Unveiling [3+2] cycloaddition reactions of pyridinium bis(methoxycarbonyl)methylides and pyridinium dicyanomethylides with cyclooctyne for indolizine synthesis from the molecular electron density theory perspective

The [3 + 2] cycloaddition (32CA) reactions of a series of pyridinium bis(methoxycarbonyl)methylides (PMYs) and pyridinium dicyanomethylides (PCYs) with cyclooctyne to generate indolizines have been studied within the Molecular Electron Density Theory (MEDT). Interestingly, the electronic structure of these azomethine ylides (AYs) revealed from the topological analysis of the electron localization function (ELF) differs considerably from that of the simplest AY and accordingly, the molecular reactivity is changed. Consequently, the corresponding 32CA reactions of PCYs and PMYs require refluxing toluene conditions to overcome the high activation barrier contrary to the unappreciable energy cost demanded by the simplest AY. This is explained by the analysis of conceptual DFT indices characterizing the ambiphilic character of the PMYs and PCYs classified as strong electrophiles and strong nucleophiles within the standard reactivity scales. The 32CA reactions of PCYs are more facile relative to the PMYs in agreement with the experimental outcome. These polar 32CA reactions show the global electron density transfer (GEDT) higher than 0.2 e and proceed through one-step mechanism with highly asynchronous TSs in which the new covalent bond formation has not been started. Herein, we report the first MEDT study to comprehend the reactivity of pyridinium methylides towards 32CA reactions leading to indolizines.