Theoretical Study of 1,3-Dipolar Cycloaddition Reactions with Inverse Electron Demand − A DFT Study of the Lewis Acid Catalyst and Solvent Effects in the Reaction of Nitrones with Vinyl Ethers

Abstract

The molecular mechanism for the inverse electron demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers has been characterized using density functional theory methods with the B3LYP functional and the 6−31G* basis set. Relative rates, regioselectivity, endo/exo stereoselectivity, Lewis acid catalyst and solvent effects are analyzed and discussed. Four reactive channels associated with the formation of two pairs of diasteromeric regioisomers have been characterized. Analysis of the geometries of the corresponding transition structures shows that the reaction in the gas phase takes place by an asynchronous concerted mechanism. These 1,3-dipolar cycloadditions present a large ortho regioselectivity, while the exo stereoselectivity depends on steric hindrance that appears along the endo approach. The inclusion of Lewis acids and solvent effects increase the asynchronicity and contribute a rate acceleration due to a decrease of the activation enthalpies associated with the most favorable ortho reactive channels. Both increase the electrophilic character of the nitrone, changing the mechanism; these cycloadditions take place by means of a nucleophilic attack of the vinyl ether on the Lewis acid coordinated nitrone, with concomitant ring closure, and without participation of an intermediate.