Concomitant polymorphs of 2-imino-2H-chromene-3-carboxylic acid amide: experimental and quantum chemical study.

2-Iminocoumarin-3-carboxamide (2-imino-2 H-chromene-3-carboxylic acid) is a perspective compound for use in the pharmaceutical industry. This compound crystallized from several solvents as two concomitant polymorphic forms. The monoclinic polymorph, crystallized initially, is formed due to strong N-H...O hydrogen bonds, weak C-H...O and C-H...N(π) hydrogen bonds, and stacking interactions of `head-to-head' type. The triclinic polymorphic form obtained due to slow evaporation of the same solution is formed due to only strong intermolecular interactions, N-H...O hydrogen bonds of two types, and stacking interactions of two types. Analysis of pairwise interaction energies showed that the monoclinic structure is columnar while the triclinic one is layered. Calculations in a periodic approximation of their lattice energies confirmed that the monoclinic polymorphic crystals are metastable as compared to the stable triclinic polymorph. Further quantum chemical modeling of possible structure deformations proved that both concomitant polymorphs can not be transformed into a new polymorphic form under external influence.

Quantum Chemical Study on Mefenamic Acid Polymorphic Forms.

Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the centrosymmetric dimer formed due to two O-H···O hydrogen bonds is a complex building unit in all of the polymorphic structures under study. On the basis of an analysis of the pairwise interaction energies between molecules, the polymorphic forms I and II are classified as columnar-layered while the polymorphic form III has a columnar structure. The stabilities of the three polymorphic forms of mefenamic acid under ambient conditions (I > II > III) correlate with the degree of anisotropy of the interaction energies between columns (primary basic structural motifs) formed due to stacking interactions. The shear deformation modeling of strongly bound layers in all of the polymorphic structures has not revealed any possibility for deformation of the crystal structure. The construction of the shift energy profiles and calculation of the energy barriers for the displacement along the (100) crystallographic plane in the [100], [010], and [011] crystallographic directions make it possible to explain the experimental data obtained for commercially available polymorphic structure I in a diamond anvil cell. The absence of any local minimum near the starting point on the shift energy profile and the extremely high energy barrier can be considered as criteria for the impossibility of a crystal structure deformation under pressure.

Polymorphic transition due to grinding: the case of 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid.

A polymorphic transition as a result of grinding was found for 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid. The thorough study of polymorphic structures before and after crystal structure transformation has revealed some pre-conditions for a polymorphic transition and regularities of changes in molecular and crystal structure. In metastable polymorph 1a, the conformationally flexible molecule adopts a conformation with the higher energy and forms a less preferable linear supramolecular synthon. Additional energy imparted to a crystal structure during the grinding process proved to be enough to overcome low energy barriers for the nitrogen inversion and rotation of the oxazole ring around the sp3-sp2 single bond. As a result, polymorph 1b with a molecule adopting conformation with lower energy and forming a more preferable centrosymmetric supramolecular synthon was obtained. The study of pairwise interaction energies in the two polymorphs has shown that metastable polymorph 1a is organized by molecular building units and has a columnar-layered structure. A centrosymmetric dimer should be recognized as a complex building unit in more stable polymorph 1b, which has a layered structure.

Crystal structures and Hirshfeld analysis of 4,6-di-bromo-indole-nine and its quaternized salt.

4,6-Di-bromo-2,3,3-trimethyl-3H-indole, C11H11Br2N, exists as a neutral mol-ecule in the asymmetric unit. The asymmetric unit of 4,6-di-bromo-2,3,3-trimethyl-3H-indol-1-ium iodide, C12H14Br2N+·I-, contains one organic cation and one iodine anion. The positive charge is localized on the quaternized nitro-gen atom. In the crystal, mol-ecules of 4,6-di-bromo-indole-nine are linked by C-Br⋯π halogen bonds, forming zigzag chains propagating in the [001] direction. The mol-ecules of the salt form layers parallel to the (010) plane where they are linked by C-H⋯Br hydrogen bonds, C-Br⋯Br and C-Br⋯I halogen bonds. The Hirshfeld surface analysis and two dimensional fingerprint plots were used to analyse the inter-molecular contacts present in both crystals.

Crystal structure of the non-steroidal anti-inflammatory drug (NSAID) tolmetin sodium.

