Resolving alternative organic crystal structures using density functional theory and NMR chemical shifts

Widdifield, Cory M.; Farrell, James D.; Cole, Jason C.; Howard, Judith A. K.; Hodgkinson, Paul

doi:10.1039/c9sc04964a

Cited by 22 publications

(24 citation statements)

References 33 publications

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“…This survey of repeat structure determinations in the CSD found that over 20% of 3132 pairs of alternative structures for the same system exhibited structural differences (mostly of hydrogen atoms) greater than 0.25 Å (i.e. significantly larger than would be expected from experimental uncertainties) [313]. DFT geometry optimisation resolved these differences in most cases, but in other cases the alternative structures solutions minimised to distinct structures.…”

Section: Validation Of Structures From Single-crystal Xrd Datamentioning

confidence: 98%

NMR crystallography of molecular organics

Hodgkinson

2020

Progress in Nuclear Magnetic Resonance Spectroscopy

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Section: Validation Of Structures From Single-crystal Xrd Datamentioning

confidence: 98%

NMR crystallography of molecular organics

Hodgkinson

2020

Progress in Nuclear Magnetic Resonance Spectroscopy

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110

112

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“…The validation of diffractographic structures is based on the comparison between experimentally measured NMR parameters with those calculated with DFT methods. This process was proven effective at resolving ambiguities related to the molecular structure [ 31 ], to choose between alternative proposed structures [ 32 , 33 ], and to refine them through optimization of atom positions in the unit cell [ 34 , 35 , 36 , 37 ]. Although optimization of hydrogen atoms usually has the biggest effect, changes in heavy atom positions obtained through full optimization of the molecule sometimes results in improved agreement with experimental NMR data.…”

Section: Introductionmentioning

confidence: 99%

Structural Refinement of Carbimazole by NMR Crystallography

et al. 2021

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The characterization of the three-dimensional structure of solids is of major importance, especially in the pharmaceutical field. In the present work, NMR crystallography methods are applied with the aim to refine the crystal structure of carbimazole, an active pharmaceutical ingredient used for the treatment of hyperthyroidism and Grave’s disease. Starting from previously reported X-ray diffraction data, two refined structures were obtained by geometry optimization methods. Experimental 1H and 13C isotropic chemical shift measured by the suitable 1H and 13C high-resolution solid state NMR techniques were compared with DFT-GIPAW calculated values, allowing the quality of the obtained structure to be experimentally checked. The refined structure was further validated through the analysis of 1H-1H and 1H-13C 2D NMR correlation experiments. The final structure differs from that previously obtained from X-ray diffraction data mostly for the position of hydrogen atoms.

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“… 43 , 66 Table S2 states the energy differences for the different DFT-D calculations, with DFT having previously been used to evaluate different crystal structures. 67 − 69 Note that for TFM RT , with the less or more highly occupied sites only as starting points, i.e. C4–NH–C5–C6 torsional angle of −7.8 and 28.6° (labeled as A and B), respectively, there remains an energy difference of only 0.8 kJ/mol after optimization of all atomic positions and unit cell parameters.…”

Section: Results and Discussionmentioning

confidence: 99%

Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)

Pawlak

Sudgen

Bujacz

et al. 2021

Crystal Growth & Design

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In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temperature polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temperature TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at −40 °C. This reversible process is related to a change in Z’ value, from 2 to 1, as observed by variable-temperature 1 H– 13 C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional 13 C– 1 H and 1 H– 1 H double-quantum MAS NMR spectra are consistent with the new room-temperature structure, including comparison with GIPAW (gauge-including projector augmented waves) calculated NMR chemical shifts. A crystal structure prediction procedure found both experimental teriflunomide polymorphs in the energetic global minimum region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the phenyl ring relative to the planarity of the TFM molecule. In the low-temperature structure, there are two torsion angles of 4.5 and 31.9° for the two Z’ = 2 molecules, while in the room-temperature structure, there is disorder that is modeled with ∼50% occupancy between torsion angles of −7.8 and 28.6°. These observations are consistent with a broad energy minimum as revealed by DFT calculations. PISEMA solid-state NMR experiments show a reduction in the C–H dipolar coupling in comparison to the static limit for the aromatic CH moieties of 75% and 51% at 20 and 40 °C, respectively, that is indicative of ring flips at the higher temperature. Our study shows the power of combining experiments, namely DSC, X-ray diffraction, and MAS NMR, with DFT calculations and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical molecules.

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Resolving alternative organic crystal structures using density functional theory and NMR chemical shifts

Abstract: DFT optimisation often resolves conflicting crystal structure determinations, with NMR shifts helping in cases where optimisation diverges to different structures.

Cited by 22 publications

References 33 publications

NMR crystallography of molecular organics

NMR crystallography of molecular organics

Structural Refinement of Carbimazole by NMR Crystallography

Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)

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