The mechanism of copper-catalyzed azide-alkyne cycloaddition reaction: a quantum mechanical investigation.

In this study, the mechanism of CuAAC reaction and the structure of copper acetylides have been investigated with quantum mechanical methods, namely B3LYP/6-311+G(d,p). A series of possible copper-acetylide species which contain up to four copper atoms and solvent molecules as ligand has been evaluated and a four-copper containing copper-acetylide, M1A, was proposed more likely to form based on its thermodynamic stability. The reaction has been modeled with a representative simple alkyne and a simple azide to concentrate solely on the electronic effects of the mechanism. Later, the devised mechanism has been applied to a real system, namely to the reaction of 2-azido-1,1,1-trifluoroethane and ethynylbenzene in the presence of copper. The copper catalyst transforms the concerted uncatalyzed reaction to a stepwise process and lowers the activation barrier. The pre-reactive complexation of the negatively charged secondary nitrogen of azide and the positively charged copper of copper-acetylide brings the azide and the alkyne to a suitable geometry for cycloaddition to take place. The calculated activation barrier difference between the catalyzed and the uncatalyzed reactions is consistent with faster and the regioselective synthesis of triazole product.