A DFT Study on the Binuclear CuAAC Reaction: Mechanism in Light of New Experiments

In this DFT study, the mechanism of the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is revisited in light of recent experimental findings that made significant contributions to unraveling this challenging and important reaction. The generally accepted binuclear mechanism was used as a framework to investigate two inquiries raised by new experiments. First, Fokin et al. have proposed ligand exchanges that can take place as possible alternative pathways to the generic path and in that way they have proved the binuclear nature of the CuAAC mechanism. In this study, the experimentally proposed ligand exchanges which deviate from the generic path were modeled with NHC as the ligand and the electronic nature of the mechanism was also investigated with the NBO analyses. The results in this study are compatible with the experimental proposals, since the ligand exchange and the generic pathways' calculated energies are on the same order. Second, possible pathways for the formation of a recently isolated bis-copper triazolide intermediate were considered by DFT calculations to explain this mechanism thoroughly. It was shown that its formation is energetically highly unfavorable during the cycloaddition step, whereas it can be facile after the formation of the mononuclear triazolide. The calculations were performed at the M06-L/6-31+G(d,p) level with the LANL2TZ+ effective core potential for copper atoms.