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

Abstract

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 H 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 H 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 H . 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.

Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst

“…Hydrogen bond catalysis has been utilized as a powerful strategy in organic synthesis, particularly in enantioselective organocatalysis. Asymmetric catalysis by chiral hydrogen bond donors and the metal-free organocatalysis involving hydrogen bonding interactions benefit from formation of hydrogen bonds with substrates and clearly select the transition states that make stronger hydrogen bonds. − Hydrogen bonds are also involved in the reaction mechanisms in the enzyme-catalyzed chemistry. , Substitution of cinchona by a good hydrogen bond donor like the thiourea group (which by itself is also a well-known organic catalyst that includes asymmetric derivatives) at the 6′ position, plays an important role in the catalytic functionality of the cinchona molecule. − …”