Conformational Equilibrium Isotope Effects in Glucose by 13C NMR Spectroscopy and Computational Studies

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Abstract
Anomeric equilibrium isotope effects for dissolved sugars are required preludes to understanding isotope effects for these molecules bound to enzymes. This paper presents a full molecule study of the α- and β-anomeric forms of d-glucopyranose in water using deuterium conformational equilibrium isotope effects (CEIE). Using 1D 13C NMR, we have found deuterium isotope effects of 1.043 ± 0.004, 1.027 ± 0.005, 1.027 ± 0.004, 1.001 ± 0.003, 1.036 ± 0.004, and 0.998 ± 0.004 on the equilibrium constant, H/DKβ/α, in [1-2H]-, [2-2H]-, [3-2H]-, [4-2H]-, [5-2H]-, and [6,6‘-2H2]-labeled sugars, respectively. A computational study of the anomeric equilibrium in glucose using semiempirical and ab initio methods yields values that correlate well with experiment. Natural bond orbital (NBO) analysis of glucose and dihedral rotational equilibrium isotope effects in 2-propanol strongly imply a hyperconjugative mechanism for the isotope effects at H1 and H2. We conclude that the isotope effect at H1 is due to np → σ* hyperconjugative transfer from O5 to the axial C1−H1 bond in β-glucose, while this transfer makes no contribution to the isotope effect at H5. The isotope effect at H2 is due to rotational restriction of OH2 at 160° in the α form and 60° in the β-sugar, with concomitant differences in n → σ* hyperconjugative transfer from O2 to CH2. The isotope effects on H3 and H5 result primarily from syn-diaxial steric repulsion between these and the axial anomeric hydroxyl oxygen in α-glucose. Therefore, intramolecular effects play an important role in isotopic perturbation of the anomeric equilibrium. The possible role of intermolecular effects is discussed in the context of recent molecular dynamics studies on aqueous glucose.

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