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–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 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 concentrationsconditions
that are known to yield crystals of the β formcarboxylic–carboxylic
hydrogen bonds are exclusively asymmetric. At higher pABA concentration
conditions in which the crystallization is known to yield the α
forma 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.
Prenucleation aggregates are important species in the crystallization pathway. Here, we combine heteronuclear Overhauser effect spectroscopy (HOESY) and molecular dynamics calculations to study solute molecule association in a model systembenzoic acid/pentafluorobenzoic acid. Our findings indicate that HOEs arise from diffusion-limited prenucleation aggregates and that association is solvent dependent.
Pre-nucleation aggregates are important species on the crystallisation pathway. Here we combine heteronuclear Overhauser effect spectroscopy (HOESY) and molecular dynamics calculations to study the self-association of a model system – benzoic acid. Our findings indicate that heteronuclear Overhauser effects arise from diffusion-limited pre-nucleation aggregates and that self-association is solvent dependant.
Pre-nucleation aggregates are important species on the crystallisation pathway. Here we combine heteronuclear Overhauser effect spectroscopy (HOESY) and molecular dynamics calculations to study the self-association of a model system – benzoic acid. Our findings indicate that heteronuclear Overhauser effects arise from diffusion-limited pre-nucleation aggregates and that self-association is solvent dependant.
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