1,3 Dipolar Cycloaddition of Münchnones: Factors behind the Regioselectivity

Abstract

The 1,3 dipolar cycloaddition reactions of münchnones and alkenes provide an expedite synthetic way to substituted pyrroles, an exceedingly important structural motif in the pharmaceutical and material science fields of research. The factors governing their regioselectivity rationalization are not well understood. Using several approaches, we investigate a set of 14 reactions (featuring two münchnones, 12 different alkenes, and two alkynes). The Natural Bond Theory and the Non-Covalent Interaction Index analyses of the noncovalent interaction energies fail to predict the experimental major regioisomer. Employing global cDFT descriptors or local ones such as the Fukui function and dual descriptor yields similarly inaccurate predictions. Only the local softness pairing, within Pearson’s Hard and Soft Acids and Bases principle, constitutes a reliable predictor for the major reaction product. By taking into account an estimator for the steric effects, the correct regioisomer is predicted. Steric effects play a major role in driving the regioselectivity, as was corroborated by energy decomposition analysis of the transition states.

Expanding horizons in conceptual density functional theory: Novel ensembles and descriptors to decipher reactivity patterns

“…[19][20][21][22][23][24][25] In the category of higher order descriptors, one can retrieve the dual descriptor proposed by Morell et al, [26][27][28] the global hyperhardness 26 that has been shown recently to be connected with reactivity through the maximum hardness principle, 29 and lastly the linear response function. 30,31 All of them have afforded valuable insight into, for instance, electrophilicity and nucleophilicity, 32 regioselectivity issues 33,34 (in the case of the dual descriptor), or electronic effects such as inductive or mesomeric ones (encoded in the linear response kernel). 30,[35][36][37] Conversely, one example of third order descriptor that was proposed but overlooked is the P descriptor (corresponding to a global hypersoftness) proposed by Parr and Fuentealba 26 in 1991:…”