Synthesis of 1,4-Disubstituted-1,2,3-Triazoles via Copper(I)-catalyzed Azide-alkyne Cycloaddition Reaction and Computational Study of the Effect of Substituents on the Reactivity of Aromatic Azides as Precursors of 1,2,3-triazoles

Introduction: Organic azides are valuable precursors of 1,2,3-triazoles, a class of heter-ocyclic compounds with broad biological relevance and diverse applications as functional materi-als. The understanding of the electronic effects of substituents on azide reactivity is crucial for optimizing copper(I)-catalyzed azide–alkyne cycloaddition processes. Methods: A series of 1,2,3-triazoles were synthesized via copper(I)-catalyzed azide–alkyne cy-cloaddition employing microwave radiation as an alternative energy source. Computational studies were performed using Molecular Electrostatic Potential maps and the dual descriptor at the B3LYP/6-311G(d,p) level of theory to analyze the electronic structure of the aromatic azides em-ployed as precursors of 1,2,3-triazoles. Results: Compounds 3a and 3e-g were obtained in moderate to good yields (72-78 %), whereas strongly electron-withdrawing substituents avoided the formation of products 3b-d. The computa-tional analysis revealed differences in the distribution charge on the azide group. Discussion: The absence of products 3b-d is attributed to the presence of strong electron-withdraw-ing substituents. According to the dual descriptor, the formation of the metallacycle between azide and alkyne is favored when N and N exhibit predominantly electrophilic and nucleophilic char-acters, respectively, which promotes the mesomeric effect of the azide. Conclusion: The molecular electrostatic potential maps and dual descriptor revealed that for the evaluated compounds, electron-withdrawing substituents modify the distribution of the electronic density on the azide group. The phenylazides with enhanced positive character at Nβ and higher electron density at Nγ showed better reactivity toward triazole formation. The integration of exper-imental and computational approaches provides insights into the electronic effects in azide reactiv-ity and supports the design of 1,2,3-triazole compounds.