The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1H-pyrrol-2-yl]acetate dihydrate, Na+·C15H14NO3 -·2H2O, contains two sodium cations, two organic anions (A and B) and two water mol-ecules. The coordination geometry around the sodium cations corresponds to a distorted octa-hedron. Each pair of sodium cations (A-A or B-B) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carb-oxy-lic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water mol-ecule. As a result, a two-dimensional polymer is formed in the crystal. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.

Conformational polymorphs of 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole, C12H11N5O, was studied on the assumption of its potential biological activity. Two polymorphic forms differ in both their molecular and crystal structures. The monoclinic polymorphic form was crystallized from more volatile solvents and contains a conformer with a higher relative energy. The basic molecule forms an abundance of interactions with relatively close energies. The orthorhombic polymorph was crystallized very slowly from isoamyl alcohol and contains a conformer with a much lower energy. The basic molecule forms two strong interactions and a large number of weak interactions. Stacking interactions of the `head-to-head' type in the monoclinic structure and of the `head-to-tail' type in the orthorhombic structure proved to be the strongest and form stacked columns in the two polymorphs. The main structural motif of the monoclinic structure is a double column where two stacked columns interact through weak C-H...N hydrogen bonds and dispersive interactions. In the orthorhombic structure, a single stacked column is the main structural motif. Periodic calculations confirmed that the orthorhombic structure obtained by slow evaporation has a lower lattice energy (0.97 kcal mol-1) compared to the monoclinic structure.

Polymorphism of methyl 4-amino-3-phenylisothiazole-5-carboxylate: an experimental and theoretical study.

Being a close analogue of amflutizole, methyl 4-amino-3-phenylisothiazole-5-carboxylate (C11H10N2O2S) was assumed to be capable of forming polymorphic structures. Noncentrosymmetric and centrosymmetric polymorphs have been obtained by crystallization from a series of more volatile solvents and from denser tetrachloromethane, respectively. Identical conformations of the molecule are found in both structures. The two polymorphs differ mainly in the intermolecular interactions formed by the amino group and in the type of stacking interactions between the π-systems. The most effective method for revealing packing motifs in structures with intermolecular interactions of different types (hydrogen bonding, stacking, dispersion, etc.) is to study the pairwise interaction energies using quantum chemical calculations. Molecules form a column as the primary basic structural motif due to stacking interactions in both polymorphic structures under study. The character of a column (straight or zigzag) is determined by the orientations of the stacked molecules (in a `head-to-head' or `head-to-tail' manner). Columns bound by intermolecular N-H...O and N-H...N hydrogen bonds form a double column as the main structural motif in the noncentrosymmetric structure. Double columns in the noncentrosymmetric structure and columns in the centrosymmetric structure interact strongly within the ab crystallographic plane, forming a layer as a secondary basic structural motif. The noncentrosymmetric structure has a lower density and a lower (by 0.59 kJ mol-1) lattice energy, calculated using periodic calculations, compared to the centrosymmetric structure.

(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-tri-methyl-cyclo-pentane-1-carb-oxy-lic acid as a new anti-diabetic active pharmaceutical ingredient.

The chiral title compound, C16H20N2O2, which can be used for producing active pharmaceutical ingredients for treatment of type 2 pancreatic diabetes and other pathologies dependent on insulin resistance, was prepared from (1R,3S)-camphoric acid and o-phenyl-enedi-amine. It crystallized from an ethanol solution in the chiral monoclinic P21 space group. The five-membered ring adopts a twisted conformation with the methyl-substituted C atoms displaced by -0.273 (5) and 0.407 (5) Šfrom the mean plane through the other three atoms. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds, forming chains along the a-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.

Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies.

Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate's anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration.

