Understanding the origin of reactivity, mechanism and regioselectivity of the [3+2] cycloaddition reaction between nitrile imine and pyrrolopyrazine

In this work, we have performed a computational study on the [3+2] cycloaddition (32CA) reaction between nitrile imine and pyrrolopyrazine within molecular electron density theory (MEDT) using B3LYP and M06-2X DFT functionnals together with 6-31G(d,p) basis set. This study shows that the popular B3LYP is the appropriate functional for performing this study. The analysis of energy profiles indicates that this 32CA reaction favours kinetically the formation of a single product as observed experimentally. The favour cycloadduct (P-1) is formed through a moderate polar stepwise mechanism, in which the first step is the determining one that is characterised by a moderate polarity and the second step by a highly polar character, while the unfavoured one is formed via a nonpolar one-step asynchronous mechanism. Solvent effects do not change the regioselectivity, but it increases the activation energies. Thermodynamic parameters analysis indicates that this 32CA reaction is characterised by an exothermic and endergonic characters favouring the formation of cycloadduct (P-1), as observed experimentally. Conceptual DFT (CDFT) reactivity indices analysis shows that pyrrolopyrazine 2 reacts as a nucleophile, while nitrile imine 3 as an electrophile. Local reactivity descriptors, such as Parr functions and dual descriptors, show that this 32CA reaction is regioselective leading to the formation of P-1. Analysis of ELF electron density demonstrated that the interaction between the high electron density reactive centre with that of low electron density leads to the formation of P-1 cycloadduct. The obtained results using MEDT method are in great agreement with what observed in the experimental data.