Stereochemical and electronic complementarity drives both arene and facial selectivity for carbohydrate CH–π Interactions

CH-π interactions between a sugar and an aromatic amino acid play an important role in carbohydrate recognition by proteins. Glycoconjugate model systems have been instructive in highlighting the importance of electronic and dispersive effects in driving carbohydrate-arene association in aqueous solution. These interactions have been probed using NMR, leveraging ring current-induced magnetic fields in arenes to effect chemical shift perturbations (CSPs) in select glycoside proton resonances upon association with aromatic rings. In this work tryptophol and phenethyl alcohol were identified as improved aromatic surrogates that overcome previous solubility limitations and allow a greater dynamic range of shift perturbations to be observed and interpreted. Armed with these aromatic probes, we examined the CSPs of a panel of methyl glycosides of biological and configurational interest to identify CH-p interaction preferences for common pyranosides. We identified clear trends that correlate the strength of the CH-π interactions with the identity of both the carbohydrate and arene. Indole and phenyl rings exhibit variations in the affinity and selectivity of their CH-π interactions, highlighting different components of the CH-π interaction driving carbohydrate-arene contacts. Our results underscore the interplay of stereoelectronic effects, arene electron density, and dispersion forces on the facial selectivity and arene interaction preferences in the carbohydrate CH-π interaction. This work highlights the role of carbohydrate conformation and the importance of carbohydrate-aromatic interfacial complementarity for effective CH-π interactions in water.