Simon E. Lawrence

Highly Enantioselective Intramolecular Copper Catalyzed C−H Insertion Reactions of α-Diazosulfones

Excellent enantiocontrol (up to 98% ee) is achieved in copper catalyzed C-H insertions of alpha-diazosulfones to form thiopyrans, with up to 60% ee in C-H insertions leading to sulfolanes.

Solid‐state characterization of novel active pharmaceutical ingredients: Cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt

The production of salt or cocrystalline forms is a common approach to alter the physicochemical properties of pharmaceutical compounds. The goal of this work was to evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemical characteristics of salbutamol forms. Novel crystals of salbutamol were produced by solvent evaporation: a cocrystal of salbutamol hemiadipate with adipic acid (salbutamol adipate, SA), salbutamol hemisuccinate tetramethanolate (SSU.MeOH), and its desolvated form (SSU). The crystalline materials obtained were characterized using thermal, X-ray, nuclear magnetic resonance, Fourier transform infrared spectroscopy, dynamic vapor sorption (DVS), and elemental analysis. The crystal forms of SA and SSU.MeOH were determined to be triclinic, (Pī), and monoclinic, (P2(1) /n), respectively. DVS analysis confirmed that SSU and SA do not undergo hydration under increased relative humidity. Both thermal and elemental analyses confirmed the stoichiometry of the salt forms. The aqueous solubilities of SA and SSU were measured to be 82 ± 2 mg/mL (pH 4.5 ± 0.1) and 334 ± 13 mg/mL (pH 6.6 ± 0.1), respectively. Measured values corresponded well with the calculated pH solubility profiles. The intrinsic dissolution rate of cocrystallized SA was approximately four times lower than that of SSU, suggesting its use as an alternative to more rapidly dissolving salbutamol sulfate.

Characterisation, solubility and intrinsic dissolution behaviour of benzamide: dibenzyl sulfoxide cocrystal

This study examined the 1:1 cocrystal benzamide:dibenzyl sulfoxide, comprising the poorly water soluble dibenzyl sulfoxide (DBSO) and the more soluble benzamide (BA), to establish if this cocrystal shows advantages in terms of solubility and dissolution in comparison to its pure components and to a physical mixture. Solubility studies were performed by measuring DBSO solubility as a function of BA concentration, and a ternary phase diagram was constructed. Dissolution was examined through intrinsic dissolution studies. Solid-state characterisation was carried out by powder X-ray diffraction (PXRD), energy-dispersive X-ray diffraction (EDX), infra-red spectroscopy (ATR-FTIR) and thermal analysis. DBSO solubility was increased by means of complexation with BA. For the cocrystal, the solubility of both components was decreased in comparison to pure components. The cocrystal was identified as metastable and incongruently saturating. Dissolution studies revealed that dissolution of DBSO from the cocrystal was not enhanced in comparison to the pure compound or a physical mix, while BA release was retarded and followed square root of time kinetics. At the disk surface a layer of DBSO was found. The extent of complexation in solution can change the stability of the complex substantially. Incongruent solubility and dissolution behaviour of a cocrystal can result in no enhancement in the dissolution of the less soluble component and retardation of release of the more soluble component.

Expanding the crystal landscape of isonicotinamide: concomitant polymorphism and co-crystallisation

Attempts to co-crystallise 3-arylbutanoic acid derivatives with isonicotinamide have led to co-crystals and novel polymorphs of the isonicotinamide co-former appearing under similar crystallisation conditions.

Structure-function analysis of the C-3 position in analogues of microbial behavioural modulators HHQ and PQS.

2-Heptyl-3-hydroxy-4-quinolone (PQS) and its precursor 2-heptyl-4-quinolone (HHQ) are key signalling molecules of the important nosocomial pathogen Pseudomonas aeruginosa. We have recently reported an interkingdom dimension to these molecules, influencing key virulence traits in a broad spectrum of microbial species and in the human pathogenic yeast Candida albicans. For the first time, targeted chemical derivatisation of the C-3 position was undertaken to investigate the structural and molecular properties underpinning the biological activity of these compounds in P. aeruginosa, and using Bacillus subtilis as a suitable model system for investigating modulation of interspecies behaviour.

Tin-119 NMR shielding anisotropy and molecular structure

Abstract The notation for shielding tensor data is presented and the method of spinning sideband analysis for obtaining the principal components is discussed. Values for the tin-119 nucleus are given and related to crystallographic considerations for a variety of symmetries, oxidation numbers and coordination types.

Evaluation of the Bruker SMART X2S: crystallography for the nonspecialist?

An evaluation of the Bruker SMART X2S for the collection of crystallographic diffraction data, structure solution and refinement is carried out with a variety of materials with different electron densities, presenting some of the successes and challenges of automation in chemical crystallography.

Orthopalladated triaryl phosphite complexes as highly active catalysts in biaryl coupling reactions

Orthopalladation of inexpensive, commercially available tris(2,4-di-tert-butylphenyl) phosphite gives a dimeric complex 3 which proves to be an extremely active catalyst in biaryl coupling reactions, giving unprecedented turnover numbers of up to 1000000 [mol product (mol Pd)–1] and turnover frequencies of nearly 900000 [mol product (mol Pd)–1 h–1] in the Suzuki reaction and turnover numbers of up to 830000 in the Stille reaction.

Rhodium catalysed decomposition of α-diazosulfoxides: Formation of α-oxo sulfines as intermediates

Abstract Decomposition of α-diazosulfoxides using rhodium carboxylate or carboxamide catalysts proceeds via a Wolff type rearrangement to form α-oxo sulfine intermediates, which can be trapped as cycloadducts with dienes. In the absence of a diene trap, dimerisation of the sulfine intermediate is observed.

Novel co-crystals of the nutraceutical sinapic acid

Sinapic acid (SA) is a nutraceutical with known anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-anxiety properties. Novel co-crystals of SA were prepared with co-formers belonging to the category of GRAS [isonicotinic acid (INC), nicotinamide (NIA)], non-GRAS [4-pyridinecarbonitrile (PYC)], and active pharmaceutical ingredients (APIs) [6-propyl-2-thiouracil (PTU)] list of compounds. Structural study based on the X-ray crystal structures revealed the intermolecular hydrogen-bonded interactions and molecular packing. The crystal structure of sinapic acid shows the anticipated acid–acid homodimer along with discrete hydrogen bonds between the acid carbonyl and the phenolic moiety. The robust acid–acid homodimer appears to be very stable and is retained in the structures of two co-crystals (SA·NIA and SA·PYC). In these cases, co-crystallization occurs via intermolecular phenol O–H⋯Naromatic hydrogen bonds between the co-formers. In the SA·PTU·2MeCN co-crystal the acid–acid homodimer gives way to the anticipated acid–amide heterodimer, with the phenolic moiety of SA hydrogen-bonded to acetonitrile. Attempts at obtaining the desolvated co-crystal led to lattice breakdown, thus highlighting the importance of acetonitrile in the formation of the co-crystal. Among the co-crystals examined, SA·INC (5 weeks), SA·NIA (8 weeks) and SA·PYC (5 weeks) were found to be stable under accelerated humidity conditions (40 °C, 75% RH), whereas SA·PTU·2MeCN decomposed after one week into individual components due to solvent loss.