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A semiempirical study of the conformational behavior of cinchonidine and its interaction with methyl pyruvate

Abstract

Hydrogenation of methyl pyruvate on a palladium or platinum surface in the presence of cinchona alkaloids leads to a high degree of enantiodifferentiation. In the present study, the semiempirical AM1 and PM3 methods are employed to perform a detailed analysis of the conformational behavior of cinchonidine and to study its interaction with methyl pyruvate. Nine different minima were located on the potential energy surface for cinchonidine by both the AM1 and the PM3 methods. Some barriers to interconversion between them are relatively high; however, it is always possible to connect two minima through barriers lower than 3.0 kcal/mol so most of the minima can interact with the substrate. The interaction between cinchonidine and methyl pyruvate was calculated by placing methyl pyruvate near the cinchonidine molecule in different orientations and optimizing the final complex. The calculated interaction energy is lower than 3.5 kcal/moland is predominantly due to van der Waals noncovalent interactions. An analysis of the structure of possible pro-R and pro-S complexes indicates that interaction between cinchonidine and methyl pyruvate alone is not enough to induce enantiodifferentiation.

heterogeneous; enantioselective; catalysis; mechanisms; calculations; molecular modelling


A SEMIEMPIRICAL STUDY OF THE CONFORMATIONAL BEHAVIOR OF CINCHONIDINE AND ITS INTERACTION WITH METHYL PYRUVATE

D.A.G.Aranda1** To whom correspondence should be addressed To whom correspondence should be addressed, J.W.M.Carneiro2, C.S.B.Oliveira3, F.B. Passos4, P.R.N. Souza1 and O.A.C.Antunes5

aLaboratório de Termodinâmica e Cinética Aplicada, Escola de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Phone. 55(21)562-7657, Fax: 55(21)562-7567, Cx. Postal 68542, CEP 21945-970, Rio de Janeiro - RJ, Brazil

** To whom correspondence should be addressed To whom correspondence should be addressedE-mail: donato@eq.ufrj.br 2Departamento de Química Geral e Inorgânica,

3Pós-Graduação em Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista, s/n, 24020-150, Niterói - RJ, Brazil

4Departamento de Engenharia Química, Escola de Engenharia, Universidade Federal Fluminense, Rua Passos da Pátria, 156, 24210-000, Niterói - RJ, Brazil

5Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, A-641, 21945-970, Rio de Janeiro - RJ, Brazil

(Received: February 2, 2001 ; Accepted: July 7, 2001)

Abstract - Hydrogenation of methyl pyruvate on a palladium or platinum surface in the presence of cinchona alkaloids leads to a high degree of enantiodifferentiation. In the present study, the semiempirical AM1 and PM3 methods are employed to perform a detailed analysis of the conformational behavior of cinchonidine and to study its interaction with methyl pyruvate. Nine different minima were located on the potential energy surface for cinchonidine by both the AM1 and the PM3 methods. Some barriers to interconversion between them are relatively high; however, it is always possible to connect two minima through barriers lower than 3.0 kcal/mol so most of the minima can interact with the substrate. The interaction between cinchonidine and methyl pyruvate was calculated by placing methyl pyruvate near the cinchonidine molecule in different orientations and optimizing the final complex. The calculated interaction energy is lower than 3.5 kcal/moland is predominantly due to van der Waals noncovalent interactions. An analysis of the structure of possible pro-R and pro-S complexes indicates that interaction between cinchonidine and methyl pyruvate alone is not enough to induce enantiodifferentiation.

Keywords: heterogeneous, enantioselective, catalysis, mechanisms, calculations, molecular modelling.

