Polymorph-Selective Role of Hydrogen Bonding and π–π Stacking in <i>p</i> -Aminobenzoic Acid Solutions

Abstract

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 p-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 supersaturation conditions. NMR reveals that dominant interactions stabilizing pABA oligomers are markedly solvent-dependent: in organic solvents, hydrogen bonds dominate, while water promotes π-πstacking. 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 crystallization 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 concentrations - 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 crystallization 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 symmetric hydrogen-bonded dimer typical of the α crystal form, is accessible, therefore directing the nucleation pathway toward the nucleation of α-pABA.

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