The [3 + 2] cycloaddition (32CA) reaction of an α-santonin derivative, which has an exocyclic C–C double bond, with p-bromophenyl nitrile oxide yielding only one spiroisoxazoline, has been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. Analysis of the conceptual density functional theory (CDFT) reactivity indices and the global electron density transfer (GEDT) account for the non-polar character of this zwitterionic-type 32CA reaction, which presents an activation enthalpy of 13.3 kcal·mol⁻¹. This 32CA reaction takes place with total ortho regioselectivity and syn diastereofacial selectivity involving the exocyclic C–C double bond, which is in complete agreement with the experimental outcomes. While the C–C bond formation involving the β-conjugated carbon of α-santonin derivative is more favorable than the C–O one, which is responsible for the ortho regioselectivity, the favorable electronic interactions taking place between the oxygen of the nitrile oxide and two axial hydrogen atoms of the α-santonin derivative are responsible for the syn diastereofacial selectivity.

The strain-promoted [3+2] cycloaddition (SP-32CA) reactions of phenyl azide with a series of five strained cycloalkynes C5–C9 have been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. These zwitterionic type SP-32CA reactions take place through a one-step mechanism, with activation enthalpies in acetonitrile between −4.2 and 19.9 kcal mol⁻¹. An excellent linear correlation between the decrease in activation enthalpies and the ring size of this series of cycloalkynes can be established. The present study shows that the highly strained cycloalkynes C5 and C6 experience a different chemical reactivity than less strained cycloalkynes C7–C9, caused by the noticeable electrophilic character of the former ones. The present MEDT study permits establishing that the loss of the cycloalkyne strain along the reaction path together with easy depopulation of the C–CC–C bonding region along these SP-32CA reactions, and not “less distortion of the 1,3-dipole in the transition state geometry”, as has been suggested, is responsible for the kinetics and thermodynamics of these SP-32CA reactions.

The BF₃Lewis acid (LA) catalyzed [3+2] cycloaddition (32CA) reaction of 1‐pyrroline‐1‐oxide (PNO) with 2,3‐dihydrofuran (DHF) has been studied within the molecular electron density theory (MEDT) at theωB97X‐D/6‐311G(d,p) computational level. Electron localization function (ELF) characterizes PNO and the corresponding PNO : BF₃complex as zwitterionic species. Conceptual DFT indices allow classifying PNO and DHF as marginal electrophiles and strong nucleophiles, while the PNO : BF₃complex is a strong electrophile. Consequently, while the non‐catalyzed 32CA reaction is non‐polar, the BF₃catalyzed one has a high polar character, revealed by the analysis of the global electron density transfer (GEDT) at the transition state structures. The BF₃catalyzed 32CA reaction, which is classified as of reverse electron density flux (REDF), presents highexostereoselectivity, and totalorthoregioselectivity. The presence of the BF₃catalyst decreases the activation enthalpy of the 32CA reaction in dichloromethane by 7.5 kcal mol⁻¹, as a consequence of the increase of the polar character of the reaction, in complete agreement with the experimentally observed acceleration.