INTRODUCTION

Enantioselective hydrogenation is an important field in catalysis due to the constantly growing need to produce optically pure chiral compounds, especially as pharmaceuticals, agrochemicals, flavorings and fragrances. The enantioselective hydrogenation of a-ketoesters on the Pt/Al2O3 catalyst surface in the presence of alkaloid modifiers, such as cinchonine and cinchonidine, has been intensively studied in the last several years (Blaser et al., 1997). This reaction plays a central role in the study of the mechanism of heterogeneous catalysis leading to optically active products. The inclusion of cinchonidine in the otherwise unselective reaction mixture leads to an enantiomeric excess of up to 90%, with a high conversion rate (Blaser et al., 1991a). Despite intensive studies, the most relevant features of the phenomena leading to enantiodifferentiation have not been completely elucidated yet (Blaser et al., 1997). Although the origin of enantioselectivity has been attributed to specific interactions between the alkaloid and the reactant molecule (Baiker, 1997; Margitfalvi et al., 2000), important aspects such as substrate specificity, influence of solvent on enantioselectivity and the interactions of the chiral modifier with either the substrate or the metal surface are still poorly understood (Blaser et al., 1997). Understanding the kind of interactions that determine enantioselectivity will help design new and more efficient modifier and catalytic systems.

Cinchona alkaloids are built of essentially three parts: (i) a heteroaromatic ring (quinoline), which is probably responsible for adsorption on the solid catalyst surface; (ii) a heterocyclic ring (quinuclidine), which is supposed to be involved in the interaction with the substract and (iii) a chiral carbon atom between these two rings (Fig. 1). The quinoline ring is essentially rigid. The quinuclidine ring is only slightly twisted in order to relieve the repulsive hydrogen-hydrogen eclipsing interaction (Dijkstra et al., 1989). Therefore, the conformational flexibility of the modifier is essentially determined by rotation around the two single bonds connecting the quinoline and quinuclidine rings. In the present work, we analyze the accessible conformations of the cinchonidine modifier by semiempirical AM1 and PM3 calculations of the partial potential energy surface for rotation around these two bonds. Additionally, we study a set of modifier-substrate complexes in order to determine the nature of interactions between them.


The substrate-modifier interaction can occur either in the bulk solvent medium or on the metallic surface. A complex between cinchonidine and methyl pyruvate in solution, resulting in the shielding of one side of the substrate molecule, has been assumed to be the species responsible for the enantiodifferentiation process (Margitfalvi et al., 1996). Cinchona modifiers are supposed to interact with the carbonyl group of a-ketoesters through the quinuclidine nitrogen atom, since N-alkylation completely eliminates enantiodifferentiation (Baiker, 1997). This interaction would be strengthened by additional p-stacking interaction (Kurita et al., 1994) between the p system of the quinoline ring and the p system of the substrate molecule (Margitfalvi et al., 2000). However, there is also evidence that the p aromatic system of the quinoline ring is essential to the adsorption of cinchonidine on the metallic surface (Baiker, 1997), yielding modified chiral active sites on the otherwise achiral metallic surface. Adsorption of the substrate on these chiral sites would result in enantiodifferentiation (Baiker, 1997). The -OH group bonded to the chiral carbon C9 (Fig. 1) seems to play a minor role, since substitution of -H for alkyl groups leads only to a moderate decrease in enantioselectivity (Blaser et al., 1991).

A clear understanding of the conformational behavior of the cinchone modifier and its interaction with the substrate molecule thus seems to be of upmost relevance in the comprehension of the mechanism operating in this process.

THEORETICAL CALCULATIONS

Our first goal in this work was to carry out a detailed analysis of the potential energy surface (PES) of the cinchonidine molecule at the semiempirical AM1 (Dewar et al., 1985) and PM3 levels (Stewart, 1989). This was done by systematically rotating the two most relevant single bonds of cinchonidine, C4'-C9 and C9-C8 (Fig. 1). Starting at -180o the C8-C9-C4'-C3' and C7-C8-C9-C4' torsional angles were independently increased in 20o steps up to a final value of 180o. A bidimensional grid of points indicates the possible minima, whose conformations were then fully relaxed to permit complete optimization of all degrees of freedom, including the dihedral angles frozen in the previous step. This procedure revealed nine minima on the PES of cinchonidine. These were further confirmed as true local minima by calculation of the second derivative matrix. Analysis of the normal modes for each minimum showed that the corresponding vibrational frequencies are all positive.

