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

Abstract

Herein the nucleation pathway of conformational polymorphs was revealed by studying the relationships and distinctions among a series of α,ω-alkanedicarboxylic acids [HOOC–(CH2) n−2–COOH, named DAn, where n = 5, 7, 9, 11, 13, 15] in the solid state and in solution. Their polymorphic outcomes, with the exception of DA5, show solvent dependence: form I with conformation I crystallizes from solvents with hydrogen-bond donating (HBD) ability, whereas form II with conformation II crystallizes preferentially from solvents with no HBD ability. In contrast, form II of DA5 does not crystallize in any of the solvents used. Quantum mechanical computation showed that there is no direct conformational link between the solvents and the resultant polymorphic outcomes. Surprisingly, solute aggregates were found in no-HBD solvents by Fourier transform infrared spectroscopy, and only monomers could be detected in HBD solvents, suggesting stronger solvation. Furthermore, it was found that all six compounds including DA5 followed the same pattern in solution. Moreover, crystal-packing efficiency calculations and stability tests stated that dimorphs of DA5 bear a greater stability difference than others. These suggest that the rearrangement from conformation II to I could not be limited by hard desolvation in HBD solvents, where form I was also obtained. In other systems, metastable II was produced in the same solvents, probably as a result of the rearrangement being limited by hard desolvation. In this work, a comparative study uncovers the proposed nucleation pathway: difficulty in desolvation has a remarkable effect on the result of rearrangement and nucleation outcome.

Insights into the Role of Solvents in Nucleation Kinetics of Glutaric Acid from Metastable Zone Widths

“…Also, the higher the concentration of glutaric acid, the higher the intensity ratio of the 1712–1740 cm –1 band. This supports that the carboxyl group of glutaric acid self-assembles in ethyl acetate after reaching a certain concentration, and the degree of aggregation increases with increasing concentration, ,, suggesting that the intermolecular interaction of solutes is not intramolecular.…”

“…Different solvents, which possess different hydrogen-bond donating (HBD) and hydrogen-bond accepting (HBA) abilities, are represented by α and β, respectively. It was confirmed in the Shi et al article that there were significant differences between solute species in solvents with different HBD capacities. A lack of HBD capacity provides more opportunities for solute self-aggregation.…”

“…As a classical research object, glutaric acid is a typically dicarboxylic acid small molecule. In its self-assembly way, it always aggregates into dimer species and further self-assembles into macrocrystals . As the main contributor to the article, Xu and co-authors demonstrated that form I of glutaric acid was harvested in ethanol, acetic acid, and ethyl acetate.…”

Template design based on molecular and crystal structure similarity to regulate conformational polymorphism nucleation: the case of α,ω-alkanedicarboxylic acids

“…Similarity analysis of the solute crystal and template There are usually two conformational polymorphs that exist under environment conditions. Different carboxyl torsions at both ends of the diacid molecules [(O 2 -C 1 -C 2 -C 3 and O 4 -C n -C nÀ1 -C nÀ2 ) are named 1 and 2 , respectively] result in different molecular conformations (Shi et al, 2021(Shi et al, , 2020. However, the carboxyl torsions of form II of a series diacids with different carbon chains are similar, as shown in Fig.…”

“…Odd-carbon ,!alkanedicarboxylic acids (diacids) usually have two conformational polymorphs under normal conditions, whose carboxyl torsions at both ends of the molecule are different (Shi et al, 2018). Our previous studies demonstrated that the stable or metastable polymorph of a series of diacids with different carbon chain lengths shared a similar crystal structure (Shi et al, 2020). Meanwhile, we found that their solubility decreased sharply with increasing chain length, especially in water.…”