Cinchonidine Research Articles

Time-Lapse STM Studies of Diastereomeric Cinchona Alkaloids on Platinum Metals

The adsorption of cinchonidine (CD) and cinchonine (CN) on Pt(111) and Pd(111) single crystals has been investigated by means of scanning tunneling microscopy (STM) in an ultrahigh vacuum system. In time-lapse series the mobilities of different adsorption species have been determined on a single molecule basis and with varying hydrogen background pressures in the system. The diastereomeric cinchona alkaloids, CD and CN, which are widely used as chiral modifiers of platinum group metals in catalytic enantioselective hydrogenation, showed similar adsorption modes and diffusion behavior on Pt(111), except that the flatly adsorbed CN molecules which were free (not in a dimer/cluster) were significantly more mobile than their CD analogues. CD adsorbed on Pd(111) showed similar adsorption modes as observed on Pt(111) but at considerably higher mobility of the flatly absorbed species already in the low-pressure region. The observed adsorption behaviors are discussed in the context of independent ATR-IR measurements and theoretical calculations. Special emphasis is put on the nonlinear effect observed in hydrogenation reactions with CD/CN mixtures. Our observations corroborate that this effect is mainly a consequence of the different adsorption strengths of CD and CN on Pt.

Origin of ligand acceleration in heterogeneous ethyl pyruvate hydrogenation

Ethyl pyruvate (EP) was hydrogenated in the presence and absence of cinchonidine (CD) over a broad concentration range of EP (0.01–2.0 mol L −1) using a commercial 5% Pt/Al 2O 3 catalyst (Strem). Ligand acceleration (LA) could be observed at a higher concentration (0.3–2.0 mol L −1), whereas at lower concentration, both enantioselective and racemic reactions have very similar reaction rates. Regardless of LA, a constant ( 84 ± 2 % ) enantiomeric excess (ee) could be obtained. As CD concentration was increased, the ee increased from 0 to 80%, while the hydrogenation rate remained constant at a low EP concentration (0.01 mol L −1). Continuous fixed-bed reactor experiments revealed that LA can be linked to catalyst deactivation. In particular, EP causes catalyst deactivation, which is faster at higher reactant concentrations. CD restores catalyst activity and suppresses catalyst deactivation, resulting in higher reaction rates compared with racemic reactions carried out without CD.

Steric and electronic effects in the enantioselective hydrogenation of activated ketones on platinum: Directing effect of ester group

Steric effects in the Pt-catalyzed asymmetric hydrogenation of nine different α-ketoesters were studied by variation of the bulkiness at the keto and ester side of the substrates, and by using cinchonidine (CD), its 6′-methoxy derivative quinine, and o-phenyl derivative PhOCD as chiral modifiers. In the presence of CD, the ( R)-enantiomer always formed in good to high ee (up to 96%), independent of the steric bulkiness of the α-ketoester. None of the mechanistic models developed for ketone hydrogenation on Pt are conform to the observations. Only additional steric effects in the modifiers and replacement of toluene by acetic acid as a reaction medium enhanced the sensitivity of the catalyst system to steric effects in the substrates ( ee = 0 – 94 % ). An important mechanistic consequence of the observations is that on CD-modified Pt preferred adsorption of the α-ketoester on the si-side is directed by the position of the ester group relative to the modifier, independent of the steric bulkiness on any side of the keto-carbonyl group. Ester, carboxyl, amido, carbonyl, acetal, and trifluoromethyl functions have similar directing effects, but when both trifluoromethyl and an ester or carbonyl groups are present in the molecule, the latter function is dominant. The directing effect of the electron-withdrawing (-activating) function on adsorption of the ketone is obviously related to the electronic environment provided by the chiral modifier. The critical role of electronic interactions is supported by the remarkable influence of aryl substituents in the hydrogenation of ethyl benzoylformates.

