technical difficulties in obtaining experimental submolecular information for complex adsorbed structures. In addition an accurate theoretical analysis is computationally very demanding due to the need of including the metal surface. The present investigation explores by means of density functional theory the supramolecular docking structures of ketopantolactone within the chiral sites formed by cinchonidine adsorbed on a platinum surface, a crucial step in the enantioselective hydrogenation of ketopantolactone over cinchonidine-modified platinum. The study is performed using periodic slabs exposing Pt(111) surfaces of (6 × 6) and (8 × 8) atoms with a depth of four layers and including complete relaxation of the first three. Twenty six docking sites are investigated thus covering the most complete configurational space until now. The implications of the physi- and chemisorption of ketopantolactone in the docking have been also explored, thus revealing the role of weak and strong adsorption of the substrate in the formation of precursor states for hydrogen uptake within a docking site. The calculations on the (8 × 8) periodic slab were performed in order to decouple the energy related to the adsorption of the substrate from the energy involved in the docking interactions with the adsorbed alkaloid. Such a surface is in fact apt to accommodate both the chiral surface site and the noninteracting substrate. The study revealed that the substrate likely approaches the chiral site either from solution or from the physisorbed state. The resulting scenario gives a basic understanding of the elements involved in the docking of substrates within the chiral sites formed by cinchona alkaloids on platinum, and constitutes a fundamental stage for the comprehensive clarification of enantioselectivity at chirally modified surfaces. 1. Introduction Catalytic routes to enantioselectivity are of paramount importance, and major achievements have been made using asymmetric homogeneous catalysts.1–3 On the other hand, heterogeneous asymmetric catalysts, although highly desirable, are not quite as developed but are regarded with growing interest due to their intrinsic technical advantages (catalyst stability, separability, regeneration, and reuse). Some recent reviews illustrating the present state of knowledge in this field4–12 point out that the most successful and versatile reaction system for asymmetric heterogeneous catalysis consists of the chiral modification of noble metals (Pt, Pd, and Rh) by means of alkaloids of the Cinchona series or by means of structurally similar molecules, which are able to impart chirality to the otherwise achiral metal surface and thus generate enantioselective reaction pathways. The first reaction of this kind was discovered by Orito13 for the enantioselective hydrogenation of ethyl pyruvate on platinum but has since then been extended to other substrates and metals.4–12 The underlying concept at the origin of enantioselection is well accepted to be closely related to the chiral recognition of the substrates by means of the surface chiral sites generated by the adsorbed modifiers. Chiral recogni* To whom correspondence should be addressed. E-mail: baiker@ chem.ethz.ch. Tel: +41 44 6323153. Fax: +41 44 6321163. † ETH Zurich. ‡ Paul Scherrer Institut.

tion at surfaces is central for asymmetric induction in heterogeneous catalysts,14–16 but the experimental determination of the submolecular structural details involved in such events is extremely difficult to achieve. Theoretical approaches toward unraveling fundamental aspects of adsorption and reactivity have undergone tremendous improvement in the past years,17–20 rendering this approach a powerful tool for resolving surface structures. Many theoretical studies have focused on the adsorption of ketones on transition metal surface.21–29 Nonetheless, very few attempts have been made to calculate from first principles the docking structures in systems related to the Orito reaction,30–33 due to the demanding computational efforts involved. As an initial step to unravel the molecular interactions governing the asymmetric surface process, several researchers have studied the adsorption behavior of cinchona alkaloids and structurally related molecules on platinum, palladium, and rhodium by means of attenuated total reflection infrared spectroscopy (ATR-IR),34–37 reflection-adsorption infrared spectroscopy (RAIRS),38–40 scanning tunneling microscopy (STM),41,42 and density functional theory (DFT) calculations.30,43–47 Beyond the fundamental uncovering of the different adsorption modes of the modifiers at the solid-liquid interface34,35 some key observations are as follows: upon adsorption, the modifier (i) changes its equilibrium conformation with respect to solution,44,45 (ii) it generates surface chiral sites that possess a conformational complexity,44,45,48 (iii) it shows differences in the adsorption

10.1021/jp8013628 CCC: $40.75  2008 American Chemical Society Published on Web 06/12/2008

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Figure 1. Periodic unit cells used for the simulation of a Pt(111) surface: (a) 144 and (b) 256 atoms. Three of the four layers have been completely relaxed during optimizations.

