Sihui Long

Solid-state identity of 2-hydroxynicotinic acid and its polymorphism

2-Hydroxynicotinic acid (2-HNA), a derivative of nicotinic acid, was found to exist in four polymorphs. In the solid state, 2-HNA is actually present as its tautomer, 2-oxo-1,2-dihydro-3-pyridinecarboxylic acid (2-ODHPCA). The polymorphism stems from distinctive packing arrangements of the molecules, and the formation of the distinct polymorphs can be affected by using various acidic additives. The thermal behaviors of the four polymorphs indicate that form I is the most stable at elevated temperature, form II converts into form I during heating, and forms III and IV transform into form II when heated. Theoretical studies showed that 2-ODHPCA is more energetically favored than 2-HNA. Condensed Fukui functions and the dual descriptor were used jointly to examine the local preference of hydrogen bonding in the crystal. Lattice energy calculations were conducted to further evaluate energetic properties of the system.

Polymorphism and solid-to-solid phase transitions of a simple organic molecule, 3-chloroisonicotinic acid

Three polymorphs (I, II, and III) have been discovered for 3-chloroisonicotinic acid. The torsion angle between the aromatic ring and the carboxylic acid in form I differs from that of forms II and III, which are similar. All three polymorphs form hydrogen-bonded chains based on the acid–pyridine heterosynthon. Despite the conformational similarity between forms II and III, the hydrogen-bonded chains in form II alternate in direction while those in form III all point in the same direction. Study of the phase behaviors of the three forms by differential scanning calorimetry, hot-stage microscopy, and thermogravimetric analysis revealed two solid-to-solid phase transitions from the metastable forms II and III to the most stable form I. Sublimation of 3-chloroisonicotinic acid also led to form I. A higher-temperature polymorph seemed to be possible but remained elusive. Lattice energy and hydrogen bonding strength calculations provided further insight into the stability of the polymorphs. A search of conformational space for the molecule suggested possibly additional polymorphs of this simple compound. The system may be valuable for further solid-state structure–property relationship studies.

Preferred formation of the carboxylic acid–pyridine heterosynthon in 2-anilinonicotinic acids

The carboxylic acid–carboxylic acid homosynthon and carboxylic acid–pyridine heterosynthon are two competing supramolecular synthons in 2-anilinonicotinic acids that possess both carboxylic acid and pyridine functionalities. Previously we demonstrated that carboxylic acid–pyridine heterosynthons can be selectively formed in crystals by chemically introducing bulky functional groups to the aniline ring of the molecules. In this study we show that with the same philosophy, but a different strategy, i.e., adding substituent groups to the nitrogen bridging the two aromatic rings, we can also achieve the preferential formation of the carboxylic acid–pyridine heterosynthon over the carboxylic acid–carboxylic acid homosynthon. This is a new case of how molecular conformation can affect intermolecular interactions and consequent crystal packing.

Solvatomorphism in (E)-2-(2,6-dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide.

The structures of orthorhombic (E)-4-(2-{[amino(iminio)methyl]amino}vinyl)-3,5-dichlorophenolate dihydrate, C(8)H(8)Cl(2)N(4)O·2H(2)O, (I), triclinic (E)-4-(2-{[amino(iminio)methyl]amino}vinyl)-3,5-dichlorophenolate methanol disolvate, C(8)H(8)Cl(2)N(4)O·2CH(4)O, (II), and orthorhombic (E)-amino[(2,6-dichloro-4-hydroxystyryl)amino]methaniminium acetate, C(8)H(9)Cl(2)N(4)O(+)·C(2)H(3)O(2)(-), (III), all crystallize with one formula unit in the asymmetric unit, with the molecule in an E configuration and the phenol H atom transferred to the guanidine N atom. Although the molecules of the title compounds form extended chains via hydrogen bonding in all three forms, owing to the presence of different solvent molecules, those chains are connected differently in the individual forms. In (II), the molecules are all coplanar, while in (I) and (III), adjacent molecules are tilted relative to one another to varying degrees. Also, because of the variation in hydrogen-bond-formation ability of the solvents, the hydrogen-bonding arrangements vary in the three forms.

