Conformational Flexibility and Crystallization: The Case of 4-Hexyloxybenzoic Acid

A thorough re-examination of sulfaguanidine’s (SGD) solid-state behavior was conducted, 65 years after the initial report on SGD polymorphism. This investigation focuses on the polymorphic nature of the compound, the formation of hydrates and solvates, and the pivotal role of experimental and computational methods in screening, assessing stability, and understanding transformation processes. The findings confirm the presence of five anhydrates (AH-I–V), two monohydrate polymorphs (Hy1-I and Hy1-II), and nine solvates (with tetrahydrofuran, methanol, ethanol, t-butanol, acetone, cyclohexanone, dimethyl sulfoxide, dimethyl formamide, and dimethyl acetamide). Notably, nine novel structures–two anhydrates and seven solvates–are reported, solved from powder X-ray diffraction data. Calorimetric measurements have revealed that AH-II is the thermodynamically stable polymorph at room and low temperatures. In contrast, AH-I emerges as the stable polymorph at higher temperatures, yet it exhibits remarkable kinetic stability at RT and demonstrates greater stability in terms of hydration. The anhydrate forms exhibit distinctive packing arrangements, while the two hydrates share a close structural resemblance. Among the seven structurally characterized solvates, only the tetrahydrofuran and dimethyl sulfoxide solvates are isostructural. Controlled desolvation experiments enabled the formation of AH-I, AH-II, and, notably, AH-V for the first time. The anhydrate and monohydrate crystal structure prediction studies reveal that the computed lowest-energy structures correspond to experimentally observed forms and propose models for the elusive AH-IV structure. Overall, the exploration of SGD’s solid-state landscape confirms a rich array of highly stable H-bonding motifs and packing arrangements, positioning this study as an ideal model for complex solid-state systems and shedding light on its intricate solid-state nature.

Section: Introductionmentioning

confidence: 86%

Comprehensive Insights into Sulfaguanidine in the Solid State: An Experimental and Computational Study

Widauer,

Petrick,

Braun

2024

“…Conformational flexibility plays an important role in the polymorphism of molecular crystals. − This is exemplified in fenamic acids (FAs), whose conformational variation mainly stems from rotation about the N–C aniline bond. − In its homologues, however, the main conformational determinants are other sigma bonds such as C1–C2 in 2-phenethylamino-benzoic acid (2-PTA-BA). In a recent study, we investigated the effect on polymorphism of anthranilic acids exerted by homologation, i.e., extension of the alkyl chain linking the two aromatic rings (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

anti/gauche Conformations Lead to Polymorphism in Homologous Phenylalkylamino-Nicotinic Acids

Zhoujin

Liang

et al. 2023

A series of phenylalkylamino-nicotinic acids (1–4) were synthesized by varying the length of the linker between the pyridine and benzene rings, and their polymorphism was investigated. Under the same crystallization conditions, one crystal form was found for compounds 1 and 2, three forms were obtained for compound 3, and two forms were harvested for compound 4. A detailed conformational analysis was performed, and the polymorphism of 3 and 4 was found to be caused by the anti and/or gauche conformation of specific sigma bonds within them. However, there appears to be no correlation between the number of polymorphs and sigma bonds, and the rotation of which sigma bond(s) is responsible for the polymorphism could not be predicted. Phase behavior studies by differential scanning calorimetry (DSC) revealed a phase transition from 4-I with a small asymmetric unit (Z′ = 1) to 4-II with a larger asymmetric unit (Z′ = 2). Computational studies including Hirshfeld surface analysis and independent gradient model (IGM) analyses were performed to highlight the most significant intermolecular interactions in the crystals.

“…Liu et al found that different solvation preferences for d -mannitol molecules in different solvents would lead to different polymorphs, indicating the critical role of solvation and desolvation in forming polymorphs. Du et al studied the crystallization of 4-hexyloxybenzoic acid and found no links between the conformational flexibility and the polymorphic outcome, indicating that the desolvation process would promote a molecular rearrangement during nucleation so as to form different crystal forms. Li et al , studied the conformational evolution path of 5-nitrofuranone in solution.…”

Section: Introductionmentioning

confidence: 99%

Conformational Selectivity and Evolution Affected by the Desolvation Process

Liu

Wang

Huang

et al. 2022

The inconsistency between solution chemistry and the crystal structure indicates the potential conformational evolution and rearrangement during the nucleation process. However, the mechanism of how the conformation is selected to form the corresponding polymorph is still not clear due to the complicated crystallization environment. In this work, conformation and polymorph selectivity of three anhydrous forms of gabapentin were investigated. Quantum chemical computation was used to analyze gabapentin conformations in the solution state and explore their transformation pathway. Besides, visual molecular dynamics was adopted to calculate the structural difference of the conformers in solution and crystal states, which was closely related to conformational selectivity. Moreover, the effects of solvent types and the supersaturation on solute−solvent interactions were investigated by Fourier transform infrared spectra and molecular dynamics simulations. Combined with the outcome of rapid cooling experiments, it was found that the solute−solvent interaction may affect the difficulty of desolvation so as to affect the conformational selectivity before nucleation. A special evaporation experiment was designed to obtain the unstable polymorph of gabapentin. Finally, the possible mechanism of selective polymorph crystallization was proposed and analyzed.