Starting with optimized conformations of cinchonidine at their minimum energy levels, a set of complexes between cinchonidine and methyl pyruvate was completely optimized. The complexes were designed so that the main proposed interaction between the two molecules (Baiker, 1997; Margitfalvi et al., 2000) would be favored. In particular, we exhaustively looked for complexes where the nitrogen atom of the quinuclidine ring would interact with the carbonyl group of methyl pyruvate. Complexes where the -OH group of cinchonidine would interact with the methyl pyruvate by hydrogen bonding were also studied. As neither of these approaches led to any relevant stabilization, we also tried to randomly put the methyl pyruvate molecule in various other positions around the modifier structure. In each case, two complexes were optimized, one starting with an arrangement that would lead to pro-R complexes and another with an arrangement which would lead to pro-S complexes. About one hundred conformations for the cinchonidine-methyl pyruvate complex were optimized. The most relevant structures that we found are discussed in the present paper.

The main parameter we use to quantify the degree of interaction between cinchonidine and methyl pyruvate is the energy of interaction, which is calculated as the difference between the energy of the cinchonidine-methyl pyruvate complex and the sum of energies of cinchonidine and methyl pyruvate (Eq. 01).

Solvent effects were calculated using the COSMO (Conductor-like Screening Model) (Stewart, 1994) methodology included in the MOPAC 93 package (Stewart, 1994). This methodology simulates the effect of a solvent surrounding the molecule and is based on a continuum approach, which generates a conducting polygonal surface around the molecule at the van der Waals distance. It calculates energies and gradients as a function of the medium's dielectric constant e . We used e = 78.4, as recommended for water as solvent (Stewart, 1994). All calculations were done using the AM1 (Dewar et al., 1985) and PM3 (Stewart, 1989) methods of the MOPAC93 package (Stewart, 1994). In all cases, the conformations were optimized for all degrees of freedom. Some structures were further characterized to identify the nature of the stationary point as minimum or transition state.

RESULTS

Conformational Analysis of Cinchonidine

The conformational analysis of cinchonidine, following the methodology described above, located nine minima on its PES. These minima are shown in Fig. 2. Table 1 gives selected dihedral angles for these nine minima. The AM1 results for stable conformations have values of -94 ± 12o (A1, B1, C1), 84 ± 21o (A2, B2, C2) and 4 ± 9o (A3, B3, C3) for the C8-C9-C4'-C3' dihedral angle (T1). The first two groups lead to an orientation of the C9-C8 bond almost perpendicular to the quinoline ring. The last group is of conformations where the C9-C8 bond almost eclipses the C4'-C3' bond. The C7-C8-C9-C4' (T2) dihedral angle, with values of -76 ± 8o (A1, A2, A3), 64 ± 8o (B1, B2, B3) and -177 ± 3o (C1, C2, C3), is more clustered together. The first two groups correspond to open conformations, while the last group is representative of closed conformations (Margitfalvi and Tfirst, 1999). The PM3 method gives results similar to the AM1 method with a C8-C9-C4'-C3' dihedral angle (T1) of -99 ± 17o (A1, B1, C1), 77 ± 12o (A2, B2, C2) and 9 ± 39o (A3, B3, C3). Individual differences between AM1 and PM3 add up to 35o. As in the case with AM1, the PM3 calculations indicate that the C7-C8-C9-C4' dihedral angle (T2) is more tightly distributed, with values of -87 ± 7o (A1, A2, A3), 76 ± 13o (B1, B2, B3) and -171 ± 4o (C1, C2, C3). The largest individual difference between AM1 and PM3 for the C7-C8-C9-C4' angle is 18o.