N-(3-Chloro-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Long, S., Siegler, M. & Li, T. (2006). Acta Cryst. E62, o4278–o4279. Nonius (2002). COLLECT. Nonius BV, Delft, The Netherlands. Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press. Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Ting, P. C., Kaminski, J. J., Sherlock, M. H., Tom, W. C., Lee, J. F., Bryant, R. W., Watnick, A. S. & McPhailt, A. T. (1990). J. Med. Chem. 33, 2697–2706. organic compounds

sp2CH⋯Cl hydrogen bond in the conformational polymorphism of 4-chloro-phenylanthranilic acid

Chlorine can participate in numerous interactions such as halogen bonding, hydrogen bonding, and London dispersion in the solid state. In this work, we report the influence of a chlorine substituent on the polymorphism of a potential anticancer drug, 4-chloro-phenylanthranilic acid (CPAA). Three polymorphs have been discovered for this compound, and the three forms were characterized by single-crystal X-ray diffraction, power X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Both conformational flexibility of the molecule and the sp2CH⋯Cl hydrogen bond seem to lead to the polymorphism of the system. The phase behavior was investigated by differential scanning calorimetry (DSC), with the conclusion that form II converts to III upon heating. A conformational scan shows the conformational minima corresponds to the conformers existing in the polymorphs. Lattice energy calculations show energies of −106.70, −104.72, and −194.42 kJ mol−1 for forms I to III, providing information on relative stability for each form. Hirshfeld analysis revealed that intermolecular interactions such as H⋯H, C⋯H, H⋯Cl, and H⋯O contribute to the stability of the crystal forms.

Cyclo­oxygenase-1-selective inhibitor SC-560

In the title compound, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), C17H12ClF3N2O, a COX-1-selective inhibitor, the dihedral angles between the heterocycle and the chlorobenzene and methoxybenzene rings are 41.66 (6) and 43.08 (7)°, respectively. The dihedral angle between the two phenyl rings is 59.94 (6)°. No classic hydrogen bonds are possible in the crystal, and intermolecular interactions must be mainly of the dispersion type. This information may aid the identification of dosage formulations with improved oral bioavailability.

Inversion Symmetry and Local vs. Dispersive Interactions in the Nucleation of Hydrogen Bonded Cyclic N-Mer and Tape of Imidazolecarboxamidines

Summary Substitutional changes to imidazolecarboxamidine that preserved intermolecular hydrogen bonding in the solid state were used to study the relationship between packing and the hydrogen bond motif. Various motifs competed, but the most common imidazolecarboxamidine crystalline phase was a C i symmetric dimer that established inversion centers by associating enantiomeric tautomers. Counter to intuition, the calculated gas-phase energies per molecule of the solid state atomic coordinates of the C i dimer motifs were higher than those of the C 1 dimer, trimer, tetramer and tape motifs, while the packing densities of C i dimers were found to be higher. This result was interpreted as an enhanced ability of the C i dimers to pack. If other motifs competed, the hydrogen bonds and conformations should be lower in energy than the C i dimer. The results detail the effect of packing on the conformation in these molecules. The results are interpreted as a rough measure of the energetic compromise between packing and the energies related to the coordinates involving one dihedral angle and hydrogen bonding. The results establish a connection between solution and solid phase conformation.

Solution growth and thermal treatment of crystals lead to two new forms of 2-((2,6-dimethylphenyl)amino)benzoic acid

We report the discovery of two new forms (II and III) of a potential non-steroidal anti-inflammatory and thyroid drug, 2-((2,6-dimethylphenyl)amino)benzoic acid (HDMPA) through solution growth and thermal treatment of crystals. Form II has been discovered through crystal growth in a variety of solvents, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Form II converts into form III upon thermal treatment, as indicated by the phase behavior study of form II with differential scanning calorimetry (DSC). Form III has been characterized by IR, Raman and PXRD. Conformational flexibility of the molecule seems to lead to the polymorphism of the system. A conformational scan shows the conformational minima correspond to the conformers in the polymorphs. Lattice energy calculations show energies of −48.14 and −50.31 kcal mol−1 for forms I and II, providing information on the relative stability for each form. Hirshfeld analysis revealed that intermolecular interactions such as C⋯C, H⋯H, C⋯H, and H⋯O contribute to the stability of the crystal forms.

CCDC 1846857: Experimental Crystal Structure Determination

Related Article: Siqing Peng, Faquan Yu, Danrui Xu, Conggang Li, Sean R. Parkin, Tonglei Li, Mingtao Zhang, Sihui Long|2018|Cryst.Growth Des.|18|4849|doi:10.1021/acs.cgd.8b00840