Rapid structure determination of molecular solids using chemical shifts directed by unambiguous prior constraints

Abstract

NMR based crystallography approaches involving the combination of crystal structure prediction methods, ab-initio calculated chemical shifts and solid-state NMR experiments are a powerful approach for crystal structure determination of microcrystalline powders. However, currently structural information obtained from solid state NMR is usually included only after a set of candidate crystal structures has already been independently generated, starting from a set of single molecule conformations. Here, we show with the case of ampicillin that this can lead to failure of structure determination. We propose a crystal structure determination method that includes experimental constraints during conformer selection. In order to overcome the problem that experimental measurements on the crystalline samples are not obviously translatable to restrict the single molecule conformational space, we propose constraints based on the analysis of absent cross-peaks in solidstate NMR correlation experiments. We show that these absences provide unambiguous structural constraints on both the crystal structure and the gas phase conformations, and therefore can be used for unambiguous selection. The approach is parameterized on the crystal structure determination of flutamide, flufenamic acid, and cocaine, where we reduce the computational cost by around 50%. Most importantly, the method is then shown to correctly determine the crystal structure of ampicillin, which would have failed using current methods
because it adopts a high energy conformer in its crystal structure. The average positional RMSE on the NMR powder structure is 〈푟_av〉 = 0.176 Å, which corresponds to an average equivalent displacement parameter 푈_eq = 0.0103 Å2.

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Identifiers

ORCID for Graeme M. Day: orcid.org/0000-0001-8396-2771

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