Developing Powder Crystallography for Molecules using NMR Parameters and Computations

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Nuclear magnetic resonance (NMR) experiments are widely used in science to elucidate many aspects of chemical structure and dynamics. Recently, NMR experiments have been applied to organic molecules in the solid state to perform crystal structure refinements, selections, verifications, and determinations. In the above tasks, the NMR data are regularly compared against computational outputs generated based on an input structure. Broadly speaking, this process is known as `NMR crystallography' (NMR-X). This research program seeks to improve several aspects of current protocols and proposes additional innovations with the aim of enhancing the accuracy, efficiency, and robustness of NMR-X. The three focus areas of our research program over the next five years are summarized below. 1. We will improve the accuracy of calculated NMR parameters for crystalline molecular organics while making minimal sacrifices in efficiency. Current state-of-the-art NMR-X computations rely largely on pseudopotentials to describe core electrons, planewaves to describe valence electrons, and use periodic boundary conditions to replicate the translational symmetry of the crystal lattice. This approach is fairly accurate when calculating NMR parameters yet has several fundamental limitations. For example, performing calculations that include exact electron exchange are highly inefficient. This creates system-dependent `blind spots' in present NMR-X approaches, which must be rectified. This research program will develop a local embedding approach that will produce more accurate NMR parameters for a larger set of organic molecules than is currently the case. 2. This research program will generate more robust NMR-X metrics. Essentially, metrics are the `rulers' by which those in the NMR-X community establish the quality of a proposed candidate structure (or other structure characterization task), and it is our contention that current metrics are not robust as they can lead to conflicting estimates of structure quality. Metrics currently exist in some form for several nuclides (e.g., 1H, 13C, 15N, 17O) and several NMR parameters (e.g., chemical shifts). We will generate more robust metrics by first establishing a database of reliable NMR parameters and NMR signal data for chemical systems whose structures are well known. We will then extend current metrics to include temperature effects and subsequently consider alternative mathematical structures for the metrics themselves. 3. By pairing the advances realized from access to more accurate NMR parameter computations and robust NMR-X metrics, we will develop NMR-X software that can be used to refine chemical structures determined using diffraction methods, with a focus on poorly resolved crystal structures. This research program will achieve meaningful results with impact in the pharmaceutical industry. Further application areas include antimicrobials and co-crystalline materials.