First principles study of the conformations of cinchonidine on a Pt(111) surface

The conformations of cinchonidine (CD) adsorbed on a Pt(111) surface were studied using first-principles methods. Eight conformationally different adsorption states due to different degrees of rotation around the τ 1 and τ 2 degrees of freedom were identified and their possible role in the formation of chiral surface sites relevant to enantioselective hydrogenation investigated in light of the currently existing experimental evidence. Comparison of the conformational behavior of CD in solution and on platinum has revealed the effect of the metal surface on the internal mobility of the alkaloid. Although the study corroborates the outstanding role of the adsorbed Open(3) conformer suggested previously, the rich conformational flexibility observed on the platinum surface points to the possibility that other conformers of CD also may be involved in enantiodifferentiation. Closed conformations of CD are found to play an important role in the conformational equilibria on the surface due to their stability and are identified as precursors of the less stable, but presumably more active, open conformers. Although the open and closed conformers are closely related to the correspondent ones found in solution, surface species that are also adsorbed via quinuclidine moiety are characteristic of the metal–modifier interaction and should serve as precursors to catalytically active conformations.

Anomalous behavior of rigid cinchona alkaloids in the enantioselective hydrogenation of ethyl pyruvate in an aprotic solvent

The enantio-differentiation (ED) ability of rigid cinchona alkaloids, such as α- and β-isocinchonines (α-ICN, β-ICN), was investigated in the asymmetric hydrogenation of ethyl pyruvate (EtPy) in toluene at low modifier (M) concentration ([ M] 0 = 1.2 × 10 −5 M). The isocinchonines showed anomalous kinetic behavior, i.e., lack of rate acceleration (α-ICN), low ee values, monotonic decrease-type ee - conversion dependencies, independence of the ee on modifier concentration and reaction temperature. When α-ICN was co-injected with either cinchonidine (CD) or cinchonine (CN) the ee-conversion dependencies observed in the presence of pure CD or CN were not altered. The new results indicate that in aprotic solvent the ED ability of flexible and rigid cinchona alkaloids, such as CD, CN and α-ICN, β-ICN should have different origin. It is suggested that ED can take place either in the liquid phase (CD, CN, β-ICN) or at the Pt surface (α-ICN). The formation of substrate–modifier complex in the liquid phase furnishes pronounced rate acceleration for cinchonidine (CD), cinchonine (CN) and β-ICN, but high ee values were obtained only for CD and CN. However, interactions taking place at the Pt surface (α-ICN) result in low ee values and no rate acceleration. Results presented in this study show that both α-ICN and β-ICN only partly resemble the properties of CD or CN, the flexible alkaloids. No RA was also observed when other rigid modifiers, such as (−)-sparteine and (+)-dihydrovinpocetine, were used. These modifiers show similar kinetic patterns as α-ICN.

Solvent-Induced Conformational Changes of O-Phenyl-cinchonidine: A Theoretical and VCD Spectroscopy Study

The conformational analysis of the synthetic chiral modifier O-phenyl-cinchonidine (PhOCD) used in enantioselective hydrogenations over noble metal catalysts has been performed at a PM3 semiempirical level in vacuum. The minimum energy conformations calculated at the DFT level with a medium-size basis set have been compared to those of the parent alkaloid cinchonidine (CD). PhOCD behaves similarly to CD and shows four main conformers, denoted as Closed(1), Closed(2), Open(3), and Open(4). Open(3) is found to be the most stable in vacuum and in CH2Cl2 and CCl4 solvents. A comprehensive normal-mode analysis has been performed for these conformers, and assignment of the infrared spectrum of PhOCD in CCl4 (epsilon = 2.2) has been performed using the calculated spectrum of Open(3), which appears to be the most populated in this solvent. A combined theoretical-experimental VCD spectroscopy approach was used to increase the spectroscopic sensitivity toward changes in the distribution of conformers upon change of solvent polarity. The VCD spectra confirm that Open(3) is by far the most stable conformation in CCl4 (epsilon = 2.2) and indicate that an excess Closed(2) conformer has to be expected in CD2Cl2 (epsilon = 8.9). The possible influence of this conformational behavior is discussed on the basis of available catalytic data and in relation to the enantioselective potential of PhOCD as a chiral modifier on supported metal catalysts.