behavior depending on the metal,36,37 and (iv) it can generate the exchange of hydrogen with the metal surface.43 The biomimetic nature of this system has also been noted.48 This is due to the combination of two factors: (i) activation of substrates and reactants by means of a metal center and (ii) presence of a flexible chiral organic framework forming a chiral site. Such combination transfers to man-made materials the same properties possessed by the more complex natural biocatalysts (enzymes) to generate highly enantioselective catalytic reactions. The understanding of the molecular interactions between functional groups able to bias the docking of substrates is of fundamental importance for engineering the properties of a functional catalytic metal surface. However, this understanding is very demanding to gain experimentally, since in situ spectroscopic techniques are required. To our knowledge, today there exists still only one experimental study,49 where the docking of a substrate with a chirally modified platinum site has been followed under near in situ conditions, using ATR-IR combined with modulation spectroscopy. This study revealed a hydrogen bonding between the quinuclidine N atom of cinchonidine and the oxygen of the R-keto group of ketopantolactone (KPL). In the present investigation, periodic metal slab calculations have been used to study the docking of KPL to the chiral sites generated by cinchonidine (CD) adsorbed on a Pt(111) surface. The asymmetric hydrogenation of KPL is widely used as a test reaction for this kind of catalyst. For modeling studies this substrate is preferred to the other widely used test substrate ethyl pyruvate since KPL does not allow for an s-cis/s-trans equilibrium. Due to its rigid five membered ring, the keto and ester carbonyl groups of KPL only exist in the s-cis conformation. Furthermore experimental data for KPL are not biased by selfcondensation side reactions reported in the case of ethyl pyruvate,50 which makes experimental data on KPL simpler to interpret. 2. Computational Methods All of the results disclosed have been obtained using the CP2K code and simulating the surface by means of slabs with periodic boundary conditions (PBC).51 The slabs used in the simulations are shown in Figure 1. All of them expose the (111) crystallographic plane. The first slab (Figure 1a) consists of a supercell of (6 × 6) Pt atoms. The orthorhombic box is defined by vectors of length 16.65 Å and 14.42 Å in the x and y Cartesian directions, respectively. In the z direction, perpendicular to the surface, a vector of 24.00 Å is used in order to leave a sufficient amount of empty space between the slab and its periodic images, thus avoiding any spurious interaction. The initial bond distances were set to 2.775 Å, as reported in the

crystallographic data.52,53 During the simulations the three top layers were completely relaxed while the atoms of the fourth layer were kept frozen to mimic bulk behavior. The second unit cell (Figure 1b) is used to investigate the long-range interactions between the organic molecules. Thus, the slab exposes a surface of (8 × 8) Pt atoms on 4 layers, for a total of 256 metal atoms. The box has vectors of length 22.20, 19.23, and 24.00 Å in the x, y, and z directions, respectively. We remark that our results can be compared to the previously published works46,47 where DFT calculations using Plane Waves and k-point sampling have been discussed. Namely our model, consisting of a (6 × 6) supercell in the x and y Cartesian directions, corresponds to a (3 × 3) k-point mesh applied to a (2 × 2) box. Likewise, the (8 × 8) supercell is analogous to a (4 × 4) k-point mesh applied to a (2 × 2) box. The CP2K package adopts a hybrid basis set formalism known as Gaussian and Plane Wave Method (GPW)51 where the Kohn-Sham orbitals are expanded in terms of contracted Gaussian type orbitals (GTO), while an auxiliary plane wave basis set is used to expand the electronic charge density. By using a reciprocal space representation of the electron density the computational time required to calculate the Hartree potential scales linearly with the dimension of the system. The GPW formalism requires the use of pseudopotentials (PP) to describe the interaction of the valence electrons with the frozen atomic cores. In the present investigation, norm-conserving Goedecker, Teter, and Hutter (GTH) pseudopotentials54 were used for all atomic species. The GTO basis sets used in CP2K are typically optimized for the specific PP. In the present case, triple valence basis sets augmented with polarization functions (TZV2P) have been used for H, C, O, and N, while a TZV basis set was used for Pt. The auxiliary PW basis set was defined by the energy cutoff of 300 Ry. The exchange and correlation term was modeled using the generalizedgradientcorrectedPerdew-Burke-Ernerhof(PBE)functional.55–61 The structures have been optimized until the geometric displacements were lower than 3 · 10-3 Bohr and the maximum forces lower than 4.5 × 10-4 Bohr/Ha. Molden,62 VMD,63 and Pymol64 were used as graphical interfaces. 3. Results and Discussion 3.1. Adsorption of the Modifier to the Surface. Asymmetric catalytic hydrogenations of ketones on modified platinum group metals occur when the uptake of activated hydrogen is in the proximity of the adsorbed chiral modifier. Obtaining an enantiomeric excess of the corresponding alcohol is possible because the ketone experiences an asymmetric chemical environment (binding and repulsive interactions) generated by both the alkaloid and the metal surface. The ensemble of such

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Figure 2. Chemical structure of cinchonidine. The angle τ1 is defined by the atoms C{9′}, C{4′}, C9 and C8, whereas the angle τ2 is defined by atoms C{4′}, C9, C8, and N1.

