Understanding the reactivity and regioselectivity of [3 + 2] cycloaddition reactions between substituted nitrile oxides and methyl acrylate. A molecular electron density theory study

Abstract

The [3 + 2] cycloaddition (32CA) reactions of three nitrile oxides (NOs) (R‐CNO; R = Ph, CO2Me, and Br) with methyl acrylate (MA) have been theoretically studied within the molecular electron density theory. Topological analysis of the electron localization function of these NOs permits to establish that they will participate in zw‐type 32CA reactions. Analysis of the conceptual DFT indices indicates that these zw‐type 32CA reactions will have a low polar character as a consequence of the relatively low electrophilic character of MA and the low nucleophilic character of NOs, in agreement with the global electron density transfer computed at the corresponding TSs. The activation enthalpies associated with these 32CA reactions range from 8.2 to 12.7 kcal·mol−1. The presence of the bromide atom provokes the larger acceleration. While the 32CA reaction involving the CO2Me substituted NO is highly ortho regioselective, the other two reactions are poorly ortho regioselective. A bonding evolution theory study of the more favorable ortho regiosiomeric channel associated with the 32CA reaction involving the Br substituted NO indicates that this reaction is associated to a nonconcerted two‐stage one‐step mechanism, in which the activation energy is mainly related to the initial rupture of the CN triple bond of the NO.

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory

“…Thus, while the simplest NI 8 is classified as a moderate nucleophile, the simplest NO 9 is classified as a marginal nucleophile within the nucleophilicity scale [29]. The low electrophilicity ω and nucleophilicity N indices of the simplest NO 9 indicate that the corresponding zw-type 32CA reaction will have a non-polar character, in agreement with the analysis of the electronic chemical potentials, and high activation energy [24].…”

“…The linear geometry of phenyl NO 9, together with this ELF analysis suggest that this TAC has a propargylic structure. Consequently, the topological analysis of the ELF of phenyl NO 4a indicates that this TAC has a zwitterionic structure [24] participating in zw-type 32CA reactions, just as the simplest NO 9, thus presenting a different reactivity to that of carbenoid diphenyl NI 2a.…”

“…Due to the non-polar character of the reaction, these bonding changes cannot be favoured [36]; (ii) formation of the first C3−C4 single bond takes place at S3-NI, at a C−C distance of ca. 1.98 Å and with an initial population of 1.95e, by donation, in an 80:20 ratio, of the non-bonding electron density of the C3 carbenoid centre of diphenyl NI 2a to a C4 pseudoradical centre created from the depopulation of the conjugated C4−C5 bonding region of (R)-carvone 1 along the reaction path (see Figure 4) [24]; (iii) formation of the second N1−C5 single bond takes place at the end of the reaction path at S5-NI, at an N−C distance of ca. 1.85 Å and with an initial population of 1.13e, by donation of non-bonding electron density of the N1 nitrogen to the C5 carbon; (iv) despite the non-polar character of the reaction, the considerably high degree of asynchronicity, ca.…”

Shedding light on the energetics, regioselectivity, stereoselectivity, and mechanistic aspects of [3 + 2] cycloaddition reaction between azomethine imines and 2‐sulfolene through molecular electron density theory

“…Indeed, as proposed by Huisgen, in a “1,2‐zwitterionic” or “1,3‐zwitterionic” electronic structure, a positive (+1 e ) and a negative charge (−1 e ) are entirely located at the adjacent or geminal centers, respectively, in quite disagreement with the electronic structure of E ‐AI‐2 confirmed with NPA. It should also be indicated that “the charge distribution distinguished by the NPA is the consequence of the asymmetric electron density delocalization within a molecule resulting from the presence of different nuclei in the molecule, rather than the consequence of the resonance Lewis structures.” Note, however, that other common TACs such as azomethine ylides, azomethine imines, nitrile oxides, diazoalkanes, and nitrones do not represent any 1,2‐ and/or 1,3‐zwitterionic electronic structure at their GSES.…”

“…In terms of the ELF analysis and independent of the phenyl ring position, both Z ‐AI‐1 and E ‐AI‐2 are able to participate in a zwitterionic‐type ( zw ‐type) 32CA reaction . It is of high great importance to emphasize that within MEDT, a zwitterionic TAC, leading to a zw ‐type reactivity in the corresponding 32CA reaction, is referred to as a specific bonding pattern without any pseudo (di)radical ( pdr ), pseudo (mono)radical ( pmr ), and carbenoid ( cb ) reactivity, an entirely different concept than what has been proposed by Huisgen.…”