Relative stability of alternative chair forms and hydroxymethyl conformations of β-d-glucopyranose

The relative energies of two hydroxymethyl conformers for each of the two chair forms (4C1 and 1C4) of β-d-glucose were calculated at much more complete levels of quantum mechanical (QM) electronic structure theory than previously, and relative free energies in solution were calculated by adding vibrational, rotational, and solvent effects. The gas-phase results are based on very large basis sets (up to 624 contracted basis functions), and the coupled cluster method for electron correlation. Solvation Model 4 was used to calculate the effects of hydration or nonpolar solvation. Molecular mechanics (MM) and QM electronic structure theory have been applied to analyze the factors contributing to the relative energies of these conformers. Relative energies varied widely (up to 35 kcal/mol) depending on theoretical level, and several levels of theory predict the experimentally unobserved 1C4 ring conformation to be the lower in energy. The highest level calculations predict the 4C1 chair to be lower in free energy by about 8 kcal/mol, and we also find that the gauche+ (gt) conformer of 4C1 is lower than the trans (tg) conformer. Low-energy structures optimized by either quantum mechanical or molecular mechanical methods were commonly characterized by multiple intramolecular hydrogen bonds. Superior hydrogen bonding geometries are available in the 13C4 chair, but are counteracted by increased steric repulsions between axial substituents; MM calculations also indicate increased torsional strain in the 1C4 chair. Manifestations of greater steric strain in the calculated 1C4 structures compared to the 4C1 structures include longer ring bonds, a larger bond angle at the ring oxygen atom, and smaller puckering amplitudes. The MM and QM 4C1 structures compare well with each other and with available X-ray diffraction data. The largest discrepancies between the two kinds of models occur for geometric parameters associated with the anomeric center - the QM structure agrees better with experiment. Greater differences between QM and MM structures are observed for 1C4 structures, especially in the relative orientations of hydroxyl groups serving as hydrogen bond acceptors. In water, the 4C1 chairs are better solvated than the 4C4 chairs by about 5 to 9 kcal/mol because of both larger polarization free energies and improved hydrogen bonding interactions with the first solvation shell. In (a hypothetical) n-hexadecane solution, the 4C1 chairs are better solvated by about 2 to 4 kcal/mol both because of larger polarization free energies and because the larger solvent accessible surface areas of the 4C1, conformers allow increased favorable dispersion interactions. The differential polarization free energies are associated primarily with the hydroxyl groups; the greater steric congestion in the 1C4 chairs reduces opportunities for favorable dielectric screening.