Figure 3. Conformations of cinchonidine adsorbed on a Pt(111) surface calculated using the cell in Figure 1a (6 × 6). The panels show only the top layer of the slab to simplify the graphic representation. At the top-right angle of each image, the designation and the relative energies (kcal/mol) of the conformations are shown.

interactions within a confined space (chiral space or chiral site) generates what is usually known in enzyme chemistry as a docking event, usually characterized by a minimum in the potential energy surface identified by the reaction coordinates. Before entering the details of the docking, the key features of the adsorption of CD on platinum must be briefly reminded. As previously shown44,45,65 different surface conformers can be distinguished according to the relative positions between the quinoline and quinuclidine moieties of the CD molecule. These conformers are usually identified by the values assumed by the angles τ1 and τ2 of CD, described in the caption of Figure 2. The conformers can be classified into two groups, which are addressed to as the surface open(3) [SO(3)] group and the surface open(4) [SO(4)] group. These are shown in Figure 3 for CD. The energies reported in the figure (top-right, kcal/ mol) refer to the energy differences between the total energy of the system and the most stable adsorption mode. The simulations are performed with the 4 layers slab of (6 × 6) atoms shown in Figure 1a. Starting from the SO(3) conformer

Vargas et al. (Figure 3e) rotation of angles τ1 and τ2 due to conformational flexibility can generate the local minima surface closed(2) [SC(2)] (Figure 3d) and surface quinuclidine bound(2) [SQB(2)] (Figure 3f). Starting from the SO(4) conformer (Figure 3b) rotation of angles τ1 and τ2 can generate the local minima surface closed(1) [SC(1)] (Figure 3a) and surface quinuclidine bound(1) [SQB(1)] (Figure 3c). Importantly the two sets of conformers cannot interconvert (as on the contrary can happen in vacuum or in solution) simply via conformational rearrangement of τ1 and τ2. In fact, the interconversion between the two groups of conformers requires a desorption-adsorption step of the quinoline moiety that is chemisorbed to the metal. Note that in conformers SC(1) and SC(2) the quinuclidine nitrogen points toward the anchoring group (closed conformers). Thus, in such conformations, the nitrogen atom can not interact with the metal. Since the docking event that leads to asymmetric hydrogenation should involve both the metal surface and the tertiary nitrogen at the same time,49 conformers SC(1) and SC(2) cannot be catalytically efficient docking sites. Also note that the SQB(1) and SQB(2) conformers have the tertiary nitrogen of the quinuclidine moiety involved in a bond to the metal and are therefore also not suitable for interacting with a substrate. In order to interact with the substrate, the tertiary nitrogen must be set free from the surface, for example by reduction with surface hydrogen thus generating N-hydrogenated surface species. It has been shown both experimentally66 and theoretically43 that such hydrogen transfer from the surface to an amine is possible. In the specific case of CD, the conformational flexibility of the quinuclidine moiety due to rotation of τ1 and τ2 allows contact with the surface hydrogen and thus hydrogen transfer. Evidences of this mechanism have also emerged from STM imaging41,42 where it was shown that introduction of hydrogen into the Pt(111)-CD-vacuum system increased the surface mobility of the adsorbed alkaloid and involved conformational rearrangements at the quinuclidine moiety. Within this context it is an N-H moiety of the adsorbed alkaloid that provides a binding site in the chiral pocket, as indicated by in situ ATR-IR spectroscopy.49 The active species must therefore have an open conformation. Due to the above-described conformational features, it is clear that the chiral sites formed by CD on the metal surface are critically influenced by the set of conformations that are populated on the surface and more in particular by the values of the angles τ1 and τ2. It is therefore important to know which group of conformers, the SO(3) or SO(4) group, is more populated. Although it has been reported that in solution (apolar solvents) the most populated conformer is the open(3),67 the theoretical analysis of the adsorption features of CD to a Pt(111) surface has shown that the most stable conformer on a platinum surface is the SQB(1),44,45 belonging to the SO(4) group. It has to be stressed that at the present stage solvent effects have not yet been included in the simulations, due to the unaffordable computational cost of such calculations. Nevertheless, experimental evidence in the presence of the solvent also exist in support of this finding. The study of the hydrogenation products of CD on Pt/Al2O3 catalyst68,69 has shown that two diastereoisomers of the 1′,2′,3′,4′,10,11-hexahydrocinchonidine were obtained: the 4′ (R) and the 4′ (S), evidently differing for the absolute configuration of the 4′ carbon atom. The 4′ (S) diastereoisomer was formed in excess, which is consistent with a surface population dominated by conformers of the SO(4) series. In brief, at the present state of our knowledge, both theoretical and experimental evidence points toward conformers of the SO(4) group as dominant on the surface, in contrast to

