Investigating the mechanism of formation of nitro-substituted nicotine analogue via the [3 + 2] Cycloaddition reaction of (E)-substituted nitroethene derivatives and (Z)- C-(3-pyridyl)-N-aryl-nitrones: A Density Functional Theory (DFT) study

This study investigates the [3 + 2] cycloaddition reaction mechanism between (E)-substituted nitroethene derivatives and (Z)-C-(3-pyridyl)-N-aryl-nitrones to form nitro-substituted nicotine analogues using Density Functional Theory (DFT) at the B3LYP-D3/6-311G(d,p) level. The results reveal that the reaction proceeds with significant regio- and stereoselectivity, favoring the exo-isoxazolidine nicotine analogue. Substituents on both nitroethene and nitrone influence the activation barriers, with electron-withdrawing groups increasing the reaction's electrophilicity and electron-donating groups increasing nucleophilicity. The calculated global reactivity indices support these trends, with the alkene acting as the electrophile and the nitrone as the nucleophile. These findings provide valuable theoretical insight into the selectivity and reactivity of cycloaddition reactions, offering guidance for the efficient synthesis of nicotine analogues with potential biological applications.