Two Competing Mechanisms for the Copper-Free Sonogashira Cross-Coupling Reaction

The mechanism of the copper-free Sonogashira cross-coupling was investigated using a model reaction with differently para -substituted phenylacetylenes and 4-iodobenzotrifluoride as coupling partners and a Pd 2 (dba) 3 ·CHCl 3 −AsPh 3 catalyst system in methanol. A carbopalladation mechanism was ruled out through a series of experiments in which the equivalent of a carbopalladation reaction intermediate was synthesized by an alternate route, and its conversion to product was monitored. A Hammett correlation study revealed a possible mechanistic changeover when going from electron-rich to electron-poor alkynes in the model reaction. It is advocated that the reaction mechanism changes from a pathway involving a fast proton transfer from a slowly forming cationic Pd complex to a pathway involving a slow proton transfer from a neutral Pd complex on going from electron-rich to electron-poor alkynes. The amine base is believed to act as a base in both pathways and as a nucleophile promoting the formation of the cationic complex in the reactions involving electron-rich alkynes. This was substantiated by the observation of a primary isotope effect ( k Alkyne-H / k Alkyne-D ≈ 2) for the electron-poor alkyne and a pronounced base dependence for the electron-rich one.