Exploring the regioselectivity in the cycloaddition of azides to alkynes catalyzed by dinuclear copper clusters (CuAAC reaction) using the topologies of ∇ ρ (r) and ∇∇ ρ (r).

The regioselectivity of the dinuclear-Cu(I)-catalyzed version of the Huisgen reaction, abbreviated in this paper to CuAAC, was analyzed using quantum topological methods in order to study how the electronic charge distribution evolved along different reaction paths. Electronic densities were computed at the LC-wPBE/6-311++G(2d,2p)//LC-wPBE/6-311++G(d,p) level. The presence of two copper ions in the catalyst was found to lead to an electrophilic site in the external alkyne carbon that, in a generalized Sharpless-type mechanism, undergoes an initial donor-acceptor interaction with the azide molecule, but with an inverted electrophile-nucleophile pattern when compared with the corresponding mononuclear process (CuAAC). Differences between the two competitive dinuclear-Cu(I)-catalyzed pathways, 1,4-CuAAC and 1,5-CuAAC, arise mainly from the presence of secondary interactions in the 1,5-CuAAC pathway and because different nitrogen atoms are involved in the formation of the second N···C bond. Overall descriptions of both processes are provided.