Experimental and Theoretical Charge Density Study on Di‐2‐pyrazylamine (Hdpza) Molecule in Crystal

Electron density distribution of Di‐2‐pyrazylamine ( Hdpza ) is studied both by single‐crystal X‐ray diffraction method at 100K and theoretical calculation. Structural determination reveals that Hdpza molecules crystalize in a syn‐anti conformation with an intramolecular C? H?N hydrogen bond between two pyrazine rings and then gather together via two intermolecular N? H?N and C? H?N hydrogen interaction and π? π stacking interaction between pyrazine rings. Charge density analysis is made in terms of deformation density (Δπ), Laplacian distribution and topological analysis of total electron density based on multipole model and theoretical calculation. The agreement between experiment and theory is good. The topological properties at bond critical points of C? C and C? N bonds reveal a covalent bond character, and those of intermolecular interactions, such as hydrogen bonds and π? π stacking interactions, reveal a closed‐shell interaction. The potential energy curve of Hdpza molecule shows that the syn‐anti conformation is the most stable one (global minima) than the other two of syn‐syn and anti‐anti conformations.     

Solid‐State Form Screen of Cardiosulfa and Its Analogues

Cardiosulfa is a biologically active sulfonamide molecule that was recently shown to induce abnormal heart development in zebrafish embryos through activation of the aryl hydrocarbon receptor (AhR). The present report is a systematic study of solid‐state forms of cardiosulfa and its biologically active analogues that belong to the N‐(9‐ethyl‐9H‐carbazol‐3‐yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1 ; R¹=NO₂, R²=H, R³=CF₃), molecule 2 (H, H, CF₃), molecule 3 (CF₃, H, H), molecule 4 (NO₂, H, H), molecule 5 (H, CF₃, H), and molecule 6 (H, H, H) were synthesized and subjected to a polymorph search and solid‐state form characterization by X‐ray diffraction, differential scanning calorimetry (DSC), variable‐temperature powder X‐ray diffraction (VT‐PXRD), FTIR, and solid‐state (ss) NMR spectroscopy. Molecule 1 was obtained in a single‐crystalline modification that is sustained by N? H???π and C? H???O interactions but devoid of strong intermolecular N? H???O hydrogen bonds. Molecule 2 displayed a N? H???O catemer C(4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain N? H???π and C? H???O interactions but no N? H???O bonds. Molecule 4 is trimorphic with N? H???O catemer in form I, and N? H???π and C? H???O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the N? H???O catemer C(4) chain, whereas the sulfonamide N? H???O dimer synthon R₂²(8) was observed in polymorphs of 6 . Differences in the strong and weak hydrogen‐bond motifs were correlated with the substituent groups, and the solubility and dissolution rates were correlated with the conformation in the crystal structure of 1 , 2 , 3 , 4 , 5 , 6 . Higher solubility compounds, such as 2 (10.5 mg mL^?1) and 5 (4.4 mg mL^?1), adopt a twisted confirmation, whereas less‐soluble 1 (0.9 mg mL^?1) is nearly planar. This study provides practical guides for functional‐group modification of drug lead compounds for solubility optimization.     

A comparative study of some lithium and hydrogen‐bonded complexes: Ab initio and QTAIM studies

The nature of the interactions of cyanide with lithium and hydrogen halides was investigated using ab initio calculations and topological analysis of electron density. The computed properties of the lithium‐bonded complexes RCN···LiX (R = H, F, Cl, Br, C?CH, CH?CH₂, CH₃, C₂H₅; X = Cl, Br) were compared with those of corresponding hydrogen‐bonded complexes RCN···HX. The results show that both types of intermolecular interactions are “closed‐shell” noncovalent interactions. The effect of substitution on the interaction energy and electron density at the bond critical points of the lithium and hydrogen bonding interactions is similar. In comparison, the interaction energies of lithium‐bonded complexes are more negative than those of hydrogen‐bonded counterparts. The electrostatic interaction plays a more important role in the lithium bond than in the hydrogen bond. On complex formation, the net charge and energy of the Li atom decrease and the atomic volume increases, while the net charge and energy of the H atom increase and the atomic volume decreases. © 2013 Wiley Periodicals, Inc.     