Chiral Recognition on Catalytic Surfaces the result found for the alkaloid in solution that indicates the open(3) as more abundant. 3.2. Docking of KPL to the Adsorbed Modifier. The aim of the present study is to identify the critical interactions between the surface, the modifier, and the substrate that will eventually lead to enantioselectivity in the catalytic hydrogenation of the substrate. Only when a clear picture of such interactions will be available, will it be possible to focus on further details of the hydrogenation process. The most stable sites for the interaction of the substrate with the chiral surface were identified by means of a systematic search of the docking sites of KPL in the chiral pocket generated by the modifier anchored to the surface. Due to the geometrical complexity of the system, a large number of different docking structures have to be considered. Both the SO(4) and the SO(3) adsorption modes of CD discussed in the previous section are used as scaffold for the docking of the KPL molecule. Since the substrate is prochiral, it can show either the Re or the Si face to the surface. In the following discussion, the face of the substrate will always be referred to by using the Re and Si nomenclature, thus indicating which face is exposed to the metal and therefore to the activated hydrogen. The structures are clustered into four different groups of supramolecular docking structures (SDS), sharing the same relative geometry of CD and KPL with respect to the surface. Each of these groups contain the supramolecular structures identified by the conformation of CD (SO(4) or SO(3)) and by the face of KPL (Re or Si) exposed to the surface. This identifies four groups: (i) SO(4)-Re, (ii) SO(4)-Si, (iii) SO(3)-Re, and (iv) SO(3)-Si. Within each group, the position of KPL differs both for its position with respect to the alkaloid, and for its adsorption state on the metal (chemisorption or physisorption). The supramolecular structures are thus further distinguished as chemisorbed (C1, C1b, C2, etc.) or physisorbed (P1, P2, etc.), with respect to the adsorption mode of KPL. Since the designation of all possible relative positions between the substrate and the adsorbed alkaloid may cause confusion, an illustration has been produced (Figure 4) showing a schematized site (CD without hydrogen atoms and the KPL schematized by showing only the two CdO moieties) and the relative positions of chemisorbed KPL. This should help the reader to understand the starting configurations of the simulations and the extent to which the space adjacent to the site has been explored. It should be noted that after relaxation the geometries differ substantially from the initial ones, nonetheless maintaining the same relative position described in Figure 4. The supramolecular docking structures where KPL is physisorbed to the metal are characterized by low energy binding of KPL with the surface, therefore such structures are only distinguished by the positions of the keto- and ester carbonyl moieties of KPL with respect to cinchonidine. Such supramolecular assemblies are not described in the scheme of Figure 4, since they do not need a complex subnomenclature. In brief, in P1 the KPL is interacting with the quinuclidine moiety only; in P2 the KPL is interacting both with the quinuclidine moiety and with the CD hydroxyl group; in P3, the KPL is interacting both with the quinuclidine moiety and with the rehybridized aromatic hydrogen atoms of the anchoring moiety (quinoline) of CD. It is worth noting that in the SO(4) conformer shown in Figure 4 the quinuclidine ring is rotated around the τ1 angle by about 100° with respect to the SO(4) conformation of CD shown in Figure 3. The obtained conformation is as stable as the SO(4)

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Figure 4. Schemes of the starting docking sites of KPL in the chiral space of adsorbed cinchonidine: the alkaloid is shown without hydrogen atoms, and the KPL is simplified by showing only the two CdO moieties and their interactions with the Pt atoms. For the shown case where KPL is chemisorbed to Pt, the relative positions between CD and KPL is constrained by the surface geometry.

conformer shown in Figure 3b, but the nitrogen and the scaffold atoms assume positions more suitable for docking. The supramolecular docking structures addressed in our investigation will thus be designated according to the following description: the first part of the name addresses the conformation of CD (SO(3) or SO(4)); the second part of the name indicates the prochiral face of KPL that is exposed to the surface (Re or Si); the third part of the name addresses the state of KPL with respect to the surface and to the adsorbed modifier (chemisorption or physisorption, and relative position with respect to the alkaloid). As explicative example SO(4)-Re-P1 indicates that (i) the supramolecular structure is formed by CD in its SO(4) adsorption mode, (ii) the substrate KPL exposes its Re face to the metal, and (iii) it is physisorbed rather than chemisorbed to the metal. A total of 26 different supramolecular structures are compared. The final structures resulting from the docking process differ from each other only by the surface conformations of CD and by the relative position of KPL with respect to the binding site. They are therefore different conformers of the same supramolecular structure. Hence, the stabilities of such supramolecular structures can be determined directly by comparing their final energies in a relative scale (Table 1). The energies are reported as the difference with respect to the most stable structure (SO(4)-Re-P1, Figure 5a) which is set to zero. The

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TABLE 1: Relative Energies of the Docking of KPL on Adsorbed Cinchonidine conformation

energy (kcal/mol)

conformation

energy (kcal/mol)

SO(4)-Re-P1 SO(4)-Si-C2b SO(4)-Si-C3 SO(4)-Si-P1 SO(4)-Re-P3 SO(3)-Si-P1 SO(4)-Re-P2 SO(3)-Re-P3 SO(3)-Re-P1 SO(4)-Re-C2 SO(4)-Re-C3 SO(4)-Si-C2 SO(3)-Si-C3 SO(4)-Si-C1

0.0 2.6 3.3 3.6 3.8 3.9 5.6 6.0 6.4 9.8 9.9 11.3 14.8 15.8

SO(4)-Si-C4 SO(3)-Si-C1b SO(3)-Si-C1 SO(4)-Re-C1 SO(4)-Si-C1b SO(3)-Re-C1 SO(3)-Si-C4 SO(3)-Re-C3 SO(3)-Si-C2 SO(3)-Re-C4 SO(3)-Re-C2 SO(4)-Re-C4 SO(3)-tilted-Re-C1 SO(4)-tilted-Re-C1

