Theory-Based Extension of the Catalyst Scope in the Base-Catalyzed Hydrogenation of Ketones: RCOOH-Catalyzed Hydrogenation of Carbonyl Compounds with H₂ Involving a Proton Shuttle

As an extension of the reaction mechanism describing the base-catalyzed hydrogenation of ketones according to Berkessel et al., we use a standard methodology for transition-state (TS) calculations in order to check the possibility of heterolytic cleavage of H₂ at the ketone's carbonyl carbon atom, yielding one-step hydrogenation path with involvement of carboxylic acid as a catalyst. As an extension of the catalyst scope in the base-catalyzed hydrogenation of ketones, our mechanism involves a molecule with a labile proton and a Lewis basic oxygen atom as a catalyst—for example, R−C(=O)OH carboxylic acids—so that the heterolytic cleavage of H₂ could take place between the Lewis basic oxygen atom of a carboxylic acid and the electrophilic (Lewis acidic) carbonyl carbon of a ketone/aldehyde. According to our TS calculations, protonation of a ketone/aldehyde by a proton shuttle (hydrogen bond) facilitates the hydride-type attack on the ketone's carbonyl carbon atom in the process of the heterolytic cleavage of H₂. Ketones with electron-rich and electron-withdrawing substituents in combination with a few carboxylic and amino acids—in total, 41 substrate–catalyst couples—have been computationally evaluated in this article and the calculated reaction barriers are encouragingly moderate for many of the considered substrate–catalyst couples.