Relative energies are given in Table 2. The A2 conformer is the most stable in the AM1 method with dihedral angles T1 of 104.2o and T2 of -68.3o, corresponding to the conformation found in the crystallographic experiment (Margitfalvi and Tfirst, 1999). This open form is more stable than closed conformers C3, C2 and C1 which are more stable than open conformer A3. The energy values for these five conformers are within a 2.0 kcal/mol range. Values for conformers B2 and A1 are within a 3.0 kcal/molrange, while conformers B1 and B3 are much less stable. The PM3 method gives a different order of stability, although in general, with small absolute differences from that in the AM1 method (the highest absolute difference is of 2.4 kcal/mol). With PM3 the most stable conformer is closed conformer C2. However, similar to the AM1 results, conformers C3, A2 and C1 are of the same order of stability as C2 with relative energies of less than 2.0 kcal/mol. Once again the less stable forms are those of the B group, with relative stabilities of up to 8.7 kcal/mol.

Fig. 3 shows a pseudopotential energy surface for interconversion along the A1, A2, A3 and C1, C2, C3 pathway (Fig. 3a) and along the C1, A1, B1 and C2, A2, B2 pathway (Fig. 3b), calculated with the AM1 method. We have not tried to locate true transition states for interconversion between the different conformers. However, the points of maximum energy in Fig. 3 represent a good approximation to the energy of the true transition state. The points on the curves that are not minima were obtained by fixing the corresponding dihedral angle and fully optimizing the other degrees of freedom. Only points at minima correspond to fully optimized geometries.


Conformers C1, C2 and C3 have similar energies with a low energy barrier (3.0 kcal/mol) for interconversion (Fig. 3a). Therefore, any of these conformers can be a representative of the group. The less stable B1 and B2 conformers can interconvert into the C1 and C2 conformers, respectively, throughout low energy barriers (Fig. 3b). Additionally, the A and C conformers can also interconvert with energy barriers of than 3.0 kcal/mol(Fig. 3b). Although the conformational space around the points where T1 is equal to - 40o or T2 is equal to 0o could not be attained at room temperature due to their high relative energy, all the conformers can interconvert into one another along pathways with low (less than 3.0 kcal/mol) energy barriers. Therefore, when discussing the interaction between modifier and substrate, at least all the A (open) and C (closed) conformers should be considered, since they are all on the same PES with similar relative energies separated by low energy barriers.

The Effect of Solvent on the Relative Energies of the Cinchonidine Conformers

In order to study the effect of solvent on the relative stability of the cinchonidine conformers, we reoptimized the conformations of the nine minima discussed before using the COSMO methodology (Stewart, 1994). Relative energies, including the effect of solvent, are also given in Table 2.

Previous calculations on the effect of solvent indicated that it can have a considerable effect on the relative stability of the different conformers (Burgi and Baiker, 1998). In particular, closed conformers were found to be preferentially stabilized relative to open conformers, when going from gas phase to polar solvents (Burgi and Baiker, 1998). In the present calculation, we observe a similar behavior. While A and B conformers are slightly destabilized when going to the polar solvent, the C2 conformer in AM1 and C1, C2 and C3 conformers in PM3 are stabilized. In the polar solvent, closed conformer C2 has essentially the same energy as open conformer A2 in AM1 and is considerably more stable than A2 in PM3. As a result of stabilization and destabilization, the relative barriers become more disperse. In the polar solvent, there are only three conformers (A2, C2 and C3) within a 2.0 kcal/mol relative energy range in AM1 and four conformers (A2, C1, C2 and C3) in PM3.

Interaction Between Cinchonidine and Methyl Pyruvate

The interaction between cinchonidine and methyl pyruvate was studied by calculation of a large set of different complexes between these two molecules. Our first approach was to locate the methyl pyruvate molecule near the cinchonidine molecule in a position where the most relevant interactions assumed to act between them would be strengthened (Baiker, 1997; Margitfalvi et al., 2000). After full optimization, we analyzed the energy of interaction and the relative positions of the two molecules. We also tried some complexes with the methyl pyruvate randomly positioned around the cinchonidine molecule. The most stable complexes are shown in Fig. 4. Total stabilization energies and the distance between the quinuclidine nitrogen atom and the carbonyl atom of methyl pyruvate are given in Table 3. R and S in Table 3 indicate arrangements of the cinchonidine and methyl pyruvate molecule which would result in a pro-R or pro-S complex, respectively.


