This study constitutes an extension of a previous research on the regioselectivity of the copper catalyzed cycloaddition of azides to alkynes (1) (the CuAAC reaction) by Quantum Chemical Topological methods. In particular, by following the evolution the topology of the laplacian of the electronic charge density and its gradient vector field along the reaction coordinates, computed with different Density Functionals (B3LYP, LCwPBE, M06-L, wB97XD, and M06-2X) and 6-311++G(d,p) basis set. For the mononuclear process, we found that a H-type interaction conditions the attack of the azide in the 1,5-CuAAC.
In addition, given that experimental evidences (2) seem to suggest the participation of a second Cu atom in the reaction coordinate, we have explored very recently (3) the mechanism involving a dinuclear copper cluster at the LCwPBE/6-311++G(d,p) level. Interestingly, the catalyst modifies the uncatalyzed Huisgen mechanism, by inducing sequentially first the terminal N-C bond and the internal afterwards in a concerted fashion for the 1,4-CuAAC and stepwise for the 1,4-Cu2AAC. Furthermore, as seen in the topology of the laplacian, the catalyst provoked that a carbon acts as a nucleophile and turned pericyclic mechanism into pseudopericyclic (3).
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