Mechanistic Exploration of the Pd-Catalyzed Copper-Free Sonogashira Reaction

The reaction mechanism for the Pd-catalyzed Cu-free Sonogashira reaction is analyzed by means of density functional theory (DFT) calculations on a model system. The most common routes proposed in the literature for this reaction, namely, the carbopalladation and deprotonation, are considered. In agreement with experiment, calculations clearly demonstrate that the carbopalladation route can be discarded. For the case of the deprotonation route, however, the reaction pathway may take place via several alternatives; calculations suggest that all of them are feasible. Moreover, an additional pathway where the halide is initially replaced by the base in the coordination sphere of the catalyst is found to be also competitive. The effects of the alkyne's substituents on the reaction are also analyzed by a combined computational and experimental work. Theoretical results suggest that these effects are rather small, and they are confirmed by experiments.