DFT Analysis of α-Bromoamide Activation Pathways in a Copper-Catalyzed Sonogashira C(sp3)-C(sp) Coupling with Phenylacetylene

The copper-catalyzed Sonogashira coupling of alkyl halides has emerged as a powerful strategy for constructing C(sp3)-C(sp) bonds. This process often occurs through pathways that differ from the traditional two-electron model observed for classical Sonogashira reactions. In particular, the activation mode of the C(sp3)-Br bond in α-bromoamides remains mechanistically ambiguous, with both radical and nonradical pathways being proposed in literature. In this work, density functional theory calculations have been employed to investigate the mechanism of the copper-catalyzed coupling between phenylacetylene and an α-bromoamide as a model for the Sonogashira C(sp3)-C(sp) coupling. A comprehensive exploration of possible C(sp3)-Br activation pathways, including single-electron transfer, halogen atom transfer, and classical two-electron processes, has been carried out. The results support a mechanism involving initial phenylacetylene coordination and deprotonation at copper, followed by halogen atom transfer between the metal and the bromoamide, radical recombination, and reductive elimination as the most energetically favorable pathway in toluene. Calculations suggest that solvent effects may have a substantial impact on the mechanistic landscape. In particular, polar solvents such as DMF have been found to reduce the reaction barriers of pathways where charged species are formed, finally producing a different reaction sequence.