Multiple Functional Organocatalyst-Promoted Inert C–C Activation: Mechanism and Origin of Selectivities

Although breakthroughs in the N-heterocyclic carbene (NHC)-catalyzed inert C–C bond activation strategy have been achieved, understanding the role of the catalyst as well as the origin of its chemo- and stereoselectivities is still one of the most challenging questions in the field of organocatalysis. Herein, we propose an NHC and NHC·H⁺ cooperative catalytic model for these kinds of reactions and perform density functional theory calculations in the case of an NHC-catalyzed [4 + 2] annulation reaction of conjugated dienal and α-aryl ketone. The calculated results indicate that the organocatalyst either works as a Lewis base to prevent the bad frontier molecular orbital overlap mode, promoting [2 + 2] cycloaddition, or as a noncovalent organocatalyst to provide a hydrogen bonding network to facilitate the release of CO₂. The latter is remarkably different from its well-known role as a Lewis base. In addition, we devised an atomic electrophilicity index to correctly predict the site of the stereoselective C–C bond formation involved in [4 + 2] cycloaddition. Further analysis results show that hydrogen bonds significantly contribute to the favorable stereoselective pathway, which was associated with axial chirality of the main final product in an experiment. The obtained insights should be valuable for the prediction and rational design of organocatalytic inert C–C activations with special chemoselectivity and high stereoselectivity.