Computational study of regio- and stereoselectivity in aza-diene cycloadditions with ethyl vinyl ether and methyl acrylate as ethylene derivatives.

Within the context of Molecular Electronic Density Theory (MEDT), this study investigates the hetero-Diels-Alder (HDA) reaction among aza-diene 1 and ethyl vinyl ether 2a (reaction 1) and methyl acrylate 2b (reaction 2) applying Density Functional Theory (DFT) simulations at the M06-2X/6-311+G(d,p) level of approximation. The results of the local reactivity indices analysis based on the Parr functions confirmed the regiochemistry experimentally observed. Exploration of potential energy surfaces (PESs) indicated the formation of 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyridine-6-carbonitrile α-regioisomer (reaction 1) and methyl 6-cyano-4-phenyl-3,4-dihydro-2H-pyridine-3-carboxylate β-regioisomer (reaction 2). Conceptual DFT reactivity indices show that 1-aza-butadiene is a strong electrophile, ethyl vinyl ether is a strong nucleophile, and methyl acrylate is a weak nucleophile. Electron localization function and quantum theory of atoms in molecules topological analyses of the electronic structures of the transition state structure reveal a high degree of similarity in their electron density distributions, highlighting the asynchronous nature of the reaction mechanism, a conclusion further supported by BET analysis, favoring a total agreement with experimental findings.