16.5 17.6 17.9 17.9 17.9 19.5 19.9 20.7 21.8 23.5 30.0 30.8 31.5 49.0

result is in agreement with both the experimental evidence that a strong preference exists for the formation of the (R)pantolactone in the asymmetric hydrogenation reaction, and that the most relevant adsorption modes of CD under reaction conditions belong to the SO(4) group. The second most stable supramolecular docking structure is the SO(4)-Si-C2b (Figure

Figure 6. Supramolecular docking structures (SDS) of KPL and CD when (i) the alkaloid has an SO(4) conformation and (ii) the KPL exposes the Si face to the surface. Calculations have been performed using the cell in Figure 1a (6 × 6). The figures show only the top layer of the slab to simplify the graphic representation. At the top-left angle of each figure, the designation and the relative energy (kcal/ mol) of the SDS are shown.

Figure 5. Supramolecular docking structures (SDS) of KPL and CD when (i) the alkaloid has an SO(4) conformation and (ii) the KPL exposes the Re face to the surface. Calculations have been performed using the cell in Figure 1a (6 × 6). The panels show only the top layer of the slab to simplify the graphic representation. At the top-left angle of each figure, the designation and the relative energy (kcal/mol) of the SDS are shown.

6e), which is 2.6 kcal/mol less stable than the first one, corresponding to 1/100th of the population at 300 K. SO(4)Re-P1 is therefore statistically the most relevant supramolecular structure. Interestingly, all the five most stable structures belong to the surface open(4) series (Table 1). The most stable supramolecular structure of the SO(3) group is 3.9 kcal/mol less stable than the most stable one, and in this structure KPL exposes its Si face to the surface (Table 1). As a general result, supramolecular docking structures from the SO(4) group seem to be dominating over the SO(3) ones. To understand the basis of the docking process, a closer look at the geometrical details of the supramolecular docked structures is necessary. The geometries are discussed separately for each group of structures. Due to the large number of SDS calculated, only the ones having an SO(4) conformation of CD have been shown as figures in the manuscript (Figure 5 and 6). Also the SDS relative to the SO(3) adsorption mode of CD will be discussed, the figures depicting such calculated structures have been included in the Supporting Informations. Figure 5 shows the group of the SO(4)-Re supramolecular structures. Here KPL docks to CD in its SO(4) adsorption mode and with its Re face exposed to the surface. As mentioned above, the most stable SDS, SO(4)-Re-P1, belongs to this group (Table 1). Interestingly, for this set of structures, all of the physisorbed

Chiral Recognition on Catalytic Surfaces states are more stable than the chemisorbed ones. The physisorbed supramolecular structures are characterized by a longdistance binding of KPL to the surface (ca. 3.3-3.8 Å). KPL keto carbonyl carbon atoms are not rehybridized, and the lengths of both keto and ester carbonyl groups are 1.2 Å, as in the nonadsorbed molecule. For CD, the dihedral angles τ1 and τ2 can rotate to relax the molecule to a low energy conformation. In the case of P1 and P3 SDS (Figure 5a and 5c), τ1 and τ2 are -179° and +154°, respectively. For the P2 SDS (Figure 5b) τ1 changes to 175°. Since both the substrate and the modifier are only slightly distorted, the docking generate quite stable structures. Moreover, in all of the physisorbed states, both of the carbonyl groups are docking some parts of the modifier, although to different extents for different binding sites. In the P1 docking the KPL ester carbonyl forms a hydrogen bond with the NH group of the quinuclidine moiety. P2 and P3 modes show interesting conceptual similarities to the interaction model recently proposed by McBreen,70,71 based on the observation of STM images of adsorbed aromatic compounds and of their interactions with ester groups. In fact such UHV experiments have shown that the aromatic hydrogen atoms of a chemisorbed system can form weak binding states with the CdO moiety of ethyl formate. This induced the authors to propose that such interactions might be relevant to the docking of ketones in the sites formed by chemisorbed CD.70,71 Also our calculations show that docking interactions can exist in the proximity of the adsorbed aromatic moiety, as in SO(4)-Re-P2 and SO(4)-ReP3 (Figure 5b,c). However, important differences arise as compared to the proposal made by McBreen: (i) for both SO(4)Re-P2 and SO(4)-Re-P3 (Figure 5b,c), the keto carbonyl group interacts with the quinuclidine nitrogen, while the ester carbonyl points toward the quinoline ring, which is the opposite interaction pattern compared to that proposed by McBreen; furthermore both of these supramolecular structures although interacting with the anchoring moiety are less stable than the SO(4)-Re-P1 where such interaction is absent; (ii) McBreen proposes a docking structure where CD is adsorbed in an SO(3) conformation while the most stable SDS involving interaction with the aromatic hydrogen atoms seems to involve an SO(4) adsorption mode of CD. It is important to note in this context that the STM experiments mentioned above concerned either the adsorption of pyrene or the adsorption of 4-methyl-naphthalene, which were taken as models for the surface sites, while our calculations involve the complete alkaloid cinchonidine. It seems that the quinuclidine moiety of CD is biasing the docking of KPL to a larger extent than the hydrogen atoms of the adsorbed aromatic moiety, but this could not be observed experimentally in the mentioned STM study since the systems were only simplified versions of the surface sites involved in chiral recognition. One of the difficulties in passing from the interpretation of experiments to the formulation of an interaction model for the Pt-CD catalytic system is due to a large bias present in literature for considering the open(3) conformation responsible for the enantioselective hydrogenation, while it is here shown that the picture can be much more complex when analyzed at a submolecular level. In the SDS where KPL is chemisorbed, i.e., SO(4)-Re-C1, SO(4)-Re-C2, SO(4)-Re-C3, and SO(4)-Re-C4 (Figure 5d-g) the keto carbonyl groups are bound to the surface, remaining within a distance of 2.2-2.4 Å from the metal. The carbon atoms of the keto carbonyl groups create new chemical bonds with the Pt atoms, and rehybridize to sp3. Consequently, the keto carbonyl moieties elongate to 1.4 Å. In these supramolecular structures the main intermolecular interaction is that of

