Carbohydrate Physicochemical Properties: The Innate Hydrogen Bond Donating Capacities of α-Glucoside and...

Despite the significance of hydrogen bonding in protein-carbohydrate interactions, carbohydrate conformation, and crystallinity (solubility), relative hydrogen bond donating capacities (HBDC) of individual alcohol groups of a given sugar are poorly characterised. Here the first systematic determination of the HBDC of individual sugar alcohol groups has been achieved, which were ranked in a HB-scale (pK_AHY-scale) that is relevant for medicinal chemistry purposes. HB determination was achieved using an IR-based protocol with methyl α-glucoside- and α-galactoside-based model compounds that exclude any contributions from HB cooperativity effects. A wide variation in HBDC was found, especially for galactose, with a strong stereochemical dependence not only of the alcohol group itself, but also at adjacent and even remote positions. The glucose 4-OH and, notably, the galactose 6-OH groups were the strongest donors, whereas the glucose 2-OH and, notably, the galactose 4-OH groups were the weakest donors. Interestingly, the galactose 6-OH is the only group with a stronger HBDC than cyclohexanol. These differences could be qualitatively rationalised by a combined IR, NMR, and computational analysis, pointing to counteracting influences from inductive and the often multiple possible intramolecular hydrogen-bonding effects. The difference between the factors that determine carbohydrate HB donating capacities and Brønsted acidities is discussed.