Predicting the Crystal Structure of Decitabine by Powder NMR Crystallography: Influence of Long-Range Molecular Packing Symmetry on NMR Parameters

Crystal structure determination in the absence of diffraction data still remains a challenge. In this contribution, we demonstrate a complete reconstruction of the crystal structure of decitabine exclusively from H-1 and C-13 solid-state NMR (ss-NMR) chemical shifts through comparison with the NMR parameters calculated for density functional theory-optimized, computer-generated crystal structure predictions. In particular, we discuss the previously unconsidered influence of long-range molecular packing symmetry on the NMR parameters and subsequent selection of the correct crystal structure. Symmetry operations considerably influenced the global molecular packing and unit cell parameters of the predicted crystal structures, while the conformations and short-range molecular arrangements were practically identical. Consequently, the NMR parameters calculated for NMR-consistent candidates were similar and barely distinguishable by the standard deviations of the experimental and calculated H-1 and C-13 chemical shifts. Therefore, to further refine the crystal structure selection, we simulated and analyzed the entire two-dimensional (2D) H-1-C-13 HETCOR and H-1-H-1 double-quantum/single-quantum NMR correlation spectra. By determining the covariance, which provides a quantitative measure of the differences between the experimental and calculated resonance frequencies of the correlation signals, the set of NMR-consistent candidates was additionally narrowed down, and the correct crystal structure was finally unambiguously identified. By applying the extended protocol including the comparative analysis of 2D ss-NMR. correlation spectra, powder NMR crystallography can thus be used to describe the crystal structures differing in the long-range symmetry of molecular packing for which ss-NMR spectroscopy is otherwise less sensitive.