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45452-B1
Asymmetric Heterogeneous Catalytic Hydrogenations
Based on our earlier findings new catalytic systems capable of strong adsorption of proline have been designed and tested. First, the effect of catalyst support on the enantioselectivity was studied. We have found that using several base supported Pd catalysts such as Pd/BaCO3, Pd/CaCO3 and Pd/SrCO3 from different suppliers the expected effect was observed. The effects of different experimental variables were also investigated. Proline appeared to be the most effective modifier. The readily available proline enantiomers provided the opposite enantiomeric products with very high ee values (99 and 97% respectively). Hydrogen pressure significantly affected the reaction rates, however, did not reasonably affect the optical purity. (S)-dihydroisophorone was obtained with 99% ee using (S)-proline, while in the presence of (R)-proline (R)-product formed in 94% optical yield. Studying the mechanism of the reaction we observed irregular ee vs. conversion curves indicating the possibility that a secondary reaction (a kinetic resolution) took place. This possibility has been verified. It was observed that (S)-proline modified catalysts consumed (R)-dihydroisophorone in a faster reaction resulting in the formation of (S)-dihydroisophorone enriched mixtures. Using (R)-proline modified catalysts, the opposite enantioselection was observed. The extent of the kinetic resolution was different in the case of different catalysts. Pd/BaCO3 resulted in enantiopure (S)-dihydroisophorone, the ee values turn to saturation at 62% ee on Pd/Al2O3 and with at 12%ee on Pd/C. It indicated that using base supported Pd catalysts the enantiodifferentiation is unambiguously more effective than on other neutral supports.
A recent paper, discussing the nature of enantioselection in the above reaction, prompted us for further investigation regarding the mode of enantioselection in the proline modified asymmetric hydrogenation of isophorone (3,5,5-trimethyl-2-cyclohexenone) on supported Pd catalysts. We have found that several experimental factors, such as modifier structure and chemical nature of the catalyst support, strongly affected the outcome of the hydrogenations. Secondary kinetic resolution appeared to be the major reason for obtaining high enantioselectivities on most catalysts. Extensive studies have been carried out to clarify the importance of modifier-catalyst interaction prior to the complex formation with the substrate. The secondary kinetic resolution of dihydroisophorone was also investigated under different conditions. First, racemic-dihydroisophorone was studied using several (S)-proline modified supported Pd catalysts, then the individual enantiomers were subjected to similar reaction on (S)-proline modified Pd/BaCO3 catalyst. The above detailed results allowed us to draw conclusions regarding the reaction mechanism. We have provided multiple experimental evidence (see below) to support the heterogeneous enantiodifferentiation model in the proline–modified Pd catalyzed C=C bond hydrogenation reactions.
(1) The first important fact is that the time frame of the catalytic hydrogenation is significantly shorter than that observed in proline-isophorone complex formation in the homogeneous medium. The reaction rate for the complete hydrogenation process (a three step reaction including complex formation between isophorone and proline, hydrogenation and decomposition of the hydrogenated complex) was significantly faster on the surface of catalysts than the complex formation itself under exclusively homogeneous conditions (2-3 h compare to 24-96 h). This clearly showed that the homogeneous formation of intermediate complex was negligible regarding the observed enantioselectivity.
(2) The reaction showed a very significant support effect. Basic supports (inorganic carbonates or basic polymers) remarkably enhanced both the enantioselectivity and chemoselectivity of the reaction. These catalysts improve proline adsorption on the catalyst's surface and decrease proline concentration in the solution. The lower concentration of proline negatively affects the complex formation in the solution.
(3) The results indicated that the very high enantioselectivities were the result of a secondary kinetic resolution on most catalysts. The reaction rates suggested that the secondary kinetic resolution occured predominantly on the surface of the catalyst.
(4) Experiments showed comparable rates of the complex formation of dihydroisophorone enantiomers with proline in solution. The observed ee is only 7.7% at equilibrium. The reaction rates of the hydrogenation of these enantiomers in the presence of proline, in contrast, are significantly different on Pd/BaCO3 catalysts. It suggests that the reaction leading to enantiodifferentiation occurs on the catalyst's surface. (Catal. Letters, in preparation)
New basic polymer-supported Pd catalysts have been prepared and characterized. These catalysts are similar to the above detailed inorganic carbonate supported catalysts. Our observations supported the above mentioned conclusions. Any support of basic character provided a possibility for a chemical proline adsorption, and significantly enhanced the enantioselectivity. However, as these polymer sufaces had a limited surface coverage of basic sites they did not catalyze the undesired side reactions so efficiently. Thus, the selectivity for the desired product had significantly increased. (J. Catal. in preparation).
