35 Cl ‐ 1 H heteronuclear correlation MAS NMR experiments for probing pharmaceutical salts

Heteronuclear multiple-quantum coherence (HMQC) pulse sequences for establishing heteronuclear correlation in solid-state NMR between 35Cl and 1H atoms in chloride salts under fast (60 kHz) magic-angle spinning (MAS) and at high magnetic field (a 1H Larmor frequency of 850 MHz) are investigated. Specifically, recoupling of the 35Cl - 1H dipolar interaction using rotary resonance recoupling with phase inversion every rotor period or the symmetry based SR421 pulse sequence are compared. In our implementation of the PT (population-transfer)-D-HMQC experiment, the satellite transitions of the 35Cl nuclei are saturated with an off-resonance WURST sweep, at a low nutation frequency, over the second spinning sideband, whereby the WURST pulse must be of the same duration as the recoupling time. Numerical simulations of the 35Cl - 1H MAS D-HMQC experiment performed separately for each crystallite orientation in a powder provide insight into the orientation dependence of changes in the second-order quadrupolar broadened 35Cl MAS NMR lineshape under the application of dipolar recoupling. Two-dimensional 35Cl - 1H PT-D-HMQC MAS NMR spectra are presented for the amino acids glycine·HCl and L-tyrosine·HCl and the pharmaceuticals cimetidine·HCl, amitriptyline·HCl and lidocaine·HCl·H2O. Experimentally observed 35Cl lineshapes are compared with those simulated for 35Cl chemical shift and quadrupolar parameters as calculated using the gauge-including projector-augmented wave (GIPAW) method: the calculated quadrupolar product (PQ) values exceed those measured experimentally by a factor of between 1.3 and 1.9

Investigating discrepancies between experimental solid-state NMR and GIPAW calculation : NC–N 13C and OH⋯O 1H chemical shifts in pyridinium fumarates and their cocrystals

An NMR crystallography analysis is presented for four solid-state structures of pyridine fumarates and their cocrystals, using crystal structures deposited in the Cambridge Crystallographic Data Centre, CCDC. Experimental one-dimensional, one-pulse 1H and 13C cross-polarisation (CP) magic-angle spinning (MAS) nuclear magnetic resonance (NMR) and two-dimensional 14N–1H heteronuclear multiple-quantum coherence MAS NMR spectra are compared with gauge-including projector augmented wave (GIPAW) calculations of the 1H and 13C chemical shifts and the 14N shifts that additionally depend on the quadrupolar interaction. Considering the high ppm (>10 ppm) 1H resonances, while there is good agreement (within 0.4 ppm) between experiment and GIPAW calculation for the hydrogen-bonded NH moieties, the hydrogen-bonded fumaric acid OH resonances are 1.2–1.9 ppm higher in GIPAW calculation as compared to experiment. For the cocrystals of a salt and a salt formed by 2-amino-5-methylpyridinium and 2-amino-6-methylpyridinium ions, a large discrepancy of 4.2 and 5.9 ppm between experiment and GIPAW calculation is observed for the quaternary ring carbon 13C resonance that is directly bonded to two nitrogens (in the ring and in the amino group). By comparison, there is excellent agreement (within 0.2 ppm) for the quaternary ring carbon 13C resonance directly bonded to the ring nitrogen for the salt and cocrystal of a salt formed by 2,6-lutidinium and 2,5-lutidine, respectively

5-amino-2-methylpyridinium hydrogen fumarate : an XRD and NMR crystallography analysis

Single‐crystal X‐ray diffraction structures of the 5‐amino‐2‐methylpyridinium hydrogen fumarate salt have been solved at 150 and 300 K (CCDC 1952142 and 1952143). A base‐acid‐base‐acid ring is formed through pyridinium‐carboxylate and amine‐carboxylate hydrogen bonds that hold together chains formed from hydrogen‐bonded hydrogen fumarate ions. 1H and 13C chemical shifts as well as 14N shifts that additionally depend on the quadrupolar interaction are determined by experimental magic‐angle spinning (MAS) solid‐state nuclear magnetic resonance (NMR) and gauge‐including projector augmented wave (GIPAW) calculation. Two‐dimensional homonuclear 1H‐1H double‐quantum (DQ) MAS and heteronuclear 1H‐13C and 14N‐1H spectra are presented. Only small differences of up to 0.1 ppm and 0.6 ppm for 1H and 13C are observed between GIPAW calculations starting with the two structures solved at 150 and 300 K (after geometry optimisation of atomic positions, but not unit cell parameters). A comparison of GIPAW calculated 1H chemical shifts for isolated molecules and the full crystal structures is indicative of hydrogen bonding strength

