Estudo computacional da metilação de nitronatos [R¹R²CNO2] em solução : mecanismo e seletividade

Abstract

Nitronates are ambidentate nucleophiles obtained by deprotonation of organonitrates and are important intermediates in organic synthesis in the formation of C-C and C-O bonding. In this work, a computational study of the nitronate methylation reactions of type [R1R2CNO2]− with the methylating agents CH3Cl, CH3I, (CH3)3O+ and MeOBs (p-BrPhSO3CH3), in gas phase and in solution (DCM, THF, CCl4 and DMF), in order to investigate the relevant factors for the determination of regioselectivity (O-methylation versus C-methylation) and esteroselectivity (E:Z) in O-methylation, both for alkylnitronates (where R1 = H, R2 = CH3) and for arylnitronates (where R1 = H, R2 = X-Ph with X = H, MeO and NO2). We have used methods based on density functional theory (DFT), in particular the functional M06-2X, were used, and the solvent effect was considered with the SMD solvation model. The study has shown that alkylnitronates reacting with methylating agents whose central carbon atom is a softer acid, for example CH3I, have the C-methylation pathway as kinetic and thermodynamically preferred, since the carbon atom in the nitronate is a softer base than the oxygen atoms. By changing the nature of the methylating agent to harder acids, the C:O regioselectivity is changed, since the O-methylation pathway becomes kinetically preferential. Also, the effects of the solvent on the selectivities of the reactions can not be disregarded, since for the [R1R2CNO2]− + CH3Cl system the tendency for O-methylation increases when the polarity of the aprotic solvent increases, this mechanism being kinetically preferential. Also due to the stabilization of the products by the solvent effect, both the C-methylation products and the O-methylation products are quite exergonic, so that the dependence of the selectivity (determined from differences in the height of the activation barriers) in the reactions, it becomes larger. For the arylnitronates in the gas phase and in solution, the reaction occurs preferentially with the attack of the carbon of the methylating agent by the oxygen of the nucleophile, the energies of activation of O(E)-methylation being smaller. This can be attributed to the conjugation between the aromatic ring and the carbanion of the nitronate, as the nucleophilic reactivity decreases with the delocalization of charges, making the attack by the carbon less reactive. However, with the CH3I methylating agent, the selectivity of the reaction continues to have the C-methylation channel as kinetic preferential and thermodynamically in the gas phase. This shows a predominance of the effect of the methylating agent on the effect of the R1 and R2 groups on the nitronate. Electron donor group attached to the aromatic ring at the para position further stabilize the transition state of O-methylation over that of C-methylation, in accordance with the experimental observations. Therefore, the computational methodology used can reproduce the trends observed experimentally and in the theoretical and computational studies available in the literature.