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.