Salts and cocrystals of substituted phenylacetic acids

Abstract

The prediction of the single crystal structure that will form due to the combination of two or more compounds to form a multicomponent crystal is one of the important areas of research in crystal engineering. Since these compounds display different properties when combined as a single crystal, knowledge of synthesis and design of the resulting compound is essential. The formation of a multicomponent crystal, such as a salt or a cocrystal generally depends on the complementarity of the functional groups present on both components. This means that basicity and acidity of the functional groups present on the selected compounds need to be considered. This study investigated salts and cocrystals of 3-chloro-4-hydroxyphenylacetic acid (CHPAA) using the ΔpKa rule. The calculated ΔpKa values were recorded and correlated with the experimental analysis in predicting the outcome of the crystallisation experiments ie. salt or cocrystal formation. This was further confirmed by the analysis of the C-O bond lengths found in the crystal structures. Salts were obtained by combinations of CHPAA with several organic bases (co-formers) such as diethylamine, dibutylamine, 2-aminopyridine, 2-amino-4-methylpyridine, 2-amino-6-methylpyridine and 4-dimethylaminopyridine. The calculated ΔpKa values were within the range of salt formation. Furthermore, the experimental analysis also showed that all resulting compounds were salts. Cocrystals were obtained by reactions of nicotinamide, isonicotinamide, phenazine and 4,4’-bipyridine with CHPAA. Again, the calculated ΔpKa values predicted cocrystals as the new solid forms. Experimental analysis carried out also confirmed cocrystal formation. For all resulting compounds, the comparison of intermolecular interactions as well as supramolecular synthons were reported. All compounds were synthesised by slow evaporation techniques using various organic solvents and characterised by single crystal X-ray diffraction, powder X-ray diffraction, thermal analysis and Fourier transformer infrared spectroscopy. From the structural analysis, it was found that all resulting structures displayed strong N-H•••O and O-H•••O intermolecular interactions including weak interactions of C-H•••Cl, C-H•••O and C-H•••π for a few of the structures. Furthermore, comparison of the crystal structures showed that no packing arrangement similarity existed between the compounds.