Concomitant polymorphic forms of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole, C10H11N5O, was studied on the assumption of its potential biological activity. Two concomitant polymorphs were obtained on crystallization from isopropanol solution and these were thoroughly studied. Identical conformations of the molecules are found in both structures despite the low difference in energy between the four possible conformers. The two polymorphs differ crucially with respect to their crystal structures. A centrosymmetric dimer formed due to both stacking interactions of the `head-to-tail' type and N-H...N(π) hydrogen bonds is the building unit in the triclinic structure. The dimeric building units form an isotropic packing. In the orthorhombic polymorphic structure, the molecules form stacking interactions of the `head-to-head' type, which results in their organization in a column as the primary basic structural motif. The formation of N-H...N(lone pair) hydrogen bonds between two neighbouring columns allows the formation of a double column as the main structural motif. The correct packing motifs in the two polymorphs could not be identified without calculations of the pairwise interaction energies. The triclinic structure has a higher density and a lower (by 0.60 kcal mol-1) lattice energy according to periodic calculations compared to the orthorhombic structure. This allows us to presume that the triclinic form of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole is the more stable.

Synthesis, X-ray crystal structure, Hirshfeld surface analysis, and molecular docking study of novel inhibitor of hepatitis B: methyl 4-fluoro-3-(morpholinosulfonyl)benzo[b]thiophene-2-carboxylate.

A method of 4-fluoro-3-(morpholinosulfonyl)benzo[b]thiophene-2-carboxylate synthesis has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single crystal X-ray analysis has revealed that it exists in a monoclinic P21/c space group, with one molecule in the asymmetric part of the unit cell. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. Molecular docking study evaluates the investigated compound as a new potential inhibitor of hepatitis B. Testing for anti-hepatitis B virus activity has shown that this substance demonstrates in vitro nanomolar inhibitory activity against HBV.

Polymorphism of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)- and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-ones.

This study of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, C17H10N2O3, 1, and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-one, C16H9N3O3, 2, was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the `head-to-head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar-layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds.

The unexpectedly uncatalyzed reaction between 2-amino-4-arylimidazoles, aromatic aldehydes and Meldrum's acid has selectively led to the corresponding Knoevenagel-Michael adducts containing a free amino group in the imidazole fragment. The adducts derived from Meldrum's acid have been smoothly converted into 1,7-diaryl-3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-ones and 3-(2-amino-4-aryl-1H-imidazol-5-yl)-3-arylpropanoic acids. The interaction of 2-amino-4-arylimidazoles with aromatic aldehydes or isatins and acyclic methylene active compounds has led to the formation of pyrrolo[1,2-c]imidazole-6-carbonitriles, pyrrolo[1,2-с]imidazole-6-carboxylates and spiro[indoline-3,7'-pyrrolo[1,2-c]imidazoles], which can be considered as the analogues of both 3,3'-spirooxindole and 2-aminoimidazole marine sponge alkaloids.

Three polymorphs of 3-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-1-benzopyran-2-one formed from different solvents.

The polymorphic study of 3-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-1-benzopyran-2-one, C17H11N3O2, was performed due to its potential biological activity and revealed three polymorphic modifications in the triclinic space group P-1, the monoclinic space group P21 and the orthorhombic space group Pbca. These polymorphs have a one-column layered type of crystal organization. The strongest interactions between the molecules of the studied structures is stacking between π-systems, while N-H...N and C-H...O hydrogen bonds link stacked columns forming layers as a secondary basic structural motif. C-H...π hydrogen bonds were observed between neighbouring layers and their role is the least significant in the formation of the crystal structure. Packing differences between the polymorphic modifications are minor and can be identified only using an analysis based on a comparison of the pairwise interaction energies.

Influence of ortho-substituent on the molecular and crystal structures of 2-(N-arylimino)coumarin-3-carboxamide: isotypic and polymorphic structures.

During a comprehensive study of a series of 2-(N-arylimino)coumarin-3-carboxamides with the aryl group substituted in the ortho-position by either a halogen atom, a methyl group or a methoxy group, the existence of three groups of isotypic crystal structures has been revealed. The similarity of crystal structures belonging to the same groups was confirmed by the analysis based on the comparison of pairwise interactions energies obtained from quantum chemical calculations. Group I includes unsubstituted, methyl-substituted and polymorphic modification 1 of fluoro-substituted 2-(N-arylimino)coumarin-3-carboxamide. Structures of polymorphic modification 2 of fluoro-substituted derivative, chloro-substituted and polymorphic modification 1 of bromo-substituted 2-(N-arylimino)coumarin-3-carboxamide may represent group II. Group III contains structures of polymorphic modification 2 of bromo-substituted derivative, iodine- and methoxy-substituted 2-(N-arylimino)coumarin-3-carboxamides. Structures of the same type group have extremely close parameters of the unit cell as well as those of molecular and crystal structures. But they are not identical. Polymorphic modifications of fluoro- and bromo-substituted 2-(N-arylimino)coumarin-3-carboxamides belong to different crystal types mainly due to different arrangement of basic structural motifs separated out using quantum chemical calculations.

