Persistent Self-Association of Solute Molecules in Solution

Abstract

The structural evolvement of a solute determines the crystallization outcome. The self-association mechanism leading to nucleation, however, remains poorly understood. Our current study explored the solution chemistry of a model compound, tolfenamic acid (TFA), in three different solvents mainly by solution NMR. It was found that hydrogen-bonded pairs of solute-solute or solute-solvent stack with each through forming a much weaker π-π interaction as the concentration increases. Depending on the solvent, configurations of the solution species may be retained in the resultant crystal structure or undergo rearrangement. Yet, the π-π stacking is always retained in the crystal regardless of the solvent used for the crystallization. The finding suggests that nucleation not only involves the primary intermolecular interaction (hydrogen bonding) but also engages the secondary forces in the self-assembly process.

Probing the structural pathway of conformational polymorph nucleation by comparing a series of α,ω-alkanedicarboxylic acids

“…Here we ascribe this difference to a solute-ethanol hydrogen-bond equilibrium [the low-and high-frequency C O stretching frequencies corresponding to hydrogen-bonded and nonhydrogen-bonded C O groups, respectively (Du et al, 2015)]. Combined with the relevant literature (Du et al, 2015, Tang et al, 2017, there is another possibility. Diacid molecule-ethanol pairs are formed by hydrogen bonds between the carboxyl and hydroxyl groups, with ethanol acting as either an HBA (the higher frequency band) or an HBD (the lower frequency band).…”

“…Considering the crystal structures as guides with one type of functional group, carboxyl-carboxyl packing could be envisaged as the possible mode of diacid molecule self-assembly in solution. Here, solution IR of diacids at different concentrations in ethanol ( = 86) and 1,4-dioxane ( = 0) was employed to analyze solute self-assembly and solute-solvent interactions in solution (Tang et al, 2017;Kulkarni et al, 2012;Sun & Xue, 2015). It is worth noting that the IR spectra of the selected solvents do not interfere with those of the carboxyl.…”

“…At present, the structural relevance between solute selfassemblies in solution and molecular synthons in the resultant crystals is of great interest (Parveen et al, 2005;Burton et al, 2010;Tang et al, 2017;Zeng et al, 2018) and could shed light on how nucleation proceeds. For instance, it was found that the formation of two conformational polymorphs of Nphenylhydroxamic acid had direct correspondence with the dominant conformers in two different solvents (Yamasaki et al, 2006;Ischenko et al, 2005), which suggested a simple nucleation pathway.…”

Form selection of concomitant polymorphs: A case study informed by crystallization kinetics modeling

“…TFA is a highly polymorphic compound. [41][42][43][44][45] It has eight structurally solved conformational polymorphs, 41,46…”

“…TFA is a highly polymorphic compound 41‐45 . It has eight structurally solved conformational polymorphs, 41,46 but forms I and II are the most encountered.…”