Optimizing Conditions for Crystalline Spherical Cluster Formation Using 5-Hydroxynicotinic Acid: An Experimental and Theoretical Approach

This manuscript provides novel insights into the optimization of synthetic procedures to obtain crystalline spherical clusters using 5-hydroxynicotinic acid (5HNA). It meticulously explores and identifies the most favorable conditions for producing spherical clusters of 5HNA. The systematic screening of various synthetic conditions has led to the successful formation of these clusters. This work not only contributes to the field of synthetic chemistry but also opens up new avenues for the potential applications of 5HNA spherical clusters. Such clusters have diverse diameters depending on the solvent and the synthesis conditions. The clusters were characterized by optical microscopy, scanning electron microscopy (SEM), and powder X-ray diffraction (PXRD). Possibly the clusters were formed by a self-assembly process driven by hydrogen bonding and π–π interactions between the 5HNA molecules. The solvents ought to play a relevant role in such self-assembly process. The clusters exhibit different crystallinity depending on the solvent. Such clusters could be used as building blocks for materials with potential applications in a multitude of fields. To unveil the role of solvents in the process, complementary molecular dynamics simulations revealed that solvation significantly influences the aggregation behavior of 5HNA in both its hydroxy and zwitterionic forms. Polar aprotic solvents, particularly DMSO, THF, and ethyl acetate, promote better solvation and reduce aggregation for the hydroxy form and Zwitterion 1. In contrast, aqueous environments favor clustering due to hydrogen bonding and π–π stacking between 5HNA molecules. Zwitterion 2, however, shows stronger solvation in water, especially around its ionic groups, while aprotic solvents tend to promote aggregation through enhanced ionic interactions and π–π stacking. Among all solvents studied, DMSO stands out as the only one capable of effectively solvating all three forms of 5HNA, underscoring its unique ability to stabilize distinct molecular states and potentially influence the self-assembly and crystallinity of the resulting aggregates.