There are some points worth noting in Table 3. The first one is the relatively low energy of interaction. With AM1 the highest energy of interaction is only 3.2 kcal/molwith an average value of 2.4 kcal/mol. The highest energy of interaction increases to 5.5 kcal/mol in the PM3 method, with an average value of 4.0 kcal/mol. We propose that these values are essentially due to nonspecific van der Waals interactions. In order to give support to this hyphothesis. we also calculated the energy of interaction between cinchonidine and the much less polar 2-ethyl,3-methyl-butadiene (Fig. 5). In this case, we found an energy of interaction of 2.0 kcal/mol and 4.5 kcal/mol with the AM1 and PM3 methods, respectively. These values are close to the average values found for the interaction between cinchonidine and methyl pyruvate, therefore confirming the hypothesis of nonpolar van der Waals interactions in the latter case. The low energy of interaction is due to the large distance between the quinuclidine nitrogen atom and the carbonyl carbon of methyl pyruvate. In the AM1 method, this distance is above 3.1 Å with an average value of 4.4 Å. In the PM3 method, this distance is above 4.4 Å with an average value of 4.8 Å.


Another relevant point in Table 3 is the difference in energy of interaction between pro-R and pro-S complexes. The values show that this difference is very small in all cases. This can be an indication that interaction between the two molecules alone is not enough to differentiate one face of the methyl pyruvate, thereby leading to enantiodifferentiation. A closer look at the structures (Fig. 4) of the various complexes we calculated shows that it is very difficult to attribute to them a clear pro-R or pro-S nature. Certainly, the metal surface plays a relevant role in the process of enantiodifferentiation.

DISCUSSION

Conformations of cinchona alkaloids in solution were reported ten years ago on the basis of NMR and X-ray experiments as well as of molecular mechanic calculations (Dijkstra et al., 1989). Dihydroquinidine and methoxydihydroquinidine adopt an open conformation, with the lone pair of the quinuclidine nitrogen pointing away from the quinoline ring (Dijkstra et al., 1989). C9-substituted quinidine derivatives, however, were found to be more stable in the closed conformation (Dijkstra et al., 1989). This corresponds to a conformation where the C9-C8 bond (Fig. 1) is almost perpendicular to the quinoline ring and the N-quinuclidine is in a antiperiplanar position relative to the oxygen atom of the hydroxyl group. The pseudoenantiomeric forms, quinine and dihydroquinine, show similar behavior (Dijkstra et al., 1989). Molecular mechanic calculations reinforced the structure found experimentally and also revealed additional conformations with similar energies.

In addition to the usual four conformations reported in previous work, NMR experiments (NOESY and COSY) at low temperatures and ab initio calculations were able to find two additional minima (Burgi and Baiker, 1998). In the stable conformations, the C3'-C4'-C9-C8 angle adopts values of either -100 ± 10o or 90 ± 10o. The C4'-C9-C8-N angle was found to have values of 60 ± 5o, 150 ± 5o or -50 ± 5o. The most stable conformer calculated at HF/6-31G(d,p) (Burgi and Baiker, 1998) has an open conformation with C3'-C4'-C9-C8 equal to 101.4o and C4'-C9-C8-N equal to 153.6o. Three other conformers were within 3.0 kcal/mol of relative energy. Increasing the basis set or changing to density functional theory had only minor effects on the gas-phase relative energies (Burgi ad Baiker, 1998). Inclusion of solvent effects using the self-consistent reaction field method stabilized closed relative to open conformations (Burgi and Baiker, 1998). The result was that the open conformation, which was calculated to prevail in the gas phase or in apolar solvent, became almost as stable as the closed conformation in a polar solvent. NOESY experiments in d6-acetone indicated the presence of closed and open conformers in solution with the predominance of the open conformer (Burgi and Baiker, 1998).

