Reactivity and regioselectivity in reactions of methyl and ethyl azides with cyclooctynes: activation strain model and energy decomposition analysis.

The structures and energies for the Huisgen 1,3-dipolar cycloaddition reactions of methyl and ethyl azides with some cyclooctynes and dibenzocyclooctynes were computed at the B3LYP/6-311++G(d,p) level. The activation strain model (ASM) and quantitative molecular orbital (MO) theory were used to investigate the reactivity and regiochemistry in these reactions. The energy decomposition analysis (EDA) was used to identify the intrinsic electronic factor that lead to the preferential formation of 1,7-regiochemistry products. The reactivity order agrees with formation of more synchronous transition states and lower distortion energies. For the reaction of N3Met with azacyclooctyne, the 1,7-regiochemistry preference is attributed to a lower FMO gap and a higher contribution of the polarization term of the interaction energy than for the 1,8-transition state. For the reaction with aza-dibenzocyclooctyne, the 1,7-preference is due to a lower strain energy and a more pronounced contribution of the exchange term of the interaction energy. Graphical Abstract In the reactions between methyl and ethyl azides with azacyclooctynes the regiochemistry is governed by the intrinsic electronic factors.