Origin of Chemoselectivity Associated with <i>N</i> -Heterocyclic Carbenes as C1 Synthons versus Organocatalysts

Recent studies have shown that N-heterocyclic carbenes (NHCs) can serve as C1 synthons beyond their conventional roles as ligands and organocatalysts, enabling scalable single-carbon atom transfer to α,β-unsaturated amides. In this theoretical investigation, we explore the mechanistic origin and chemoselectivity associated with the dual reactivity of NHCs as C1 synthons versus organocatalysts when N-arylacrylamides are used as the substrate. Chemoselectivity-determining transition states are identified, including the concerted C–N bond cleavage with proton transfer transition state in the C1 synthon pathway and the catalyst regeneration transition state in the organocatalyst pathway. Computational analyses indicate a positive correlation between the electron-withdrawing properties of NHC substituents and their selectivity toward the C1 synthon pathway. Moreover, steric repulsion in the concerted C–N bond cleavage with proton transfer transition state disfavors the C1 synthon pathway, thereby resulting in chemoselectivity reversal. Based on these mechanistic insights, we propose two strategies to promote the conversion from the organocatalyst pathway to the C1 synthon pathway: (i) catalyst structural modification to reduce steric repulsion and (ii) replacement of the base with tert-butoxide. These findings provide a fundamental understanding and design principles for modulating NHC-mediated single-carbon atom transfer reactions, thereby expanding the synthetic utility of NHCs as C1 synthons in organic synthesis.