Crystal structures, thermal stabilities, and dissolution behaviours of tinidazole and the tinidazole–vanillic acid cocrystal: insights from energy frameworks

The crystal structures of the antimicrobial drug tinidazole [TNZ; systematic name: 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole, C8H13N3O4S] and the 1:1 cocrystal of TNZ with the naturally occurring compound vanillic acid (VA; systematic name: 4-hydroxy-3-methoxybenzoic acid, C8H8O4), namely, the TNZ–VA cocrystal, were determined by single-crystal X-ray analysis at 100 K. The supramolecular structure of the TNZ–VA cocrystal is composed of a carboxylic acid dimer and an O—H...N(heterocycle) synthon in the form of layers made up of O—H...N and O—H...O hydrogen bonds. The layers are joined via C—H...O hydrogen bonds, π–π stacking and C—H...π interactions. The energy framework analysis, together with interaction energy calculations using the DLPNO-CCSD(T) method, indicates that the TNZ–VA cocrystal inherits strong interactions from the TNZ and VA crystals, which accounts for the enhanced thermal stability and reduced dissolution rate. To the best of our knowledge, this is the first example of a cocrystal containing TNZ.

N-Tosyl-L-proline benzene hemisolvate: a rare example of a hydrogen-bonded carboxylic acid dimer with symmetrically disordered H atoms

The carboxylic acid group is an example of a functional group which possess a good hydrogen-bond donor (–OH) and acceptor (C=O). For this reason, carboxylic acids have a tendency to self-assembly by the formation of hydrogen bonds between the donor and acceptor sites. We present here the crystal structure of N-tosyl-L-proline (TPOH) benzene hemisolvate {systematic name: (2S)-1-[(4-methylbenzene)sulfonyl]pyrrolidine-2-carboxylic acid benzene hemisolvate}, C12H15NO4S·0.5C6H6, (I), in which a cyclic R 2 2(8) hydrogen-bonded carboxylic acid dimer with a strong O—(1 \over 2H)...(1 \over 2H)—O hydrogen bond is observed. The compound was characterized by single-crystal X-ray diffraction and NMR spectroscopy, and crystallizes in the space group I2 with half a benzene molecule and one TPOH molecule in the asymmetric unit. The H atom of the carboxyl OH group is disordered over a twofold axis. An analysis of the intermolecular interactions using the noncovalent interaction (NCI) index showed that the TPOH molecules form dimers due to the strong O—(1 \over 2H)...(1 \over 2H)—O hydrogen bond, while the packing of the benzene solvent molecules is governed by weak dispersive interactions. A search of the Cambridge Structural Database revealed that the disordered dimeric motif observed in (I) was found previously only in six crystal structures.

Supramolecular architectures in two 1:1 cocrystals of 5-fluorouracil with 5-bromothiophene-2-carboxylic acid and thiophene-2-carboxylic acid

In solid-state engineering, cocrystallization is a strategy actively pursued for pharmaceuticals. Two 1:1 cocrystals of 5-fluorouracil (5FU; systematic name: 5-fluoro-1,3-dihydropyrimidine-2,4-dione), namely 5-fluorouracil–5-bromothiophene-2-carboxylic acid (1/1), C5H3BrO2S·C4H3FN2O2, (I), and 5-fluorouracil–thiophene-2-carboxylic acid (1/1), C4H3FN2O2·C5H4O2S, (II), have been synthesized and characterized by single-crystal X-ray diffraction studies. In both cocrystals, carboxylic acid molecules are linked through an acid–acid R 2 2(8) homosynthon (O—H...O) to form a carboxylic acid dimer and 5FU molecules are connected through two types of base pairs [homosynthon, R 2 2(8) motif] via a pair of N—H...O hydrogen bonds. The crystal structures are further stabilized by C—H...O interactions in (II) and C—Br...O interactions in (I). In both crystal structures, π–π stacking and C—F...π interactions are also observed.

2-(Acetoxymethyl)benzoic acid

The title compound, C10H10O4, crystallizes with the well-known carboxylic acid dimer-formingR22(8) hydrogen-bond motif. Chains approximately parallel to (-1-12) are then built through C(methylene,phenyl)–H...O(carbonyl) interactions [C(6) andC(8) motifs] with one (methyl)C—H...π interaction providing interplanar binding. The weakness of the latter interaction is consistent with the difficulty experienced in obtaining suitable single crystals.

Hydrogen bond strength and bond geometry in cyclic dimers of crystalline carboxylic acids

In a study of 101 crystal structures of carboxylic acids we have observed a clear trend in the difference between the formally single and formally double C—O bond distances, as observed by X-ray diffraction, with a clear-cut distinction between aromatic acids, where the two distances are similar, and non-aromatic acids, where the two distances distinctly differ by 0.06–0.12 Å. A tentative energy classification – within the limits of the many assumptions – and a correlation with the O...O separation over the hydrogen bond indicate that the stability of the carboxylic acid dimer increases as the difference between the two apparent C—O distances becomes smaller, owing to an increasing Coulombic contribution to the dimerization energy. No simple hypothesis is adequate for a complete explanation of the origin, of the details and of the variations of this phenomenon. As often happens in crystal chemistry problems, one is presumably confronted with a balance of several subtle intra- and intermolecular factors.