³¹P MAS Refocused INADEQUATE Spin−Echo (REINE) NMR Spectroscopy: Revealing <i>J</i> Coupling and Chemical Shift Two-Dimensional Correlations in Disordered Solids

Two-dimensional (2D) variations in 2JP1,P1, 2JP1,P2, and 2JP2,P2 are obtainedusing the REINE (REfocused INADEQUATE spin−Echo) pulse sequence presented by Cadars et al. (Phys. Chem. Chem. Phys. 2007, 9, 92−103)from pixel-by-pixel fittings of the spin−echo modulation for the 2D correlation peaks due to linked phosphate tetrahedra (P1−P1, P1−P2, P2−P1, and P2−P2) in a 31P refocused INADEQUATE solid-state MAS NMR spectrum of a cadmium phosphate glass, 0.575CdO−0.425P2O5. In particular, separate variations for each 2D 31P REINE peak are obtained which reveal correlations between the J couplings and the 31P chemical shifts of the coupled nuclei that are much clearer than those evident in previously presented 2D z-filtered 31P spin−echo spectra. Notably, such correlations between the J couplings and the 31P chemical shifts are observed even though the conditional probability distributions extracted using the protocol of Cadars et al. (J. Am. Chem. Soc. 2005, 127, 4466−4476) indicate that there is no marked correlation between the 31P chemical shifts of neighboring phosphate tetrahedra. For 2D peaks at the P2 31P chemical shift in the direct dimension, there can be contributions from chains of three units (P1−P2−P1), chains of four units (P1−P2−P2−P1), or longer chains or rings (−P2−P2−P2−): for the representative glass considered here, best fits are obtained assuming a glass comprised predominantly of chains of four units. The following variations are found: 2JP1,P1 = 13.4 ± 0.3 to 14.8 ± 0.5 Hz, 2JP1,P2 = 15.0 ± 0.3 to 18.2 ± 0.3 Hz, and 2JP2,P2 = 5.9 ± 0.6 to 9.1 ± 0.9 Hz from the fits to the P1−P1, P1−P2, and P2−P2 peaks, respectively. The correlation of a particular J coupling with the 31P chemical shifts of the considered nucleus and the coupled nucleus is quantified by the coefficients CF2 and CF1 that correspond to the average pixel-by-pixel change in the J coupling with respect to the chemical shift of the observed (F2) and neighboring (F1) 31P nuclei, respectively

Probing Proton−Proton Proximities in the Solid State: High-Resolution Two-Dimensional ¹H−H Double-Quantum CRAMPS NMR Spectroscopy

A new 1H DQ (double-quantum) CRAMPS (combined rotation and multiple-pulse sequence) solid-state nuclear magnetic resonance experiment incorporating DUMBO homonuclear 1H dipolar decoupling is presented. The major resolution enhancement enables DQ peaks corresponding to all 22 close (2 proton resonances

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution ¹H Solid-State NMR Spectroscopy

An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the γ polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the 1H chemical shift for specific aliphatic and aromatic protons of over −1 ppm that are due to intermolecular CH-π interactions. For the OH proton, 1H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H–H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons. The enhanced resolution in 1H DQ–13C spectra, recorded at 850 MHz, enables separate 1H DQ build-up curves (as a function of the DQ recoupling time) to be extracted for the aromatic CH protons. Supported by eight-spin density-matrix simulations, it is shown how the relative maximum intensities and rates of build-up provide quantitative insight into intramolecular and intermolecular H–H proximities that characterize the crystal packing

Identification by ¹⁵N Refocused INADEQUATE MAS NMR of Intermolecular Hydrogen Bonding that Directs the Self-Assembly of Modified DNA Bases

15N solid-state NMR refocused INADEQUATE spectra of two lipophilic deoxyguanosine derivatives unambiguously identify different intermolecular hydrogen-bonding arrangements that are indicative of either guanine ribbon or quartet self-assembly. The observation of guanine quartet formation in the absence of metal ions is a further example that challenges the accepted dogma that quartet formation requires metal ions

NMR Crystallography of Campho[2,3-c]pyrazole (<i>Z</i>′ = 6): Combining High-Resolution ¹H-¹³C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations

1H-13C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC experiment, are presented for campho[2,3-c]pyrazole. For each 13C moiety, there are six resonances associated with the six distinct molecules in the asymmetric unit cell (Z′ = 6). The one-bond C−H correlations observed in the 2D 1H-13C MAS-J-HMQC spectra allow the experimental determination of the 1H and 13C chemical shifts associated with the separate CH, CH2, and CH3 groups. 1H and 13C chemical shifts calculated by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calculations for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the experimental 1H and 13C chemical shifts to the six distinct molecules. The calculated chemical shifts for the full crystal structure are compared with those for isolated molecules as extracted from the geometry-optimized crystal structure. In this way, the effect of intermolecular interactions on the observed chemical shifts is quantified. In particular, the calculations are sufficiently precise to differentiate the small (1H chemical shifts of the six resonances associated with each distinct CH or CH2 moiety

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution ¹H Solid-State NMR Spectroscopy

An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the γ polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the 1H chemical shift for specific aliphatic and aromatic protons of over −1 ppm that are due to intermolecular CH-π interactions. For the OH proton, 1H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H–H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons. The enhanced resolution in 1H DQ–13C spectra, recorded at 850 MHz, enables separate 1H DQ build-up curves (as a function of the DQ recoupling time) to be extracted for the aromatic CH protons. Supported by eight-spin density-matrix simulations, it is shown how the relative maximum intensities and rates of build-up provide quantitative insight into intramolecular and intermolecular H–H proximities that characterize the crystal packing

