On the Polymorph-Selective Role of Hydrogen Bonding and π - π Stacking in Para-Aminobenzoic Acid Solutions

Understanding molecular self-association in solution is vital for uncovering polymorph- selective crystal nucleation pathways. In this paper, we combine solution NMR spectroscopy and molecular dynamics simulations to shed light on the structural and dynamical features of para-aminobenzoic acid (pABA) in solution, and on their role in pABA crystals nucleation. pABA is known to yield different crystal forms (α, and β) depending on solvent choice and su- persaturation conditions. NMR reveals that dominant interactions stabilising pABA oligomers are markedly solvent-dependent: in organic solvents, hydrogen bonds dominate, while water promotes π - π stacking. Despite this clear preference, both types of interactions contribute to the variety of self-associated species in all solvents considered. MD simulations support this observation and show that pABA oligomers are short-lived and display a fluxional character, therefore indicating that the growth unit involved in pABA crystallisation is likely to be a single molecule. Nevertheless, we note that the interactions dominating in pABA oligomers are indicative of the polymorph obtained from precipitation. In water, at low pABA concen- trations - conditions that are known to yield crystals of the β form - carboxylic-carboxylic hydrogen bonds are exclusively asymmetric. At higher pABA concentration conditions in which the crystallisation is known to yield the α form - a small but statistically significant fraction of symmetric carboxylic-carboxylic hydrogen-bonded dimers is present. We interpret the presence of these interactions in solvated pABA oligomers as indicative of the fact that a simultaneous and complete desolvation of two carboxylic groups, necessary to form the sym- metric hydrogen-bonded dimer typical of the α crystal form, is accessible, therefore directing the nucleation pathway towards the nucleation of α-pABA.