Ordered mesoporous silicates of MCM-41 type as support of pt catalysts for the enantioselective hydrogenation of 1-phenyl-1,2-propanedione

Platinum catalysts (1 wt.%) supported on MCM-41 type and SiO2have been prepared, characterized and evaluated in the enantioselective hydrogenation of 1-phenyl-1,2-propanedione at 298 K and 20 bar of hydrogen pressure, using cinchonidine (CD) as chiral modifier. Chemisorption and TEM results revealed that both catalysts posses similar metal dispersion, however, significant differences in the catalytic behavior were observed. With dichloromethane as solvent, high hydrogenation rates and ee values around 47% were obtained for the Pt/MCM-41 catalyst. This fact is attributed to a confinement effect. The initial reaction rate is strongly dependent on the CD concentration, and the reaction rate (or ee) vsCD concentration plot exhibits bell-type curves. The main products were (R) -1-hydroxy-1-phenylpropanone and (S) -1-hydroxy-1-phenylpropanone.

Hydrogenation of β-isocinchonicine in mild conditions on Pt and Pd catalysts using HPLC-ESI-ion-trap MS: New results on the role of structure of cinchona alkaloids in the Orito reaction

The hydrogenation of β-isocinchonicine (β-ICNN) was studied on Pt- and Pd-alumina catalysts for the first time. Using mild experimental conditions (293 K, 1 bar hydrogen pressure) in toluene and in AcOH as solvents it was established that the enolo-ethereal C C double bond of β-ICNN is hydrogenated to the two DH-β-ICNN diastereomers. In toluene, hydrogenation proceeds at a significantly higher rate on Pd-alumina catalyst than on Pt-alumina. In AcOH, hydrogenation is fast on both catalysts. There was no significant difference between the selectivities of diastereomer formation on Pd and Pt catalysts. The presence of cinchonidine (CD) and cinchonine (CN) reduced the hydrogenation rate of β-ICNN and had no effect on the stereoselectivity of hydrogenation. Ethyl pyruvate (EtPy) hydrogenation on Pt-alumina catalyst modified with β-ICNN proceeded with low enantioselectivity, which is another piece of evidence for the essential role of the conformation of the chiral modifier in the Orito reaction.

Selective recognition in molecularly imprinted polymer and its chromatographic characterization for cinchonine

A molecularly imprinting polymer (MIP) was synthesized via bulk polymerization under different conditions using anti-ague drug cinchonine (CN) as template. Infrared spectra (IR) results show that the template CN and functional monomer α-methyl acrylic acid (MAA) formed complexes before polymerization and the structure of complexes was simulated by Hyperchem. The results indicate that there are hydrogen bond or ionic bond between functional monomer and template molecule in acetonitrile solution. The MIP made in cold-initiated photo-polymerization has higher separation performance than that in the therm-initiated polymerization. The separation of the isomers CN and cinchonidine (CD) can be successfully obtained when its separate factor α reaches 1.82. Scatchard analysis suggests that the MIP recognizing CN with two classes of binding sites. The partition coefficient Kd, 1 and apparent maximum number nmax, 1 of binding sites with high affinity are 131.43 µmol/L and 58.90 µmol/g, respectively, while Kd, 2 and nmax, 2 of binding sites with low affinity are 2.32 mmol/L and 169.08 mmol/g, respectively.

Rhodium-catalyzed enantioselective hydrogenation of ketopantolactone

Hydrogenation of ketopantolactone was investigated on a 5 wt.% Rh/Al 2O 3 catalyst modified by cinchonidine (CD) and its O-methyl (MeOCD) and O-phenyl (PhOCD) derivatives. Weakly polar solvents, moderate pressure, and relatively high modifier/substrate ratios were advantageous for enantioselection. Chiral modification resulted in significant rate acceleration. The major enantiomer was ( R)-pantolactone in the presence of CD and MeOCD, while an inversion was observed when using the bulky PhOCD. The similar ees measured with CD and MeOCD indicated that the OH function of CD is not involved in the enantioselection. The nonlinear behaviour of CD–PhOCD mixtures is probably due to the weaker adsorption of the latter modifier on rhodium. The highest ee achieved in this study with CD was 40%, less than half of that reported for CD-modified platinum. The lower efficiency of the rhodium–cinchona system is attributed partly to the weaker adsorption of the modifier and the faster hydrogenation of the quinoline ring of the alkaloid resulting in a gradual loss of enantioselectivity at high pressures.