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Figure 7. Comparison of supramolecular docking structures (SDS) of KPL and CD when (a) the alkaloid has an SO(3) conformation or (b) it has an SO(4) conformation. Calculations have been performed using the cell in Figure 1a (6 × 6). The panels show only the top layer of the slab to simplify the graphic representation. At the top-right angle of each panel, the designation of the SDS is shown.

the keto carbonyl group of KPL with the quinuclidine moiety of CD. Only in the SO(4)-Re-C4 (Figure 5g) KPL docks to the quinuclidine with its ester carbonyl moiety. Finally in all structures where KPL is chemisorbed to the metal, the conformations of CD are strongly influenced by the positions of KPL. The values of the τ1 dihedral angle vary from 184° for C1b to 150° for C4 modes, correlating with the adsorption energies of the chemisorbed docking sites: it seems that if τ1 is closer to the value assumed when KPL is in a physisorbed state then the supramolecular structure is more stable. The final energies of the supramolecular structures where KPL is chemisorbed are therefore a compromise between the energy gains from the chemisorption of KPL to the surface and its docking to CD on one side, and the energy losses caused by the distortions of the molecules on the other side. Figure 6 shows the docking of KPL to SO(4) CD with the Si face of the substrate exposed to the surface. In the SO(4)-Si-P1 supramolecular structure (Figure 6a) the CD has a conformation very close to the one of SO(4)-Re-P1 (Figure 5a), with the values of τ1 and τ2 dihedral angles of 176° and 151°. KPL exposes its Si face to the surface, so that the interactions of the carbonyl groups of KPL with the quinuclidine ring are inverted. The substrate molecule in this geometry is more distant from the surface than in the corresponding conformer where the Re face is exposed to the surface. These differences contribute to the lower stability of the SDS. From the analysis of the supramolecular structures having KPL chemisorbed to Pt, it results that their stability strongly depends on the distortion of the adsorbed alkaloid, as determined by the angles τ1 and τ2. The SO(4)-SiC1 and SO(4)-Si-C1b structures (Figure 6b and 6c) are characterized by distorted conformations of CD. In general, the SDS in Figure 6 have very similar features compared to the ones of Figure 5, but minor contributions can determine the prevailing population of one surface docking geometry and thus asymmetric reaction pathways. As mentioned in the previous section, the figures illustrating the SDS for which CD has an SO(3) adsorption mode are available as Supporting Information (Figure S1 and S2). We will discuss such structures with reference to these figures and to Table 1. At a first glance, the docking interactions of KPL to SO(3) and SO(4) are similar. The conformations of the CD scaffold seems to be the main point of difference between the different supramolecular structures. Figure 7 illustrates the main difference between docking sites formed by SO(3) (Figure 7a) and SO(4) (Figure 7b) adsorbed CD: due to the presence of the hydroxyl group, the SO(3) conformation has less freedom to bend down toward the metal, while the SO(4) conformation is more free to rotate and generate a more stable site. Such differences are reflected in

