Electronic Structure–Driven Hydrogen-Bond Site Selectivity in Ketohexose Crystals: DV-Xα Calculations and Full Interaction Maps

Rare sugars are monosaccharides and their derivatives that are found in very small amounts in nature. Single crystals of sugars selectively adopt specific hydrogen-bonding motifs from the vast number of possible patterns derived from their molecular structures. However, the principles governing this selection remain unresolved crystallography. In this study, we investigate the origin of site selectivity in ketohexose crystals using molecular orbital calculations (DV-Xα method) combined with Full Interaction Maps (FIMs) analysis. Bond overlap population values (~10⁻²) were used to quantify hydrogen-bond strength. The results show that dominant hydrogen-bonding sites are consistently identified as O2 in fructose- and allulose-type compounds, O3 in sorbose-type compounds, O3–O4 in D-tagatose, and O2–O5 in 1-deoxy-D-tagatose. These sites correspond to regions predicted by FIMs as favorable for hydrogen bonding. These findings demonstrate that hydrogen-bond site selectivity is governed by intrinsic electronic structure and provide a framework for predicting intermolecular interactions in molecular crystals.