NMR Crystallography of Campho[2,3-c]pyrazole (<i>Z</i>′ = 6): Combining High-Resolution ¹H-¹³C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations

1H-13C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC experiment, are presented for campho[2,3-c]pyrazole. For each 13C moiety, there are six resonances associated with the six distinct molecules in the asymmetric unit cell (Z′ = 6). The one-bond C−H correlations observed in the 2D 1H-13C MAS-J-HMQC spectra allow the experimental determination of the 1H and 13C chemical shifts associated with the separate CH, CH2, and CH3 groups. 1H and 13C chemical shifts calculated by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calculations for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the experimental 1H and 13C chemical shifts to the six distinct molecules. The calculated chemical shifts for the full crystal structure are compared with those for isolated molecules as extracted from the geometry-optimized crystal structure. In this way, the effect of intermolecular interactions on the observed chemical shifts is quantified. In particular, the calculations are sufficiently precise to differentiate the small (1H chemical shifts of the six resonances associated with each distinct CH or CH2 moiety

Strong Intermolecular Ring Current Influence on ¹H Chemical Shifts in Two Crystalline Forms of Naproxen: a Combined Solid-State NMR and DFT Study

The anhydrous crystalline forms of Naproxen [(S)-(+)-2-(6-methoxy-2-naphthyl)­propionic acid], (NAPRO-A) and its sodium salt (NAPRO-S), widely used anti-inflammatory drugs, have been investigated by means of 1D and 2D MAS NMR and density functional theory (DFT) based calculations. From calculations, 1D 13C CP MAS and 1H CRAMPS and 2D 1H–13C MAS-J-HMQC, refocused INEPT, FSLG-HETCOR, and 1H–1H DQ-CRAMPS solid-state NMR experiments, 1H and 13C resonances have been fully assigned for NAPRO-A and -S. In the case of NAPRO-S, all of the nuclei belonging to the two inequivalent molecules of the asymmetric cell gave rise to distinct signals, which could be completely assigned. Interesting intermolecular ring current effects on 1H chemical shifts have been experimentally observed for the two samples, even if with significant differences between the two cases. The measured and calculated proton chemical shift values showed a very good agreement for both NAPRO-A and -S, allowing us to correlate the different ring current effects with the crystal structures. The comparison between the proton chemical shifts calculated in the crystal structures and in vacuo allowed us to confirm the mainly intermolecular character of the ring current effects and to quantify them

Density Functional Theory Calculations of Hydrogen-Bond-Mediated NMR <i>J</i> Coupling in the Solid State

A recently developed method for calculating NMR J coupling in solid-state systems is applied to calculate hydrogen-bond-mediated 2hJNN couplings across intra- or intermolecular N−H···N hydrogen bonds in two 6-aminofulvene-1-aldimine derivatives and the ribbon structure formed by a deoxyguanosine derivative. Excellent quantitative agreement is observed between the calculated solid-state J couplings and those previously determined experimentally in two recent spin-echo magic-angle-spinning NMR studies (Brown, S. P.; et al. Chem. Commun.2002, 1852−1853 and Pham, T. N.; et al. Phys. Chem. Chem. Phys. 2007, 9, 3416−3423). For the 6-aminofulvene-1-aldimines, the differences in 2hJNN couplings in pyrrole and triazole derivatives are reproduced, while for the guanosine ribbons, an increase in 2hJNN is correlated with a decrease in the N−H···N hydrogen-bond distance. J couplings are additionally calculated for isolated molecules of the 6-aminofulevene-1-aldimines extracted from the crystal with and without further geometry optimization. Importantly, it is shown that experimentally observed differences between J couplings determined by solution- and solid-state NMR are not solely due to differences in geometry; long-range electrostatic effects of the crystal lattice are shown to be significant also. J couplings that are yet to be experimentally measured are calculated. Notably, 2hJNO couplings across N−H···O hydrogen bonds are found to be of a similar magnitude to 2hJNN couplings, suggesting that their utilization and quantitative determination should be experimentally feasible

An Investigation of the Hydrogen-Bonding Structure in Bilirubin by ¹H Double-Quantum Magic-Angle Spinning Solid-State NMR Spectroscopy

The complex hydrogen-bonding arrangement in the biologically important molecule bilirubin IXα is probed by using 1H double-quantum (DQ) magic-angle spinning (MAS) NMR spectroscopy. Employing fast MAS (30 kHz) and a high magnetic field (16.4 T), three low-field resonances corresponding to the different hydrogen-bonding protons are resolved in a 1H MAS NMR spectrum of bilirubin. These resonances are assigned on the basis of the proton−proton proximities identified from a two-dimensional rotor-synchronized 1H DQ MAS NMR spectrum. An analysis of 1H DQ MAS spinning-sideband patterns for the NH protons in bilirubin allows the quantitative determination of proton−proton distances and the geometry. The validity of this procedure is proven by simulated spectra for a model three-spin system, which show that the shortest distance can be determined to a very high degree of accuracy. The distance between the lactam and pyrrole NH protons in bilirubin is determined to be 0.186 ± 0.002 nm (corresponding to a dominant dipolar coupling constant of 18.5 ± 0.5 kHz). The analysis also yields a distance between the lactam NH and carboxylic acid OH protons of 0.230 ± 0.008 nm (corresponding to a perturbing dipolar coupling constant of 9.9 ± 1.0 kHz) and an H−H−H angle of 122 ± 4°. Finally, a comparison of 1H DQ MAS spinning-sideband patterns for bilirubin and its dimethyl ester reveals a significantly longer distance between the two NH protons in the latter case