Competition at Chiral Metal Surfaces: Fundamental Aspects of the Inversion of Enantioselectivity in Hydrogenations on Platinum

O-Phenylcinchonidine (PhOCD) is known to efficiently induce inversion of enantioselectivity with respect to cinchonidine (CD) in the enantioselective hydrogenation of various activated ketones on Pt/Al(2)O(3). To understand the origin of the switch of enantioselective properties of the catalyst, the adsorption of PhOCD has been studied by in situ ATR-IR spectroscopy, in the presence of organic solvent and dissolved hydrogen, i.e., under conditions used for catalytic hydrogenation. The adsorption structures and energies of the anchoring group of CD and PhOCD were calculated on a Pt 38 cluster, using relativistically corrected density functional theory (DFT). Both approaches indicate that both modifiers are adsorbed via the quinoline ring and that the spatial arrangement of the quinuclidine skeleton is critical for the chiral recognition. New molecular level information on the conformation of CD relative to PhOCD adsorbed on a surface is extracted from the ATR spectra and supported by DFT calculations. The result is a clearer picture of the role played by the phenyl group in defining the chiral space created by the modifiers on Pt. Moreover, when CD was added to a pre-equilibrated adsorbed layer of PhOCD, a chiral adsorbed layer was formed with CD as the dominant modifier, indicating that CD adsorbs more strongly than PhOCD. Conversely, when PhOCD was added to preadsorbed CD, no significant substitution occurred. The process leading to nonlinear effects in heterogeneous asymmetric catalysis has been characterized by in situ spectroscopy, and new insight into a heterogeneous catalytic R-S switch system is provided.

Enantioselective hydrogenation of ethyl pyruvate catalysed by cinchonine-modified Pt/Al2O3: tilted adsorption geometry of cinchonine

The enantioselective hydrogenation of ethyl pyruvate (EtPy) was studied on Pt-alumina catalyst modified by cinchonine (CN) and for comparison by cinchonidine (CD) in toluene and in AcOH. The effects of the modifiers concentration on the reaction rate and the enantioselectivity were examined. Using the Engelhard 4759 catalyst under mild experimental conditions (room temperature, hydrogen pressure 1 bar) in the case of CN (S)-ethyl lactate (EtLt) formed in excess (ee) (in AcOH ee max ∼ 88%; in toluene ee max ∼72%). In the case of CD (R)-EtLt formed in excess (in AcOH ee max ∼93%; in toluene ee max ∼84%). The results of H-D exchange measurements and results of modifier mixtures suggest that the compounds responsible for chiral induction are different intermediates, which structure depends mostly on the acidic or non-acidic nature of the hydrogenation medium. The proposed structure of intermediate responsible for enantioselection is an 1:1 CN- or CD-EtPy surface complex in which the quinoline skeleton of CD approximately parallel on the Pt surface while the quinoline plane of CN being tilted relative to the Pt surface under identical experimental conditions.

The solvent effect in the enantioselective hydrogenation of ( E)-2-methyl-2-butenoic acid with cinchonidine doped Pd/Al 2O 3

The hydrogenation of ( E)-2-methyl-2-butenoic acid (tiglic acid), using a commercial 5 wt% Pd/Al 2O 3 catalyst (Engelhard) doped with cinchonidine (CD) ( P = 4.0 MPa, T = 298 K) was investigated in depth to evidence the nature of the interaction CD:acid and the specific role of the solvent polarity on the enantiomeric excess (e.e.). Previous results reported in the literature on the same substrate or on similar unsaturated short chain acids have been verified for a feasible industrial application. A linear correlation between the dielectric constant of the solvent ( ɛ) and the e.e. was observed, with a decrease in e.e. by increasing ɛ. The highest enantiomeric excess (e.e. = 48%) was obtained with n-hexane.

