Lithium Hexamethyldisilazide-Mediated Ketone Enolization: The Influence of Hindered Dialkyl Ethers and Isostructural Dialkylamines on Reaction Rates and Mechanisms

Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS2NLi) solvated by hindered dialkyl ethers (ROR′) are described. Rate studies using in situ IR spectroscopy show that enolizations in the presence of i-Pr2O, 2,2,5,5-tetramethyltetrahydrofuran, and cineole proceed via dimer-based transition structures [(TMS2-NLi)2(ROR′ )(ketone)]≠. Comparing the relative solvation energies and the corresponding solvent-dependent activation energies shows that the highly substituted ethers accelerate the enolizations by sterically destabilizing the reactants and stabilizing the transition structures. Comparisons of hindered dialkyl ethers with their isostructural dialkylamines reveal that the considerably higher rates elicited by the amines derive from an analogous relative destabilization of the reactants and relative stabilization of the transition structures