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

Luis Domingo,Mar Ríos Gutiérrez,Jorge Castellanos Soriano

doi:10.3390/org1010003

Luis Domingo, Mar Ríos Gutiérrez + Show 1 more

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https://doi.org/10.3390/org1010003

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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.

Highlights

Cycloaddition reactions are one of the most useful tools in organic synthesis as they permit to obtain cyclic organic compounds with a regio- and/or stereoselective fashion [1,2]. [3+2] cycloaddition (32CA) reactions are an important class of cycloaddition allowing the formation of five-membered heterocycles of great pharmaceutical and industrial interest [3,4]
TACs can be classified as bent TACs (B-TACs) or linear TACs (L-TACs)
Reactivity models associated to the four different TAC structures. These findings have provided a rationalisation of experimental outcomes [17−21]

Summary

Introduction

Cycloaddition reactions are one of the most useful tools in organic synthesis as they permit to obtain cyclic organic compounds with a regio- and/or stereoselective fashion [1,2]. [3+2] cycloaddition (32CA) reactions are an important class of cycloaddition allowing the formation of five-membered heterocycles of great pharmaceutical and industrial interest [3,4]. [3+2] cycloaddition (32CA) reactions are an important class of cycloaddition allowing the formation of five-membered heterocycles of great pharmaceutical and industrial interest [3,4]. This kind of cycloaddition implies the 1,3-addition of an ethylene derivative to a three-atom-component (TAC) (see Scheme 1). Many of the TACs participating in 32CA reactions are non-symmetric with respect to the central www.mdpi.com/journal/organics atom. When ethylenes, such as 1-substituted or 1,1-disubstituted ethylenes, are non-symmetric, at least a pair of regioisomeric cycloadducts can be formed along the reaction (see Scheme 2).

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