More recently, the MM+ force field was used to undertake a detailed conformational analysis of the cinchonidine alkaloid (Margitfalvi and Tfirst, 1999). Margitfalvi and Tfirst located nine minimum energy conformations on the PES of cinchonidine. However, only three of them, including, the crystallographic form of cinchonidine, were considered to be stable conformers. The other conformers are unstable, with a barrier energy of about 1.0 kcal/mol to convert them into other more stable conformers.

The conformational behavior of cinchonidine is strongly influenced by the two torsional angles, C3'-C4'-C9-C8 (T1) and C4'-C9-C8-N (T2) (Fig. 1). These are the angles determining the relative orientation of the two rigid quinoline and quinuclidine rings. Also relevant is the orientation of the O-H bond, specially due to the possibility of hydrogen bonding with an acceptor substrate. A qualitative analysis of the two most relevant dihedral angles leads to the following considerations. Carbon atoms C9 and C8 are both sp3 hybridized (Fig. 1). In this case, stable conformations are those with a gauche orientation of substituents. A full rotation of 360o around this bond leads to three possible minima, corresponding to three different conformers. Carbon atom C4 is sp2 hybridized (Fig. 1). In this case, stable conformers are those where a single bond of the sp3 hybridized atom eclipses to the double bond of the sp2 hybridized atom. As the two ring atoms bonded to C4 are not equivalent, each of the three single bonds to substituents on C9 can eclipse with either of the two ring bonds to C4. This results in six minima, corresponding to six different conformers for a full 360o rotation around the C4-C9 bond. Taking the combination of rotation around the two dihedral angles would result in 18 minima for the two-dimensional conformational subspace involving the T1 and T2 torsional angles. Of course, some of these conformers would result in strongly repulsive interactions and would probably not result in a minimum. For example, conformations where the C9-C8 bond eclipses the C4-C5 bond would lead to repulsive interactions with hydrogen H6', thereby distorting this to more stable conformations. The combination of stabilization by electronic interactions and destabilization due to steric repulsive interactions results in only nine of the 18 possible minimum conformers only nine been located by the semiempirical AM1 and PM3 methods. The results obtained in the present work nicely agree with previous experimental measurements or higher level theoretical calculations (Dijkstra et al., 1989; Margitfalvi and Tfirst, 1999; Burgi and Baiker, 1998). Open conformer A2, which was found in the crystallographic experiment (Margitfalvi and Tfirst, 1999), is the most stable conformer according to the AM1 method. The PM3 method shows that closed conformers C2 and C3 are more stable than A2, although with differences in relative energies of less than 1.0 kcal/mol. Most probably at least the three closed conformers, C1, C2 and C3, together with open conformer A2 would be present as an equilibrating mixture in any experiment, with the prevalence of one conformer over the others as a function of environmental conditions. As the solvent effects indicate, the closed conformers would be predominant in a highly polar environment while the open conformer would predominate in an apolar environment. These results are in full agreement with the NMR NOESY experiment which detected the presence of a mixture of open and closed conformers in acetone with the predominance of the open conformer (Burgi and Baiker, 1998). It is also noteworthy that the semiempirical methods are able to reproduce almost exactly the relative order of stability found in more sophisticated ab initio and DFT calculations. HF/6-31G(d) and B3LYP/6-31G(d) calculations for six and four conformers, respectively, also showed the open conformer to be the most stable, with the closed conformers within a 3.0 kcal/mol energy range. In agreement with these higher level calculations, our results also indicate that polar solvent preferentially stabilizes the closed conformers which then become as stable as the open conformers. Therefore, we conclude that the semiempirical AM1 and PM3 methods are able to qualitatively reproduce most of the effects that dictate the conformational behavior of these modifiers. Besides this, both open and closed conformers of cinchonidine should be taken into account when trying to interpret its interaction with other molecules. As the barriers for interconvertion are relatively low, even the less stable forms, like B2 for example, may be stable enough to participate in the complex which results in stereoselectivity.

