Mechanistic Insights into the Regio- and Stereoselectivity of [3+2] Cycloaddition Reactions between N-methyl-phenylnitrone and trans-1-chloro-2-nitroethylene within the Framework of Molecular Electron Density Theory

Abstract

The [3+2] cycloaddition (32CA) reaction between N-methyl-phenylnitrone 1 and trans-1-chloro-2-nitroethylene 2 have been studied using Molecular Electron Density Theory (MEDT) to analyze the reaction mechanism and the regioselectivity. The global reactivity indices show that 2 is classified as a strong electrophile while 1 is a strong nucleophile. Four reaction pathways, including ortho/meta regioselective and endo/exo stereoselective modes, were explored in vacuo and in solution (benzene,  = 6.0). The study reveals ortho regioselectivity with high endo stereoselectivity, consistent with experimental results. The BET study shows a one-step asynchronous reaction mechanism, where the O–C bond forms before the C–C bond in ortho/endo(exo) pathways and inversely in the meta/endo(exo) ones. The reaction mechanism involves the depopulation of V(N,C) and V(C,C) basins, leading to the new bonds formation. Molecular docking studies suggest that the cycloadducts, particularly CA-mx, exhibit strong binding to the HCT-116 colorectal cancer resistance protein, with favorable ADMET properties, indicating potential as therapeutic agents for colorectal cancer.