A<sup>13</sup>C solid-state NMR investigation of four cocrystals of caffeine and theophylline

Vigilante, Nicolas J.; Mehta, Manish

doi:10.1107/s2053229617000869

Cited by 12 publications

(26 citation statements)

References 37 publications

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“…Note that in some cases, the dispersion of the 1 H spectrum under fast MAS [208,209] may be sufficient for 1 H assignments to be made purely from 1 H DQ/SQ spectra. In less favourable cases, however, long T 1 's (commonly encountered in co-crystal systems) may preclude the use of 2D techniques for assignment [210].…”

Section: Spectral Assignmentmentioning

confidence: 99%

NMR crystallography of molecular organics

Hodgkinson

2020

Progress in Nuclear Magnetic Resonance Spectroscopy

125

112

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Section: Spectral Assignmentmentioning

confidence: 99%

NMR crystallography of molecular organics

Hodgkinson

2020

Progress in Nuclear Magnetic Resonance Spectroscopy

125

112

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“…16,17 Paramagnetic materials also often show substantial susceptibility broadenings which can be on the order of 10 ppm. 18 We were also able to identify several other solid-state NMR studies of APIs/organic solids containing aromatic rings where there is likely substantial ABMS broadening present, [19][20][21] however, the ABMS broadening is not acknowledged or commented upon. Even in crystalline samples free of aromatic groups, ABMS broadening is predicted to be the ultimate factor that limits resolution at high magnetic fields, 22 or when ultrafast MAS is applied to directly acquire 1 H solid-state NMR spectra.…”

Section: Introductionmentioning

confidence: 96%

Enhancing the resolution of¹H and¹³C solid-state NMR spectra by reduction of anisotropic bulk magnetic susceptibility broadening

Hanrahan

Venkatesh

Carnahan

et al. 2017

Phys. Chem. Chem. Phys.

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We demonstrate that natural isotopic abundance 2D heteronuclear correlation (HETCOR) solid-state NMR spectra can be used to significantly reduce or eliminate the broadening of H andC solid-state NMR spectra of organic solids due to anisotropic bulk magnetic susceptibility (ABMS). ABMS often manifests in solids with aromatic groups, such as active pharmaceutical ingredients (APIs), and inhomogeneously broadens the NMR peaks of all nuclei in the sample. Inhomogeneous peaks with full widths at half maximum (FWHM) of ∼1 ppm typically result from ABMS broadening and the low spectral resolution impedes the analysis of solid-state NMR spectra. ABMS broadening of solid-state NMR spectra has previously been eliminated using 2D multiple-quantum correlation experiments, or by performing NMR experiments on diluted materials or single crystals. However, these experiments are often infeasible due to their poor sensitivity and/or provide limited gains in resolution. 2D H-C HETCOR experiments have previously been applied to reduce susceptibility broadening in paramagnetic solids and we show that this strategy can significantly reduce ABMS broadening in diamagnetic organic solids. Comparisons of 1D solid-state NMR spectra and H andC solid-state NMR spectra obtained from 2D H-C HETCOR NMR spectra show that the HETCOR spectrum directly increases resolution by a factor of 1.5 to 8. The direct gain in resolution is determined by the ratio of the inhomogeneous C/H linewidth to the homogeneous H linewidth, with the former depending on the magnitude of the ABMS broadening and the strength of the applied field and the latter on the efficiency of homonuclear decoupling. The direct gains in resolution obtained using the 2D HETCOR experiments are better than that obtained by dilution. For solids with long proton longitudinal relaxation times, dynamic nuclear polarization (DNP) was applied to enhance sensitivity and enable the acquisition of 2DH-C HETCOR NMR spectra. 2D H-C HETCOR experiments were applied to resolve and partially assign the NMR signals of the form I and form II polymorphs of aspirin in a sample containing both forms. These findings have important implications for ultra-high field NMR experiments, optimization of decoupling schemes and assessment of the fundamental limits on the resolution of solid-state NMR spectra.

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“…Caffeine and theophylline (Scheme ) make good candidates for this sort of study. It has been well documented that these compounds can easily form cocrystals with small organic molecules. , One of the common features of many of these cocrystals is the tendency for contacts to form between the methyl carbons of caffeine or theophylline and oxygen atoms. These contacts are often linear (θ N–C···O = 160–180 deg), and the distance between the two atoms tends to be shorter that the sum of their van der Waals radii (3.22 Å) (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Experimental ¹³C and ¹H Solid-State NMR Response in Weakly Tetrel-Bonded Methyl Groups

et al. 2021

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Like halogens, pnictogens, and chalcogens, group 14 tetrel atoms have the ability to exhibit areas of elevated electrostatic potential on their surfaces (σ-holes) which can engage in noncovalent interactions with electron donors. Evidence for tetrel bonds involving spin-1/2 nuclei, such as 13C, may be found by careful observation of the isotropic chemical shift in solid-state NMR experiments. Here, we study the 13C and 1H solid-state NMR spectroscopic responses to weak tetrel bond formation by examining a series of eight caffeine and theophylline cocrystals along with similar compounds not featuring tetrel bonds. Overall, we observe a moderate increase in the methyl 13C chemical shift on the order of ppm in cocrystals featuring tetrel bonds as compared to their nonbonded counterparts. The value of δ(13C) shows a weak inverse correlation with the tetrel bond length, while no strong correlation with the tetrel bond angle is observed experimentally. Methyl proton chemical shifts are also influenced by the presence of a tetrel bond, but no strong correlations with structural features are noted based on the experimental data. With the aid of DFT calculations, we explore the relationship between the tetrel bond and the 13C chemical shift tensor, furthering our understanding of how tetrel bonds and potentially competing weak CH···O hydrogen bonds affect the NMR response, which is of importance in NMR crystallography applications. While computations generally show clear correlations between chemical shifts and structural features, this experimental work demonstrates that other interactions and crystal packing effects can weaken and even obscure the expected correlations.

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A¹³C solid-state NMR investigation of four cocrystals of caffeine and theophylline

Cited by 12 publications

References 37 publications

NMR crystallography of molecular organics

NMR crystallography of molecular organics

Enhancing the resolution of¹H and¹³C solid-state NMR spectra by reduction of anisotropic bulk magnetic susceptibility broadening

Experimental ¹³C and ¹H Solid-State NMR Response in Weakly Tetrel-Bonded Methyl Groups

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A13C solid-state NMR investigation of four cocrystals of caffeine and theophylline

Cited by 12 publications

References 37 publications

NMR crystallography of molecular organics

NMR crystallography of molecular organics

Enhancing the resolution of1H and13C solid-state NMR spectra by reduction of anisotropic bulk magnetic susceptibility broadening

Experimental 13C and 1H Solid-State NMR Response in Weakly Tetrel-Bonded Methyl Groups

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Product

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A¹³C solid-state NMR investigation of four cocrystals of caffeine and theophylline

Enhancing the resolution of¹H and¹³C solid-state NMR spectra by reduction of anisotropic bulk magnetic susceptibility broadening

Experimental ¹³C and ¹H Solid-State NMR Response in Weakly Tetrel-Bonded Methyl Groups