Catalyst Activation, Chemoselectivity, and Reaction Rate Controlled by the Counterion in the Cu(I)-Catalyzed Cycloaddition between Azide and Terminal or 1-Iodoalkynes

A comprehensive mechanistic analysis of the copper-catalyzed azide–alkyne cycloaddition to form 5-protio-1,2,3-triazoles (from terminal alkynes) or 5-iodo-1,2,3-triazoles (from 1-iodoalkynes) is presented. Through various mechanistic probes, we elucidate several salient features of this well-known reaction that have yet to be fully articulated in the literature: Kinetic evidence is provided that supports (i) the copper-catalyzed cycloadditions to form 5-protiotriazoles and 5-iodotriazoles are mechanistically distinct, (ii) the catalyst counterion has a linchpin role in facilitating the chemoselective generation of 5-iodotriazoles from 1-iodoalkynes in the presence of terminal alkynes, (iii) “activation” of the requisite catalyst for protiotriazole synthesis is highly influenced by the nature of the catalyst counterion, and last (iv) a more nuanced interpretation of the role of copper acetylides in triazole synthesis is required. An expanded reaction manifold is offered to provide the most comprehensive image to date of the different copper-catalyzed processes active during triazole synthesis, which are obscured behind what appears to be a simple catalytic system. Ultimately, mechanistic and kinetic insight is provided that can be utilized in the development of chemoselective methods where 1-iodoalkynes and terminal alkynes are simultaneously present.