Crystal structure prediction (CSP) methods, which use first-principles calculations for structural prediction, are revolutionizing explorations of a wide range of molecular crystals. CSP has found a powerful companion in NMR crystallography (NMRX), which combines information from solid-state NMR (SSNMR) spectroscopy, X-ray diffraction, and first-principles calculations for the prediction, refinement, and validation of crystal structures. The majority of modern NMRX-CSP studies of crystalline organic compounds depend on the measurement of chemical shifts and their accurate calculation. In contrast, despite the abundance of useful quadrupolar nuclides (e.g., ¹⁴N, ¹⁷O, ²³Na, and ³⁵Cl), the measurement and calculation of electric field gradients (EFGs) are seldom used in NMRX-CSP protocols. EFGs are highly sensitive to their surrounding electronic environments, including covalent and dative bonding, as well as weaker interactions (e.g., hydrogen bonding, π-stacking, etc.), which often do not strongly impact chemical shifts. Furthermore, first principles calculations of EFG tensors are not computationally expensive in comparison to those of chemical shifts, as the former are dependent only on the ground-state electron density. The use of experimental and calculated EFG tensors in NMRX protocols could greatly expand the purview of NMRX-CSP methods.

To this end, our group has designed a nascent quadrupolar guided NMR crystallography crystal structure prediction (QNMRX-CSP) protocol, with its initial focus on the use of ³⁵Cl EFG tensor parameters for the prediction, refinement, and validation of structures of simple organic HCl salts. Herein, we discuss the QNMRX-CSP protocol, its applications to molecular crystals of organic HCl salts of increasing complexity (i.e., increased numbers of atoms, greater torsional flexibility, and multiple body problems), and predictions of hitherto unknown structures. It is anticipated that this work will open new pathways to study a wide range of organic molecular solids, with applications to HCl salts of APIs, and perhaps even in situ structural prediction in dosage forms.

Kirill Levin

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