Exploring the Copper(I)-Catalyzed Azide-Alkyne Cycloaddition: A Unified Reaction Valley Approach and Local Vibrational Mode Study.

The mechanism of the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), an adaptable, regioselective, and high-yielding click reaction, was investigated using the Unified Reaction Valley Approach (URVA) and Local Mode Analysis (LMA). The cycloaddition and ring contraction steps of catalysis via both mononuclear and dinuclear catalysts, in the form of Cu(I)-acetylides forming 1,4- and 1,5-products, were explored at the B3LYP/cc-pVTZ level of theory as well as at the CCDT(T) level. The dinuclear mechanism for 1,4-addition was found to have the lowest activation energy and was identified as the most effective catalytic pathway. With the first cycloaddition step presenting the highest energy barrier, single-point energy calculations showed that this barrier is lowest for the dinuclear catalyst, while LMA suggests that regioselectivity may arise from catalyst dissociation and stronger stabilization of the final product. URVA analysis indicated that the transition state of the first step occurs prior to any C-N bond formation, signifying that the energy barrier originates from initial electronic structural changes. These mechanistic insights provide a basis for the design of more efficient CuAAC catalysts.