Hyperconjugative and Electrostatic Interactions as Anomeric Triggers in Archetypical 1,4-Dioxane Derivatives

Abstract

The anomeric effect accounts for the greater thermodynamic stability of axially arranged six-membered heterocycles holding an electronegative substituent at the C1 position. Within a frame of no general consensus, two different theories are typically claimed to justify this effect mostly based on either hyperconjugative or electrostatic factors. Here we report a theoretical- experimental study of the role of both as anomeric triggers in two archetypical 1,4-dioxane derivatives, using a suitable combination of spectroscopic (IR and vibrational circular dichroism) and computational techniques for the analysis of the solvation environment effect in their anomeric choices. VCD and IR spectroscopies are used as conformer-discriminating tools: a detailed analysis of the evolution of the spectral profiles allows assessing the theoretically predicted changes in the experimental a/b ratios when changing the polar solvent, which are fully explained on the basis of an extensive NBO energy partition scheme that provides a detailed view of the role of hyperconjugative and electrostatic interactions as anomeric regulators. Our results suggest that the anomeric equilibrium cannot be described by a single stereoelectronic effect but by the combined contribution of hyperconjugation and electrostatic repulsions, so that the b-anomeric choice in polar solvents is markedly driven by the strong attenuation of electrostatic repulsive interactions that occurs in solution.