Revealing Stepwise Mechanisms in Dipolar Cycloaddition Reactions: Computational Study of the Reaction between Nitrones and Isocyanates

The mechanism of cycloaddition reactions
of nitrones with isocyanates
has been studied using density functional theory (DFT) methods at
the M06-2X/cc-pVTZ level of theory. The exploration of the potential
energy surfaces associated with two reactive channels leading to 1,2,4-oxadiazolidin-5-ones
and 1,4,2-dioxazolidines revealed that the cycloaddition reaction
takes place through a concerted mechanism in gas phase and in apolar
solvents but a stepwise mechanism in polar solvents. In stepwise mechanisms,
the first step of the reaction is a rare case in which the nitrone
oxygen acts as a nucleophile by attacking the central carbon atom
of the isocyanate (interacting with the π-system of the CO
bond) to give an intermediate. The corresponding transition structure
is stabilized by an attractive electrostatic interaction favored in
a polar medium. The second step of the reaction is the rate-limiting
one in which the formation of 1,2,4-oxadiazolidin-5-ones or 1,4,2-dioxazolidines
is decided. Calculations indicate that formation of 1,2,4-oxadiazolidin-5-ones
is favored both kinetically and thermodynamically independently of
the solvent, in agreement with experimental observations. Noncovalent
interactions (NCI) and topological analysis of the gradient field
of electron localization function (ELF) bonding confirmed the observed
interactions.