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/Al₂O₃ 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.

The relation between the electronic structure of α-substituted ketones and their reactivity in the racemic and enantioselective platinum-catalyzed hydrogenation has been investigated using a combined theoretical and experimental approach. A correlation between the keto carbonyl orbital energy and the hydrogenation rate has been found, which rationalizes the effect of the substituent on the rate of hydrogenation. The uncovered relationship between the keto carbonyl orbital energy and the hydrogenation rate provides a rational explanation for the often observed rate acceleration that occurs when cinchona-modified platinum is used as a enantioselective hydrogenation catalyst. The previously suggested model for enantiodiscrimination based on the different stability of the diastereomeric complexes formed between the reactant and the cinchona modifier is discussed in the light of the new kinetic findings.