Combining experimental solid-state NMR and X-ray diffraction with density functional theory calcualtion to characterise multicomponent forms of organic molecules

Structure analysis is an important step in the process of developing new solid forms of active pharmaceutical ingredients (APIs) and agrochemical ingredients (AIs) as it can provide a starting point for related structures to be designed and represents an intellectual property (IP) opportunity. This thesis investigates the complementarity of XRD and solid-state magic-angle spinning (MAS) NMR, alongside density functional theory (DFT) calculations, for the characterisation of five related pyridine based molecules, each co-crystallised with fumaric acid. Structures and stabilities were investigated using both single crystal and powder XRD at a range of temperatures, 1H MAS, 13C cross polarisation (CP) MAS solid state NMR spectra and 1H1H, 1H13C and 14N1H 2D correlation experiments and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). DFT-based geometry optimisations were performed with the unit cell parameters both fixed and variable to investigate the convergence of structures recorded at different temperatures and calculations of the NMR parameters were conducted for both the full crystal structures and for isolated molecules from within the structures, highlighting the intermolecular interactions present. Chapter 3 identifies the loss of the base molecule, through slow evaporation, from the system, resulting in formation of crystalline fumaric acid in the affected regions. Splitting of reflections in the powder XRD patterns was linked to the existence of a second ‘polymorph’, which shows noticeable variation in unit cell parameters while maintaining the overall molecular packing. Chapter 4 investigates the co-occurrence of at least three multicomponent forms from the same crystallisation media, isolates the transitions between the structures (from hydrated to anhydrous) and identifies methods both for improving the selectivity of their formation and allowing their co-identification by NMR. In Chapter 5 the multicomponent forms of three substitutional analogue bases are compared, one of which shows evidence of polymorphism. Chapter 6 presents the trend in the 14N shift with crystal form for tertiary amine nitrogens as well as classifying common bonding patterns which, in a Cambridge Structural vi Database (CSD) search, show significant differences in incidence depending on crystal form. Two chemical environments that show significant differences between experiment and calculation are also identified

Data for An XRD and NMR crystallographic investigation of the structure of 2,6-lutidinium hydrogen fumarate

Fumarate is a pharmaceutically acceptable counterion often used to modify the biophysical properties of active pharmaceutical ingredients (APIs) through salt formation. With 2,6-lutidine (2,6-dimethylpyridine), fumaric acid forms the salt 2,6-lutidinium hydrogen fumarate. An NMR crystallography approach was employed to investigate the salt structure and the intermolecular interactions involved in its formation and stability. The crystallographic unit cell was determined by both single crystal XRD (SXRD) and synchrotron powder X-ray diffraction (PXRD) to contract at low temperature with a skew in the β angle. Density functional theory (DFT)-based geometry optimisations were found partially to replicate this. A second room temperature structure was also identified which exhibited a similar skew of the β angle as the low temperature structure. DFT calculation was also employed, alongside 2D 1H double-quantum (DQ) magic angle spinning (MAS) and 14N-1H HMQC MAS NMR spectra, to investigate the hydrogen bonding network involved in the structure. DFT-based gauge-including projector-augmented wave (GIPAW) calculations highlighted both strong N+-H···O− and O-H···O intermolecular hydrogen bonds between the molecules, as well as several weaker CH···O hydrogen bonds. Both PXRD and solid-state MAS NMR, supported by thermal gravimetric analysis (TGA) and solution-state NMR analysis, show formation of fumaric acid within samples over time. This was evidenced by the identification of reflections and peaks associated with crystalline fumaric acid in the PXRD pattern and in 1H MAS and 13C cross polarization (CP) MAS solid-state NMR spectra, respectively

Data for 5-amino-2-methylpyridinium hydrogen fumarate : an XRD and NMR crystallography analysis

