Azide–alkyne cycloaddition catalyzed by Cu(i), Ag(i), and Au(i) complexes and the influence of the deuterium isotope: DFT-based computational insights

Abstract

The azide–alkyne cycloaddition reaction, particularly its copper-catalyzed variant (CuAAC), remains a cornerstone of click chemistry due to its efficiency, regioselectivity, and broad applicability in fields such as pharmaceutical synthesis, materials science, and bioconjugation. We present a comprehensive computational DFT study (wB97X-D4/def2-TZVP level of theory) of the thermodynamics and kinetics of the azide–alkyne cycloaddition reaction between 2-azidoethanol and 3-propargylamine in both the presence and the absence of various transition metal catalysts (viz. Cu(I), Ag(I), and Au(I)) and different substituents in the alkyne moiety (viz. hydrogen, methyl, propargylamine, chlorine, phenyl, and chlorine + phenyl). Additionally, we explored the effect of isotopic substitution by modeling all reactions with deuterated compounds.