Adsorption and surface mobility of cinchonidine on Pt(111) studied by STM

The adsorption of cinchonidine (CD) on Pt(111) has been investigated by means of STM in the presence and absence of hydrogen. The time-resolved studies revealed that the mobility of adsorbed CD molecules depends on the hydrogen pressure. At low hydrogen pressure the CD molecules are rather immobile, whereas considerable mobility is observed at higher hydrogen pressure. Based on the different adsorption geometries and the surface mobility three different species could be distinguished and their dynamic behaviour was investigated on a single molecule level.

Fine tuning the “chiral sites” on solid enantioselective catalysts

A fundamental point in the mechanism of enantioselective hydrogenation over chirally modified metals is the nature of “chiral sites” developed by adsorption of the modifier on the metal surface. Despite considerable effort toward unraveling the adsorption mode of the modifier by surface science techniques, most of these spectroscopic measurements were done under conditions relatively far from those met under real reaction conditions. Here we applied a truly in situ “synthetic” approach, the systematic variation of the structure of the chiral modifier used for enantioselective hydrogenation over 5 wt% Pt/Al 2O 3. We have synthesized various O-alkyl, -aryl, and -silyl derivatives of cinchonidine (CD) and tested them in the enantioselective hydrogenation of ethyl pyruvate, ketopantolactone, 4,4,4-trifluoroacetoacetate, and 1,1,1-trifluoro-2,4-diketopentane. With increasing bulkiness of the ether group, the ee gradually decreased or even the opposite enantiomer formed in excess (up to 53% ee). We propose that the increasing bulkiness of the ether group prevents the strong, π-bonded adsorption of the quinoline ring of CD close to parallel to the Pt surface. In this tilted position the modifier adsorbs weaker via the quinoline N and also the position of the interacting function, the quinuclidine N, is shifted. This shift results in a different shape and size of the “chiral pocket” available for adsorption of the activated ketone substrate. The weaker adsorption of the bulky ether derivatives was proved by UV–vis spectroscopy and by the nonlinear behavior of modifier mixtures. The tilted adsorption mode was corroborated by the lower hydrogenation rate of the quinoline ring of the ether derivatives, relative to that of CD.

On the role of modifier structure in the palladium-catalyzed enantioselective hydrogenation of furan-2-carboxylic acid

Abstract Enantioselective hydrogenation of the aromatic ring of furancarboxylic acids is an important new application of cinchona-modified palladium as there is no synthetically useful method yet available for this transformation. Here we report a mechanistic investigation of the hydrogenation of furan-2-carboxylic acid. The 5 wt.% Pd/Al 2 O 3 catalyst was chirally modified by cinchonidine (CD) derivatives, ( R )-1-(1-naphthyl)ethylamine derivatives, and ( R )-1-(1-naphthyl)-ethanol. Variation of the structure of the modifiers revealed that the major requirement an efficient chiral modifier has to fulfill is the presence of a basic N and an OH function. The relative position of the two functional groups and the acidity (proton donor ability) of the OH group are not critical as indicated by the similar efficiency of 1,2- and 1,3-amino alcohols and amino phenols. The enantioselection is attributed to the formation of a cyclic, 2:1 acid:modifier complex that adsorbs close to parallel to the Pd surface via π-bonding of the aromatic rings of substrate and modifier. The model can interpret also the effect of a strong acid additive. The poor performance of amine type modifiers is attributed to the formation of too flexible, acyclic structures.

New data on enantiomeric excess versus conversion during enantioselective hydrogenation of activated ketones on a platinum catalyst

The initial transient period (ITP) was studied in the enantioselective hydrogenation of activated ketones (ethyl pyruvate, pyruvaldehyde dimethyl acetal, methyl benzoyl formate) on Pt-alumina (E4759) catalyst modified by cinchonidine (CD) or dihydrocinchonidine (DHCD) under mild experimental conditions in toluene (hydrogen pressure: 1 bar, temperature: 253–298 K, modifier concentration: 0.001–1 mmol/L). The effects of temperature, modifier concentration, different pretreatments of the catalyst, and structure of the reactants on the relationship of the enantiomeric excess (ee) and conversion were studied. Our results suggest that the ITP is affected not only by impurities/contaminants present in the catalytic system but also by the competitive adsorption of reactants, modifier, and solvent. Consequently it may not be excluded that the ITP can be considered an intrinsic feature of this type of enantioselective hydrogenation reaction.

