Two Major Pre-Nucleation Species that are Conformationally
Distinct and in Equilibrium of Self-Association
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Abstract
To
understand how solution chemistry governs polymorphic formation
of organic crystals, solution NMR measurements of tolfenamic acid
were conducted in ethanol. It was unveiled by chemical shift and diffusivity
results that the solute molecules self-associated as dimers in solution.
Further nOe (nuclear Overhauser effect) analyses indicate that a more
twisted conformation became dominant over a planar conformation under
the solution conditions that favored the dimer formation. This discovery
is rationalized in terms of the energy balance between the conformation
and intermolecular hydrogen bonding of the solute molecule, suggesting
a significant role of the cooperability between a molecule’s
conformation and its intermolecular interaction in determining the
nucleation outcome of distinct crystal structures