Single-crystal X-ray diffraction structures of the 5-amino-2-methylpyridinium hydrogen fumarate salt have been solved at 150 and 300 K (CCDC 1952142 and 1952143). A base-acid-base-acid ring is formed through pyridinium-carboxylate and amine-carboxylate hydrogen bonds that hold together chains formed from hydrogen-bonded hydrogen fumarate ions. 1H and 13C chemical shifts as well as 14N shifts that additionally depend on the quadrupolar interaction are determined by experimental magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) and gauge-including projector augmented wave (GIPAW) calculation. Two-dimensional homonuclear 1H-1H double-quantum (DQ) MAS and heteronuclear 1H-13C and 14N-1H spectra are presented. Only small differences of up to 0.1 ppm and 0.6 ppm for 1H and 13C are observed between GIPAW calculations starting with the two structures solved at 150 and 300 K (after geometry optimisation of atomic positions, but not unit cell parameters). A comparison of GIPAW calculated 1H chemical shifts for isolated molecules and the full crystal structures is indicative of hydrogen bonding strength

Weak intermolecular CH···N hydrogen bonding : determination of 13CH-15N hydrogen-bond mediated J couplings by solid-state NMR spectroscopy and first-principles calculations

Weak hydrogen bonds are increasingly hypothesised to play key roles in a wide range of chemistry from catalysis to gelation to polymer structure. Here, 15N/13C spin-echo magic-angle spinning (MAS) solid-state NMR experiments are applied to “view” intermolecular CH···N hydrogen bonding in two selectively labelled organic compounds, 4-[15N] cyano-4’-[13C2] ethynylbiphenyl (1) and [15N3,13C6]-2,4,6-triethynyl-1,3,5-triazine (2). The synthesis of 2-15N3,13C6 is reported here for the first time via a multistep procedure, where the key element is the reaction of [15N3]-2,4,6-trichloro-1,3,5-triazine (5) with [13C2]-[(trimethylsilyl)ethynyl]zinc chloride (8) to afford its immediate precursor [15N3,13C6]-2,4,6-tris[(trimethylsilyl)ethynyl]-1,3,5-triazine (9). Experimentally determined hydrogen-bond mediated 2hJCN couplings (4.7 ± 0.4 Hz (1), 4.1 ± 0.3 Hz (2)) are compared with density functional theory (DFT) gauge-including projector augmented wave (GIPAW) calculations, whereby species independent coupling values 2hKCN (28.1 (1), 26.1 (2) × 1019 kg m–2 s–2 A–2) quantitatively demonstrate the J couplings for these CH···N hydrogen bonds to be of a similar magnitude to those for conventionally observed NH···O hydrogen-bonding interactions in uracil (2hKNO: 28.1 and 36.8 × 1019 kg m–2 s–2 A–2)

Indicative Distribution Maps for Ecological Functional Groups - Level 3 of IUCN Global Ecosystem Typology

This dataset includes the original version of the indicative distribution maps and profiles for Ecological Functional Groups - Level 3 of IUCN Global Ecosystem Typology (v2.0). Please refer to Keith et al. (2020). The descriptive profiles provide brief summaries of key ecological traits and processes for each functional group of ecosystems to enable any ecosystem type to be assigned to a group. Maps are indicative of global distribution patterns are not intended to represent fine-scale patterns. The maps show areas of the world containing major (value of 1, coloured red) or minor occurrences (value of 2, coloured yellow) of each ecosystem functional group. Minor occurrences are areas where an ecosystem functional group is scattered in patches within matrices of other ecosystem functional groups or where they occur in substantial areas, but only within a segment of a larger region. Most maps were prepared using a coarse-scale template (e.g. ecoregions), but some were compiled from higher resolution spatial data where available (see details in profiles). Higher resolution mapping is planned in future publications. We emphasise that spatial representation of Ecosystem Functional Groups does not follow higher-order groupings described in respective ecoregion classifications. Consequently, when Ecosystem Functional Groups are aggregated into functional biomes (Level 2 of the Global Ecosystem Typology), spatial patterns may differ from those of biogeographic biomes. Differences reflect the distinctions between functional and biogeographic interpretations of the term, biome