Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory

Abstract

The regioselectivity in non-polar [3+2] cycloaddition (32CA) reactions has been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311G(d,p) level. To this end, the 32CA reactions of nine simplest three-atom-components (TACs) with 2-methylpropene were selected. The electronic structure of the reagents has been characterized through the Electron Localisation Function (ELF) and the Conceptual DFT. The energy profiles of the two regioisomeric reaction paths and ELF topology of the transition state structures are studied to understand the origin of the regioselectivity in these 32CA reactions. This MEDT study permits to conclude that the least electronegative X1 end atom of these TACs controls the asynchronicity in the C−X (X=C, N, O) single bond formation, and consequently, the regioselectivity. This behaviour is a consequence of the fact that the creation of the non-bonding electron density required for the formation of the new single bonds has a lower energy demand at the least electronegative X1 atom than at the Z3 one.

On the Mechanism of the Synthesis of Nitrofunctionalised Δ2-Pyrazolines via [3+2] Cycloaddition Reactions between α-EWG-Activated Nitroethenes and Nitrylimine TAC Systems

“…Therefore, the more preferred reaction channel for analyzed [3+2] cycloaddition reactions are forming 5-nitrosubstituted ∆ 2 -isoxazolines 4a,c,e according to path B. The regioselectivity of 32CA between nitrylimines 1a,c,e and nitroalkenes 2a-c cannot be determined using similar approach due to the non-polar nature of these processes [45].…”

Application of β-Phosphorylated Nitroethenes in [3+2] Cycloaddition Reactions Involving Benzonitrile N-Oxide in the Light of a DFT Computational Study

“…It should be underlined that the molecular mechanism of the presented reaction cannot be defined a priori. For 32CAs, several more mechanisms are possible, e.g., nonpolar mechanisms, including synchronous mechanisms, a biradical one-step mechanism and a stepwise biradical mechanism [31], as well as polar mechanisms, including synchronous mechanisms, a one-step-two-stage mechanism or a stepwise zwitterionic mechanism [32,33]. It is impossible to predict the relevant mechanism a priori without any data, which are obtained in the practice.…”

Mpro-SARS-CoV-2 Inhibitors and Various Chemical Reactivity of 1-Bromo- and 1-Chloro-4-vinylbenzene in [3 + 2] Cycloaddition Reactions

“…Along a polar reaction engaging the contribution of non-symmetric reagents, the most favorable reactive channel is that involving the initial two-center interaction between the most electrophilic center of the electrophile and the most nucleophilic center of the nucleophile [70]. In this context, the electrophilic P + k and nucleophilic P − k Parr functions [71] derived from the excess of spin electron density reached via the GEDT [55] process from the nucleophile toward the electrophile have shown to be the most accurate and insightful tools for the study of the local reactivity in polar and ionic processes.…”

“…Along a polar reaction engaging the contribution of non-symmetric reagents, the most favorable reactive channel is that involving the initial two-center interaction between the most electrophilic center of the electrophile and the most nucleophilic center of the nucleophile [70]. In this context, the electrophilic The experimental formation of the meta isoxazolines B-m and C-m, which are the main cycloadducts, indicates that these 32CA reactions present complete regioselectivity [46].…”