10206 J. Phys. Chem. C, Vol. 112, No. 27, 2008 the adsorption energies: for the SO(3) conformation the physisorbed adsorption modes of KPL are by far the more stable (Table 1) indicating that the chemisorption of KPL in proximity of the modifier destabilizes the system, as already noted for the SO(4) conformation. In physisorbed states the distance of KPL from the surface is larger for those SDS where CD has an SO(3) conformation than for those where CD has an SO(4) conformation, while the interactions with the quinuclidine moiety are comparable. In supramolecular structures where KPL is chemisorbed, the interactions between KPL and the quinuclidine ring are weaker with SO(3) conformations of CD than with SO(4) conformations. Analysis of geometries and energies of all the twenty six sites (Figures 4 and 5, Supporting Information, and Table 1) leads to a general picture of the interactions between the adsorbed alkaloid and the substrate. In the first place, the docking of the substrate in the chiral site is dominated by three main factors: (i) the formation of weak interactions (hydrogen bonds) with the modifier in the region of the hydrogenated quinuclidine, (ii) the interactions of the substrate with the metal surface, that can lead to physisorbed or chemisorbed adsorption modes, and (iii) the steric hindrance by the molecules on the surface causing distortions to the whole of the supramolecular structure. The energy gain due to chemisorption in general is not sufficient to compensate for all such effects. The most stable supramolecular structures are the ones where KPL is physisorbed, and more conformational freedom is left for both CD and KPL. Further evidence in favor of a dominant catalytic role of the SO(4) conformations of CD have also been found: (i) the most stable supramolecular docking structures are formed with an SO(4) conformation of CD, (ii) in this conformation the alkaloid has better access to the surface hydrogen, and (iii) the quinuclidine moiety can optimize its interactions with the metal, and thus form more stable sites. 3.3. Docking of KPL to the Tilted Adsorbed Modifier. Throughout the literature dedicated to cinchona modified platinum catalysts the existence of so-called tilted adsorption modes of CD is found. By tilted adsorption modes of the alkaloid, such modes are intended where the quinoline ring (anchoring group) is not adsorbed parallel to the metal but rather forms only partially chemisorption bonds to some of the metal atoms, in particular via the quinoline nitrogen. The importance of the tilted modes has always been considered relatively low for enantioselection since their relative surface fraction increases with increasing surface coverage,34 whereas enantioselectivity concomitantly decreases.72,73 This has led to the conclusion that tilted adsorption of the alkaloid constitutes a nonefficient docking site. Such modes are described elsewhere44,45 and have also been used for a computational docking study when naphthyl-ethylamine is used as surface modifier.32 In the present investigation the docking of KPL to tilted CD was performed to check the relative energies of the corresponding supramolecular docking structures. The images of such structures have been included in the Supporting Information. KPL has been docked with both the Re and Si faces to CD in both SO(3) and SO(4) tilted configurations, and the results have been compared to the corresponding supramolecular structures where the quinoline has a parallel adsorption mode with respect to the metal. The former are less stable by more than 10 kcal/mol compared to their parallel adsorbed counterparts. From a geometrical point of view, KPL interacts with the surfacemodifier complex in a similar way for the four adsorption modes of CD. The overall relative instability of these supramolecular

Vargas et al. structures is evidently due to the lesser stability of the tilted adsorption modes of quinoline. 3.4. Rate Acceleration. An important aspect of this intriguing reaction system is the rate acceleration that is often observed upon performing the asymmetric hydrogenation. In other words the hydrogenation reaction has a higher apparent rate in the presence of the modifier than in the racemic reaction.74–76 Several contributions have dealt with this aspect,77–81 but the most simple explanation seems to arise from the mentioned biomimetic nature of the system. In fact rate acceleration is a well-known phenomenon in enzyme catalysis, and a classic explanation has been reported by Page and Jencks82 which points out that the specific binding process per se plays an important role in reducing the free energy of activation of reactions catalyzed by enzymes. The mentioned explanation is based on the concept that enzymes utilize substrate-binding forces to act as entropy traps and well applies to the system that is described in the present contribution. This observation strengthens the analogy traced between man-made catalysts based on chiral surface modification and enzyme chemistry, and adds importance to the concept that also for chiral surface modification the docking of the substrate to the chiral site is a central event. 3.5. Reaching of the Docking Sites. In the previous sections, it has been pointed out that the physisorbed SDS are in general more stable than the chemisorbed ones. This behavior seems to be due to the fact that upon chemisorption the interacting system is rigid, because it is strongly constrained by directional surface bonds. In the present section, we will analyze this point more in detail, by trying to decouple the energies in play during the docking process. Such simulations require the use of the larger slab (Figure 1b) in order to calculate the energies of systems where the substrate and the modifier are both on the surface but are distant enough not to interact. Let us assume that KPL docks to CD as in Figure 5a, the energetically more stable supramolecular structure found. Reaching this structure either implies the direct docking of the substrate from solution or the migration of a surface adsorbed KPL from the unmodified surface to the docking center. The former case is the simplest, since the KPL finds its way from the solution to a stable binding site. However, any substrate will also interact with the metal, i.e., adsorb to the metal, and will then have to reach the chiral binding site in order to receive the asymmetric information. For this case it is useful to study the steps that a surface adsorbed species has to take in order to reach the binding site. First KPL reaches the surface, in some region distant enough from the binding site. Figure 8a shows this case for a physisorbed state of KPL. The energy value (top left) is relative to the state depicted in Figure 8d, that was found to be the most stable and thus set as reference (zero value). As shown, in the position in Figure 8a, the system is approximately 13 kcal/mol less stabilized than in its most convenient docking site (position d, Figure 8). In order to reach its energy minimum the physisorbed KPL can either directly reach the docking state which, as mentioned, is also physisorbed, or it can first chemisorb (position b, Figure 8) and then migrate through surface bonds to the docking site. Upon distant chemisorption (position b, Figure 8), the system gains approximately 4.6 kcal/mol and is at ca. 7 Å from the chiral site. When KPL migrates nearer to the CD, still remaining chemisorbed (position c, Figure 8), the system gains another 1.5 kcal/mol. If at this point chemisorption of KPL is released (position d, Figure 8), the system gains another 7 kcal/mol. The energies of the intermediates are schematized in Figure 9, where solid lines indicate physisorbed states of the substrate while

