Chemical Shift Tensors of Cimetidine Form A Modeled with Density Functional Theory Calculations: Implications for NMR Crystallography

Abstract

The principal components of the 13 C chemical shift tensors for the ten crystallographically distinct carbon atoms of the active pharmaceutical ingredient cimetidine Form A have been measured using the FIREMAT technique. Density functional theory (DFT) calculations of 13 C and 15 N magnetic shielding tensors are used to assign the 13 C and 15 N peaks. DFT calculations were performed on cimetidine and a training set of organic crystals using both plane-wave and cluster-based approaches. The former set of calculations allowed several structural refinement strategies to be employed, including calculations utilizing a dispersion-corrected force field that was parametrized using 13 C and 15 N magnetic shielding tensors. The latter set of calculations featured the use of resource-intensive hybrid-DFT methods for the calculation of magnetic shielding tensors. Calculations on structures refined using the new force-field correction result in improved values of 15 N magnetic shielding tensors (as gauged by agreement with experimental chemical shift tensors), although little improvement is seen in the prediction of 13 C shielding tensors. Calculations of 13 C and 15 N magnetic shielding tensors using hybrid functionals show better agreement with experimental values in comparison to those using GGA functionals, independent of the method of structural refinement; the shielding of carbon atoms bonded to nitrogen are especially improved using hybrid DFT methods.

Characterizing the Turbostratic Disorder in COF-5 with NMR Crystallography

“…[21,23] The present study demonstrates that the P6/mmm structure is also incompatible with 13 tensor principal values which shows that the expected error for a pure phase material is approximately ± 3.3 ppm. [42] In contrast the best fit candidate structures for COF-5 have errors of ± 5.7-6.0 ppm. This outcome is consistent with experimental 13 C tensor data that represent an average of differing principal values from three phases.…”

“…High probability crystal structures were selected from among the 52 CSP candidates by calculating the agreement between theoretical and experimental 13 C shift tensors using an approach described elsewhere. [42] The space groups P6/mmm and P31m gave poor agreement with experimental data with rms errors of ± 8.3 ppm and ± 8.7 ppm, respectively and were therefore rejected with high statistical confidence (i.e. 90% confidence).…”

NMR Chemical Shift and Methylation of 4-Nitroimidazole: Experiment and Theory

“…[20] More recently, solid-state NMR methods have advanced to refine molecular structures. [16,[21][22][23] Often such NMR refinements result in only minor changes to structures but, in some cases, these adjustments provide new structural insights. For example, the original diffraction structure for cellulose Ia contained ambiguities at several O-H hydrogen orientations, suggesting that two significantly different hydrogen bonding arrangements were equally probable.…”

“…Chemically linking these small chemical building blocks is generally expected to yield potent molecules that may evolve into a drug. [23] In particular, the positions of hydrogen atoms, which are generally determined inaccurately by XRD techniques, can be refined using solid-state NMR and quantum mechanical density functional theory (DFT) calculations to yield precise structures of the compounds. [23] Hence, NMR and XRD techniques combined with DFT calculations are powerful for refining crystal structures of drug building blocks.…”

“…[23] In particular, the positions of hydrogen atoms, which are generally determined inaccurately by XRD techniques, can be refined using solid-state NMR and quantum mechanical density functional theory (DFT) calculations to yield precise structures of the compounds. [23] Hence, NMR and XRD techniques combined with DFT calculations are powerful for refining crystal structures of drug building blocks. A large number of bioactive ligands and compounds, such as nitroimidazole and derivatives, are nitrogen containing compounds.…”