Unveiling the Chemo‐ and Regioselectivity of the [3+2] Cycloaddition Reaction between 4‐Chlorobenzonitrile Oxide and β‐Aminocinnamonitrile with a MEDT Perspective**

Abstract

AbstractA molecular electron density theory (MEDT) study for the [3+2] cycloaddition (32CA) reaction of 4‐chlorobenzonitrile oxide (CBNO) and β‐aminocinnamonitrile (ACN) has been performed at the MPWB1K/6‐311G(d,p) computational level. This 32CA reaction, characterised as the zwitterionic type (zw‐type), presents an activation enthalpy of 11.8, 14.2 and 16.6 kcal mol−1, in gas phase, benzene and methanol. The formation of 3‐aryl‐5‐(β‐aminostyryl)‐1,2,4‐oxadiazole is predicted as the energetically feasible one following a non‐concertedtwo‐stage one‐stepmechanism. Thiszw‐type32CA reaction shows a total chemo and regioselectivity. The global electron density transfer at the most favourable transition state structure (TS), higher than 0.14 e, suggests some polar character. The most energetically favoured TS shows an intramolecular hydrogen bond between the amine −NH2of ACN and the oxygen of CBNO, which favours thiszw‐type32CA reaction. This behaviour is enhanced with the inclusion of a methanol molecule hydrogen bonded to this oxygen atom. The present MEDT study suggests that the best experimental conditions are to use a non‐polar solvent such as benzene containing catalytic amounts of a protic solvent such as methanol.