Hydroxynicotinic acid crystallisation and solubility systematic studies?

New Journal of Chemistry Pub Date: 2022-09-30 DOI: 10.1039/D2NJ00627H

Abstract

Crystallisation from solution is an important process that has been used for centuries in the preparation and purification of products tailored for specific applications. Nevertheless, there is still a considerable lack of understanding about the molecular mechanisms behind the formation of crystals, in particular, on the relationships between the conformational preferences that emerge from solute–solvent interactions in solution and the packing motifs observed in crystallised materials. In this work, the link between the molecular structure of a solute in a saturated solution and in the crystalline solid in equilibrium with that solution was investigated using the 2-, 4-, 5-, and 6-hydroxynicotinic acid (HNA) family as a model; solubility data for these compounds were largely lacking in the literature. These studies, which were carried out in two protic solvents (water and ethanol), with distinct hydrogen bonding abilities and polarities, allowed the evaluation of not only how systematic changes in the molecular structure of the solute, but also how such variations on the solvent affect solubility. The HNA solubility trends were determined over a temperature range of 288 to 333 K by the gravimetric method. In water, the observed trend was 4HNA ? 2HNA > 5HNA ≈ 6HNA, at 293 ± 2 K, which was essentially mimicked in ethanol, with slight differences: 2HNA ≈ 4HNA > 5HNA > 6HNA. 4HNA was found to be the most soluble compound, at 293 ± 2 K, in water, while in ethanol, 2HNA was the most soluble. Notably, an intramolecular hydrogen bond occurring in both 2HNA and 4HNA played a role in their increased solubility, in both solvents, showing a more pronounced effect in water, probably due to their higher polarity and ability to form hydrogen bonds. Moreover, the solubilities of all HNAs are less disperse in ethanol, which demonstrates the weight of the solvent structure, polarity, and hydrogen bonding ability in solubility, which results in different interactions. In this case, as ethanol is a better hydrogen bond acceptor than a donor, the overall solubilities are lower when compared to water. NMR studies assisted with clues for the intramolecular H-bond in 4HNA and for the aggregation and crystallisation of the nicotinic acid (NA) and 5HNA in solutions.

Graphical abstract: Hydroxynicotinic acid crystallisation and solubility systematic studies
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