From Disorder to Continuum: Accurate Hydrogen-Atom Positioning in Molecular Solids

High Resolution Image Download MS PowerPoint Slide Accurate localization of hydrogen atoms in short intermolecular hydrogen bonds remains challenging in X-ray crystal structure analysis, particularly for systems near the salt–cocrystal boundary. Many such structures have been reported to exhibit hydrogen-atom disorder, raising questions about the underlying proton potential-energy landscape. Here, we combine Hirshfeld atom refinement (HAR) of X-ray diffraction data, solid-state NMR spectroscopy, and periodic density functional theory (DFT) calculations to re-examine hydrogen bonding in molecular crystals featuring short O–H···N/N–H···O contacts. We selected 29 candidate structures with reported hydrogen disorder; original diffraction data for 14 systems were rerefined using HAR, and several additional systems were newly crystallized and structurally redetermined. In all experimentally accessible cases, HAR refinements converged without disorder and yielded proton positions consistent with independent ssNMR measurements. Periodic DFT calculations revealed shallow and method-sensitive potential-energy surfaces for short hydrogen bonds, rationalizing the frequent misassignment of proton positions in conventional refinements. These results demonstrate that apparent hydrogen-atom disorder in short hydrogen bonds is predominantly an artifact of spherical-atom refinement models rather than evidence for genuine proton positional disorder. The results establish a robust experimental–theoretical framework for distinguishing between salt, cocrystal, and continuum structures.