Carbohydrate Physicochemical Properties: The Innate Hydrogen Bond Donating Capacities of α‐Glucoside and α‐Galactoside Alcohol Groups

Abstract

ABSTRACT 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 (p K 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.