Inversion of enantioselectivity in the platinum-catalyzed hydrogenation of substituted acetophenones

The enantioselective hydrogenation of ring-substituted acetophenones that possess no functional group in the α-position to the keto group represents the latest extension of the application range of the Pt–cinchona system. The influence of the type of solvent, pressure, temperature, and modifier/substrate/Pt molar ratios was investigated in the hydrogenation of 3,5-di(trifluoromethyl)acetophenone. Modification of a 5 wt% Pt/Al 2O 3 catalyst by cinchonidine (CD) afforded the corresponding ( S)-1-phenylethanol (69.5% ee). Working in strongly polar solvents, addition of trifluoroacetic acid in a weakly polar solvent, and replacing CD by its ether derivatives resulted in the inversion of enantioselectivity. Addition of CD or any of its derivatives always led to a lower reaction rate, contrary to the generally observed rate acceleration in the hydrogenation of α-functionalized activated ketones over the same catalyst system. Another fundamental difference to the hydrogenation of α-functionalized activated ketones is that both the quinuclidine N and the OH functions of CD influence the stereochemical outcome of the reaction, as clarified by using O- and N-substituted derivatives of CD. Ab initio calculations confirmed these remarkable mechanistic differences. Inversion of enantioselectivity in the presence of strongly polar and acidic solvents is attributed to special interactions with the OH function of CD, and to the formation of a CD–acid ion pair, respectively. A possible explanation for the moderate ee's in the hydrogenation of ring-substituted acetophenones is that a reaction pathway without involvement of the OH function of CD is also feasible. This competing pathway is even faster and provides low ee to the opposite enantiomer.

Rhodium-catalyzed heterogeneous enantioselective hydrogenation of 3,5-di-(trifluoromethyl)-acetophenone

Asymmetric hydrogenation of 3,5-di-(trifluoromethyl)-acetophenone (1) to 1-[3,5-di-(trifluoromethyl)-phenyl]ethanol (2) was studied over 5 wt.% Rh/Al2O3 modified by cinchonidine (CD) and its O-methyl, O-ethyl, O-phenyl, O-trimethylsilyl, N-methyl, and N-benzyl derivatives. Replacement of CD by the ether derivatives resulted in the inversion of enantioselectivity from (S)-2 to (R)-2, and an improvement in chemoselectivity up to 100%. Interestingly, O-phenyl-CD (36% enantiomeric excess (ee)) is a more effective chiral modifier for the reaction than CD (27% ee). CD and its ether derivatives induced a small rate acceleration compared to the unmodified reaction. The basic quinuclidine N of CD seems to be a necessary prerequisite for enantioselection, whereas the role of the OH group is not clear yet. Blocking of the OH group changes the absolute configuration of the major enantiomer.

Continuous enantioselective hydrogenation in fixed-bed reactor: towards process intensification

The platinum-catalyzed enantioselective hydrogenation of ethyl pyruvate (EP) has been studied in a continuous fixed-bed reactor working under trickle bed conditions. The alumina-supported platinum catalyst was chirally modified by continuous dosing of small amounts of cinchonidine (CD) to the reactor feed containing EP and hydrogen dissolved in acetic acid. A parametric sensitivity study, including CD/EP ratio, hydrogen pressure, temperature, solvent/EP ratio and total liquid feed rate indicated significant dependence of reaction rate and enantiomeric excess (ee) on these parameters. Optimization using the Box Wilson method with hydrogenation rate as objective function and ee>90% as boundary condition afforded a site–time–yield, expressed as average turnover frequency (TOF), of 84 000 h −1. The space–time–yield was found to be approximately one order of magnitude higher than that achieved in a batch reactor (autoclave) under otherwise similar conditions. These findings indicate that the continuous fixed-bed reactor operation may provide an interesting opportunity for process intensification of this type of asymmetric catalytic hydrogenations.