Ketone-Alcohol Hydrogen Transfer Equilibria: Is the Biooxidation of Halohydrins Blocked?

FABRICIO R. BISOGNO; EDUARDO GARCÍA-URDIALES; HAYDEE VALDÉS; IVÁN LAVANDERA; WOLFGANG KROUTIL; DIMAS SUÁREZ; VICENTE GOTOR

CHEMISTRY-A EUROPEAN JOURNAL

WILEY-V C H VERLAG GMBH

Año: 2010

0947-6539

In order to ensure the quasi-irreversibility of the oxidation of alcohols coupled with the reduction of ketones in a hydrogen transfer (HT) fashion, stoichiometric amounts of £-halo carbonyl compounds as hydrogen acceptors have been employed. The reason why these substrates lead to quasi-quantitative conversions has been tacitly attributed to both thermodynamic and kinetic effects. In order to provide a clear rationale for this behavior, we study here the redox equilibrium of a selected series of ketones and 2-propanol by undertaking an approach that combines experimental and theoretical elements. First, the activity of the R-specific alcohol dehydrogenase from Lactobacillus brevis (LBADH) with these substrates is studied. The docking of acetophenone/ (R)-1-phenyethanol, and £-chloroacetophenone/ (S)-2-chloro-1-phenylethanol in the active site of the enzyme confirms that there seems not to be any structural reason for the lack of reactivity of halohydrins. This assumption is confirmed by the fact that the corresponding aluminum-catalyzed Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reactions afford similar conversions as those obtained with LBADH, evidencing that the observed reactivity is independent from the catalyst employed. While the initial rates of the enzymatic reductions and the IR ƒÞ(C=O) values contradict the general belief that electron-withdrawing groups increase the electrophilicity of the carbonyl group, the calculated £GG values of the isodesmic redox transformations of these series of ketones/alcohols with 2-propanol/ acetone support the thermodynamic control. As a result, a general method to predict the degree of conversion obtained in the HT-reduction process of a given ketone based on the IR absorption band of the carbonyl group is proposed, and a strategy to achieve the HT oxidation of halohydrins is also shown. R-specific alcohol dehydrogenase from Lactobacillus brevis (LBADH) with these substrates is studied. The docking of acetophenone/ (R)-1-phenyethanol, and £-chloroacetophenone/ (S)-2-chloro-1-phenylethanol in the active site of the enzyme confirms that there seems not to be any structural reason for the lack of reactivity of halohydrins. This assumption is confirmed by the fact that the corresponding aluminum-catalyzed Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reactions afford similar conversions as those obtained with LBADH, evidencing that the observed reactivity is independent from the catalyst employed. While the initial rates of the enzymatic reductions and the IR ƒÞ(C=O) values contradict the general belief that electron-withdrawing groups increase the electrophilicity of the carbonyl group, the calculated £GG values of the isodesmic redox transformations of these series of ketones/alcohols with 2-propanol/ acetone support the thermodynamic control. As a result, a general method to predict the degree of conversion obtained in the HT-reduction process of a given ketone based on the IR absorption band of the carbonyl group is proposed, and a strategy to achieve the HT oxidation of halohydrins is also shown.