Crystal structure of {µ-6,6'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methanylyl-idene)]diphenolato}(meth-anol)(nitrato)nickel(II)sodium.

In the molecular structure of the title compound, [NaNi(C18H18N2O4)(NO3)(CH3OH)], the Ni(2+) ion has a slightly distorted square-planar coordination environment defined by two N and two O atoms which belong to a Schiff base ligand, viz. 6,6'-dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methanylyl-idene)]diphenolate. Seven O atoms form the coordination environment of the Na(+) ion: four from the Schiff base ligand, two from a bidentate chelating nitrate anion and one O atom from a coordinating methanol mol-ecule. In the crystal, the bimetallic complexes are assembled into chains along the b-axis direction via weak C-H⋯O hydrogen-bond inter-actions. Neighbouring chains are in turn connected through bifurcated O-H⋯O hydrogen bonds that involve the coordinating methanol mol-ecules and the nitrate anions, and through π-π stacking inter-actions between phenyl rings of neighbouring mol-ecules.

Tetra-methyl N,N'-(2,2,3,3,4,4-hexa-fluoro-1,5-dioxopentane-1,5-di-yl)bis-(phospho-ramidate).

The mol-ecule of the title compound, C(9)H(14)F(6)N(2)O(8)P(2), lies on a twofold rotation axis that passes through the middle C atom of the three-atom fluoro-methyl-ene unit. The carbonyl and phosphoryl groups are in an antiperiplanar conformation. In the crystal, N-H⋯O=P hydrogen bonds link the mol-ecules into polymeric chains parallel to the c axis.

Tetra-methyl-ammonium dimethyl (phenyl-sulfonyl-amido)phosphate(1-).

The title compound, C(4)H(12)N(+)·C(8)H(11)NO(5)PS(-), was obtained from tetra-methyl-ammonium hydroxide and dimeth-yl(phenyl-sulfon-yl)amido-phosphate. The tetra-methyl-ammonium cation has a slightly distorted tetra-hedral configuration and the N-C bond lengths lie in the range 1.457 (3)-1.492 (3) Å. In the crystal, no classical hydrogen bonds are observed between the cation and the anion.

Intra- and intermolecular interactions in the crystals of 3,4-diamino-1,2,4-triazole and its 5-methyl derivative. Experimental and theoretical investigations of charge density distribution.

In this paper intra- and intermolecular interactions in crystals of 3,4-diamino-1,2,4-triazole (DAT) and its 5-methyl derivative (DAMT) were investigated in details by experimental (high-resolution X-ray diffraction) and theoretical (ab initio quantum chemistry (MP2/aug-cc-pvdz), AIM, and NBO) methods. Influence of n-π conjugation and n→σ* hyperconjugation on the geometry of DAT and DAMT molecules was shown. All intermolecular interactions in crystals of the DAT and DAMT including weak X-H···π and mixed X-H···N/X-H···π hydrogen bonds were considered. Comparison of BCP characteristics of these interactions from experimental and theoretical charge density distribution demonstrates systematic increase of bonding in isolated dimers compared with dimers in the crystal phase. The ability of amino groups in both crystals serve as proton acceptors in hydrogen bonding was confirmed.

cis-Diaqua-bis-[dimethyl (phenyl-sulfonyl-imino)-phospho-nato]cobalt(II).

In the title diaqua-cobalt complex, [Co(C(8)H(11)NO(5)PS)(2)(H(2)O)(2)], the Co(II) atom is surrounded by six O atoms belonging to the phosphoryl and sulfonyl groups of two deprotonated chelate ligands and two additional O atoms from water mol-ecules which are in cis positions with respect to one another. The coordination environment of cobalt can be described as a distorted octa-hedron. O-H⋯O hydrogen bonds between the water and sulfonyl O atoms of neighboring mol-ecules form chains running parallel to [010]. Two methoxy groups attached to one phosphorus are disordered over two sets of sites in a 0.6:0.4 ratio.