Next we analyze the possible interaction modes between cinchonidine and methyl pyruvate. In this analysis we should first consider the geometry of the cinchonidine molecule. In open conformer A2, the C4'-C9-C8-N dihedral angle is about 150o. The C3'-C4'-C9-C8 dihedral angle has values of 104.2o (AM1) and 76.2o (PM3). The corresponding values at HF/6-31G(d) are 153.6o and 101.4o, respectively (Burgi and Baiker, 1998). This results in a conformation where the lone pair of the N-quinuclidine points away from the aromatic quinoline ring (Fig. 1). In principle it is possible to design a complex where both the interaction between the nitrogen atom of the quinuclidine ring and the carbonyl carbon as well as between the p system of methyl pyruvate and the p system of the quinoline ring would be favored. However, in the final optimized geometry for this complex, these interactions are not observed. The N-quinuclidine to C-carbonyl distance is above 4.0 Å and there is no evidence for the p-p interaction refered to above (Fig. 4). We tried many initial conformations, but none of the final optimized complexes showed any relevant interaction. The low interaction energy is an indication that noncovalent van der Waals forces are predominant. Since these forces are not stereospecific, they are not able to selectively distinguish between the two stereotopic sides of the substrate. As we have shown recently for some model systems (Carneiro et al.), at large C...N distances, dipolar interactions are the main forces acting between a nucleophilic NR3 group and a carbonyl group. Nevertheless, dipolar interactions are stronger when the R3N...C=O groups are in an arrangement where the N...C=O angle is 180o. In this orientation the N...C=O interaction per se can not be stereoselective (Carneiro et al.). We are therefore proposing that additional variables be included in the analysis in order to achieve a better understanding of the stereoselective process. Although we can not yet clearly indicate what these additional variables should be, obvious candidates are the metal surface and the protonation or semihydrogenation of the modifier or substrate, respectively, as proposed previously (Baiker, 1997; Wells and Wilkinson, 1998), in contrast to the interaction between neutral species discussed in this and in previous work (Margitfalvi et al., 2000; Margitfalvi and Tfirst, 1999).

When considering the other cinchonidine conformers, the conclusions are the same. In the closed C2 conformers, with the lone pair of the quinuclidine nitrogen atom pointing to the quinoline ring, the possiblity for interaction is still smaller. This reflects the slightly lower energy of interaction for this group (Table 3), an arrangement whereby the pyruvate molecule moves away from the quinoline ring (Fig. 4). From a geometric standpoint the best modifier geometry for interaction with the substrate are those of the B group (Fig. 4). However, in this case also there is no strong stabilization, as shown by the stabilization energy given in Table 3.

CONCLUSIONS

The conformational behavior of the cinchonidine modifier and its interaction with methyl pyruvate were studied by the semiempirical AM1 and PM3 methods. These are able to qualitatively reproduce experimental data (Baiker, 1997) or results obtained at higher theoretical levels (Djikstra et al., 1989; Burgi and Baiker, 1998). There are nine minima on the PES for rotation around the single bonds of cinchonidine, C4'-C9 and C9-C8. Of these at least four have similar relative energies and therefore should be considered when analyzing its interaction with a substrate molecule. These minima can be interconverted through energy barriers that are lower than 3.0 kcal.mol–1. Although open conformers are more stable in the gas phase, polar solvents stabilize preferentially closed conformers, rendering them as or even more stable than the open conformers. We calculated a high number (over one hundred) of complexes between cinchonidine and methyl pyruvate. Neither a high stabilization energy nor a geometry which showed in any of them a clear interaction was found. We are therefore proposing that the interaction between cinchonidine and methyl pyruvate in the gas phase per se is not enough to induce the observed enantioselectivity on hydrogenation. This is the same conclusion we reached when studying model systems at high ab initio levels (Carneiro et al.).

ACKNOWLEDGEMENTS

We gratefully acknowledge research fellowships from CNPq (D. A. G. A., J. W. de M. C., F. B. P and P. R. N. de S.) and from CAPES (C. da S. B. de O.). Grant 62.0211/97-0 from PADCT III QEQ/CNPq and E-26/170.329/2000 from FAPERJ provided partial support for this work.

