The anomeric and exo-anomeric effects of a hydroxyl group and the stereochemistry of the hemiacetal linkage

Abstract

The conformational properties and the anomeric and exo-anomeric effects of the hydroxyl group linked to the anomeric carbon in aldopyranoses have been studied with ab initio methods using 2-hydroxytetrahydropyran ( 1) as a model. The potential of rotation around the hemiacetal anomeric C–O bond has been calculated with the 6-31G* and 6-311++G**//6-31G* basis sets. The ab initio geometry and energy of the conformers have been determined by gradient optimization at various levels of the Hartree–Fock and density functional theory (DFT). Vibrational frequencies were calculated at the 6-31G* level and used to evaluate zero-point energies, thermal energies, and entropies for minima. Solvent effects on the stability of conformers were estimated using the continuum model. At all levels of theory, and contrary to the result on 2-methoxytetrahydropyran ( 2), three minima were found on the rotation curves around the C1–O1 bond for both anomers of 1. Variations in calculated valence geometries for compounds display structural changes distinctive for the anomeric and exo-anomeric effects. The calculations predict the axial form of 1 as the preferred anomer in vacuum. Solvent effects change the equilibrium and the equatorial form is favored in aqueous solution. The calculated energy differences are in agreement with the experimental data on 2-hydroxytetrahydropyran. The magnitude of the anomeric effect for the hydroxyl group was estimated to be 2.0 kcal/mol. The hydroxyl group in the axial and equatorial position exhibits the exo-anomeric effect of 2.3 and 2.9 kcal/mol, respectively.