Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

To better understand the thermodynamics and molecular self-assembly mechanism of diastereomeric salt/cocrystalinduced chiral separation, a series of 1:1 cocrystals and salts consisting of chiral valines (VAL) and tartaric acid derivatives were synthesized via different methods. Powders of these as-screened cocrystals/salts were characterized by PXRD, TGA, DSC, FT-IR, and Raman spectroscopy. The crystal structures of the five cocrystals/salts were determined and analyzed. It was found that both DBTA and DTTA form diastereomeric salt pairs with VAL enantiomers. Interestingly, L-DMTA cocrystallizes with D-VAL and L-VAL via hydrogen bonding and proton transfer, respectively. Considering this particularity, the differential isothermal (10 °C) ternary phase diagrams (TPDs) of D-DMTA and L-VAL (D-VAL) cocrystals (salt) were constructed in the mixed solvent of MeOH/ H 2 O. Moreover, a pure L-VAL:D-DMTA cocrystal and D-VAL:D-DMTA:0.5CH 4 O:0.25H 2 O salt were prepared via equimolar slurry conversion at 10 °C. In situ Raman spectroscopy was applied to monitor the molecular assembly process during the incubation of the cocrystal/salt. Molecular dynamics simulation was employed to rationalize the molecular recognition mechanism, demonstrating the excellent chirality preference of L-DMTA toward L-VAL instead of D-VAL. Calculations of density functional theory approved the synergistic instead of antagonistic effects of binding energy and solvation free energy toward chiral separation.

Section: Introductionsupporting

confidence: 70%

Section: ■ Introductionmentioning

confidence: 99%

Thermodynamic and Molecular Recognition Mechanism of Diastereomeric Salt/Cocrystal-Induced Chiral Separation

Sui

Wang

et al. 2022

“…The relative stability of polymorphs was simulated using DFT. Lattice energy is an important parameter, which can reflect the stability of the crystals, as well as explain and predict the characteristics of crystals. − The calculation data of the lattice energy of different DFL forms are summarized in Table , in which the crystal form with zero relative energy was the most stable. The order of thermodynamic stability of the five crystal forms of DFL was as follows: I > III > IV > VI > V. From the Hirshfeld analysis, Form I has the highest contributions of main hydrogen bond interaction (O ··· H bond).…”

Section: Resultsmentioning

confidence: 99%

Study on Structure, Stability, and Phase Transformation of Dufulin Polymorphs

Gong

Ren

et al. 2021

Although plant virus disease is destructive for economic losses of agricultural production, few studies focus on the field of solid state of pesticides. Dufulin (DFL) is a novel plant antiviral agent with high efficiency but low solubility and is easy to agglomerate during the process of crystallization. In this paper, the polymorphism behavior of DFL was systematically studied. Five polymorphs (Forms I–IV and VI), a solvate (Form V) and an amorphous form were discovered and characterized by powder X-ray diffraction and thermal analytical methods. Single crystals of Forms I, III, IV, V, and VI were obtained and their structures were identified by single-crystal X-ray diffraction. Based on the results of stability experiments (solid-state stability and solvent-mediated transition), thermal analysis methods, solubility studies and powder dissolution experiments, Form I appeared to be the thermodynamically most stable phase with the lowest solubility under ambient conditions, closely followed by Form III. In addition, the relative stability of the different crystal forms was simulated by density functional theory. As the result, the thermodynamic order of different forms was as follows: I > III > II > IV > VI > V. It is the first time that seven crystalline forms of DFL are reported, which fills the blank of DFL in the crystal engineering field and prompts the development of the formulation.

“…It was observed that the crystals of this compound are built of ribbon synthons that can be described by a R 2 2 (8) R 4 2 (8) graph set. 10 For 2-(4-t-butylphenyl)propionamide, only the racemic form has been studied (ZEPGAF), and a R 2 2 (8) R 6 4 (16) layer synthon was observed. 12 In one of our previous studies, 8 we solved crystal structures of racemic and enantiopure forms of 2-phenylbutyramide (VOQGUF, VOQHAM, and VOQHEQ) and unambiguously assigned the absolute configurations of its enantiomers.…”

Section: ■ Introductionmentioning

confidence: 99%

Remarkable Similarity of Molecular Packing in Crystals of Racemic and Enantiopure 2-Phenylpropionamide: Z′ = 4 Structures, Molecular Disorder, and the Formation of a Partial Solid Solution

Castañeda

Lindeman

Krivoshein

et al. 2022

Substituted acetamides (many of which are chiral) are known to be pharmacologically active. 2-Phenylpropionamide (2PPA) is one of the simplest chiral α-substituted acetamides and thus is of interest as a model compound in the growth and design of pharmaceutical crystals. In this study, the crystal structures of racemic and enantiopure forms of 2PPA were determined for the first time using single-crystal X-ray diffraction at 100 K. The relationship between the signs of optical rotation and the absolute configurations is (+)-(S)-2PPA and (−)-(R)-2PPA. Four symmetrically independent molecules with different conformations are observed in crystals of both racemic and enantiopure forms. Remarkably, all forms adopt very similar supramolecular structures, H-bonded corrugated layers, that can be described using a R 2 2(8)R 6 4(16) graph set. The outer surfaces of these layers are built of nonpolar phenyl groups, and their inner structures are composed of H-bonded amide groups. The presence of these layers determines the thin plate shape of 2PPA crystals. Spectroscopically, the racemic and enantiopure forms substantially differ only in the low-frequency Raman region. X-ray diffraction data suggest that the racemic form of 2PPA is a partial solid solution made possible by statistical occupancy of molecular positions by (R)- and (S)-enantiomers.