  • Baiker, A., Progress in Asymmetric Heterogeneous Catalysis: Design of Novel Chirally Modified Platinum Metal Catalysts, J. Mol. Catal. A 115, 473 (1997).
  • Blaser, H. U., Jalett, H. P. and Wiehl, J., Enantioselective Hydrogenation of Alpha-Ketoesters with Cinchona-Modified Platinum Catalysts - Effect of Acidic and Basic Solvents and Additives, J. Mol. Catal. 68, 215 (1991a).
  • Blaser, H. U., Jalett, H. P., Monti, D. M., Baiker, A., and Wehrli, J. T., Stud. Surf. Sci. Catal. 67, 147 (1991b).
  • Blaser, H. U., Jalett, H. P., Müller, M., and Studer, M., Enantioselective Hydrogenation of a-Ketoesteres using Cinchona Modified Platinum Catalysts and Related Systems, Catal. Today 37, 441 (1997).
  • Bürgi, T. and Baiker, A., Conformational Behavior of Cinchonidine in Different Solvents: A Combined NMR and Ab Initio Investigation, J. Am. Chem. Soc. 120, 12920 (1998).
  • Carneiro, J. W. M., Oliveira, C. S. B., Passos, F. B., Aranda, D. A. G., Souza, P. R. N., Antunes, and O. A. C., Host-Guest Interactions and their Role in Enantioselective Hydrogenation of a-Ketoesters. An Analysis of Model Systems, J. Mol. Catal. A, submitted for publication.
  • Dewar, M. J. S., Zoebisch, E. G., Healy, E. F. and Stewart, J. J. P., AM1: A New General Purpose Quantum Mechanical Molecular Model, J. Am. Chem. Soc. 107, 3902 (1985).
  • Dijkstra, G. D. H., Kellogg, R. M., Wynberg, H., Svendsen, I. M. and Sharpless, K. B., Conformational Study of Cinchona Alkaloids. A Combined NMR, Molecular Mechanics and X-Ray Approach, J. Am. Chem. Soc. 111, 8069 (1989).
  • Kurita, Y., Takayama, C. and Tanaka, S., Decomposition Analyses of the Intermolecular Interaction Energies in 2 Pi-Pi Stacking Complexes Quinhydrone and N, N, N', N'- Tetramethyl- p- Diaminobenzene- Chloranil Complex, J. Comput. Chem. 15, 1013 (1994).
  • Margitfalvi, J. L., Hegedus, M. and Tfirst, E., Enantioselective Hydrogenation of a-Ketoesters over Cinchona-Pt/Al2O3 Catalyst. Kinetic Evidence for the Substrate-Modifier Interaction in the Liquid Phase, Tetrahedron: Asymmetry 7, 571 (1996).
  • Margitfalvi, J. L. and Tfirst, E., Enantioselective Hydrogenation of a-Ketoesters over Cinchona-Pt/Al2O3 Catalyst. Molecular Modelling of the Substrate-Modifier Interaction, J. Mol. Catal. A 139, 81 (1999).
  • Margitfalvi, J. L., Tálas, E., Tfirst, E., Kumar, C. V. and Gergely, A., The Role of Cinchona Alkaloids in Enantioselective Hydrogenation Reactions: Are They Modifiers or Hosts Involved in Supramolecular Hetrogeneous Catalysis ? Appl. Catal. A 191, 177 (2000).
  • Stewart, J. J. P., Optimization of Parameters Quantum Mechanical Molecular Model, J. Comp. Chem. 10, 209 (1989).
  • Stewart, J. J. P., Mopac 93 Manual Ver. Number 2, Fujitsu Limited (1994).
  • Wells, P. B. and Wilkinson, A. G., Platinum Group Metals as Heterogeneous Enantioselective Catalysts, Topics in Catal. 5, 39 (1998).
  • * To whom correspondence should be addressed
    To whom correspondence should be addressed
  • Publication Dates

    • Publication in this collection
      10 Oct 2001
    • Date of issue
      Sept 2001

    History

    • Received
      02 Feb 2001
    • Accepted
      07 July 2001
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