Chiral Recognition on Catalytic Surfaces

J. Phys. Chem. C, Vol. 112, No. 27, 2008 10207 4. Conclusions

Figure 8. Interactions of KPL forming the Re enantiomer with SO(4) CD. Calculations have been performed using the cell in Figure 1b (8 × 8). The panels show only the top layer of the slab to simplify the graphic representation. At the top-left angle of each panel, the designation of the SDS and the relative energy (kcal/mol) are shown.

Figure 9. Schematic representation of the relative energies of the docking process of KPL. Calculations have been performed using the cell in Figure 1b (8 × 8). The solid lines indicate physisorbed states of the substrate, whereas the dashed lines indicate its chemisorption states. The states a-d correspond to the SDS in Figure 8.

dashed lines indicate its chemisorption states. Chemisorption and chemisorbed migration likely imply the highest activation barriers, and it seems likely that the preferred pathway might not involve chemisorbed substrates. In brief the resulting picture is that adsorbed CD can conveniently interact with species coming from solution or alternatively with species that are physisorbed to the metal, in both cases requiring little activation. For what concerns species that are chemisorbed to the surface, the effect of the chiral binding site is that of decreasing the energy of their chemisorption bond, thus promoting detachment from the metal. Both mechanisms (direct and surface mediated docking) should be present in amounts that depend upon the relative concentration between surface adsorbed species and species in solution and furthermore upon the degree of coverage of the modifier. In fact if the surface concentration of the modifier approaches the monolayer, formation of chemisorbed or physisorbed intermediates of the substrate will become unlikely for lack of space and consequently for the high energy involved in displacing the modifier.

Docking events on chiral surface sites dominate the enantiodiscriminating potential of chiral surfaces used for catalysis, and their understanding is of fundamental importance for the design and engineering of functional metal surfaces. Throughout the competent literature dedicated to the platinum-cinchona alkaloid catalytic system the oversimplified assumption that chiral sites are generated by only one surface conformer of CD (open(3)) is generally made, based on the results of conformational studies obtained for the alkaloid in solution. It is in fact a challenging task to extrapolate submolecular details from the experimental studies on the alkaloids adsorbed to a metal. In addition, performing electronic structure calculations in the presence of a large model surface is computationally very demanding. The present investigation for the first time discloses the complexity of the docking events that can occur on conformationally complex surface chiral sites, and shows in detail the docking interactions of one of the most commonly used substrate for test reactions, namely ketopantolactone. Twenty six supramolecular docking structures have been calculated and analyzed concerning their geometrical and energetic features, thus showing that the SO(4) conformation of CD forms the most efficient surface docking site. The resulting supramolecular structure exposes the Re face of the substrate to the metal, in accord to the experimental observation that the (R)-pantolactone is being formed in the catalytic hydrogenation over cinchonidine modified platinum. The other important result consists in the understanding that the supramolecular docking structures where the substrate is chemisorbed to the surface are in most cases extremely unstable when compared to supramolecular structures for which the substrate is only physisorbed. Although uncovering the details of the dynamics of the hydrogenation process needs further investigation, the role of the adsorbed alkaloid seems to be that of docking a solute or physisorbed species, or of destabilizing the adsorption of a strongly surface-bound substrate. In fact the energy gained by the system upon chemisorption and docking of the KPL is overcome by the larger energy gain implied in the release of the substrate from the surface, when in close contact with the chiral site. The rate acceleration is interpreted following a scheme widely used in the catalysis by enzymes, according to which the entropic contribution implied in the docking event is a sufficient condition for the lowering of the activation barrier of the hydrogenation. Further investigations will be needed to explore the complete reaction pathway of the hydrogenation process. The main elements required for the understanding of this complex reaction system have been elucidated leading to a consistent view of the crucial surface phenomena involving the chiral recognition and docking procedures occurring on the modified metal surface. Acknowledgment. Financial support from the Swiss National Science Foundation is kindly acknowledged. The Swiss Center for Scientific Computing (CSCS) in Manno and ETH Zurich are acknowledged for providing computational resources. Matthias Krack (Laboratory for Reactor Physics and System Behavior, Paul Scherrer Institut) is thanked for useful discussions. Supporting Information Available: Figures illustrating the minimized docking structures with the cinchonidine in the SO(3) adsorption mode (two figures, S1 and S2, each illustrating six supramolecular docking structures). In addition, one figure illustrating the supramolecular docking structures relative to the cinchonidine in a tilted adsorption mode (S3). The Cartesian matrices of the supercells of all the supramolecular docking

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