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 phenyl acetylenes and 4-iodobenzotrifluoride as coupling partners and a Pd-2(dba)(3) center dot CHCl3-AsPh3 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) approximate to 2) for the electron-poor alkyne and a pronounced base dependence for the electron-rich one.