Structure of Amido Pyridinium Betaines: Persistent Intermolecular C−H⋅⋅⋅N Hydrogen Bonding in Solution

A hydrogen bond of the type C?H???X (X=O or N) is known to influence the structure and function of chemical and biological systems in solution. C?H???O hydrogen bonding in solution has been extensively studied, both experimentally and computationally, whereas the equivalent thermodynamic parameters have not been enumerated experimentally for C?H???N hydrogen bonds. This is, in part, due to the lack of systems that exhibit persistent C?H???N hydrogen bonds in solution. Herein, a class of molecule based on a biologically active norharman motif that exhibits unsupported intermolecular C?H???N hydrogen bonds in solution has been described. A pairwise interaction leads to dimerisation to give bond strengths of about 7 kJ mol^?1 per hydrogen bond, which is similar to chemically and biologically relevant C?H???O hydrogen bonding. The experimental data is supported by computational work, which provides additional insight into the hydrogen bonding by consideration of electrostatic and orbital interactions and allowed a comparison between calculated and extrapolated NMR chemical shifts.     

How the oxazole fragment influences the conformation of the tetraoxazocane ring in a cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane): single‐crystal X‐ray and theoretical study

Single crystals of (2S,5R)‐2‐isopropyl‐5‐methyl‐7‐(5‐methylisoxazol‐3‐yl)cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane), C₁₆H₂₆N₂O₅, have been studied via X‐ray diffraction. The tetraoxazocane ring adopts a boat–chair conformation in the crystalline state, which is due to intramolecular interactions. Conformational analysis of the tetraoxazocane fragment performed at the B3LYP/6‐31G(d,2p) level of theory showed that there are three minima on the potential energy surface, one of which corresponds to the conformation realized in the solid state, but not to a global minimum. Analysis of the geometry and the topological parameters of the electron density at the (3,?1) bond critical points (BCPs), and the charge transfer in the tetraoxazocane ring indicated that there are stereoelectronic effects in the O—C—O and N—C—O fragments. There is a two‐cross hyperconjugation in the N—C—O fragment between the lone electron pair of the N atom (lpN) and the antibonding orbital of a C—O bond (σ*_C—O) and vice versa between lpO and σ*_C—N. The oxazole substituent has a considerable effect on the geometry and the topological parameters of the electron density at the (3,?1) BCPs of the tetraoxazocane ring. The crystal structure is stabilized via intermolecular C—H…N and C—H…O hydrogen bonds, which is unambiguously confirmed with PIXEL calculations, a quantum theory of atoms in molecules (QTAIM) topological analysis of the electron density at the (3,?1) BCPs and a Hirshfeld analysis of the electrostatic potential. The molecules form zigzag chains in the crystal due to intermolecular C—H…N interactions being electrostatic in origin. The molecules are further stacked due to C—H…O hydrogen bonds. The dispersion component in the total stabilization energy of the crystal lattice is 68.09%.     

7‐Amino‐2‐methylsulfanyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid as the dimethylformamide and water monosolvates at 293 K

The molecular structure of 7‐amino‐2‐methylsulfanyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid is reported in two crystal environments, viz. as the dimethylformamide (DMF) monosolvate, C₇H₇N₅O₂S·C₃H₇NO, (I), and as the monohydrate, C₇H₇N₅O₂S·H₂O, (II), both at 293 (2) K. The triazolo[1,5‐a]pyrimidine molecule is of interest with respect to the possible biological activity of its coordination compounds. While the DMF solvate exhibits a layered structural arrangement through N...O hydrogen‐bonding interactions, the monohydrate displays a network of intermolecular O...O and N...O hydrogen bonds assisted by cocrystallized water molecules and weak π–π stacking interactions, leading to a different three‐dimensional supramolecular architecture. Based on results from topological analyses of the electron‐density distribution in X—H...O (X = O, N and C) regions, hydrogen‐bonding energies have been estimated from structural information only, enabling the characterization of hydrogen‐bond graph energies.     

Structures of Trichloromethyl Thiocyanate,CCl3SCN,in Gaseous and Crystalline State

Trichloromethyl thiocyanate, CCl₃SCN, was structurally studied in both the gas and crystal phases by means of gas electron diffraction (GED) and single‐crystal X‐ray diffraction (XRD), respectively. Both experimental studies and quantum chemical calculations indicate a staggered orientation of the CCl₃ group relative to the SCN group. This conclusion is supported by the similarity of the C?SCN bond length to that of the anti‐structure of CH₂ClSCN (Berrueta Martínez et al. Phys. Chem. Chem. Phys. 2015, 17, 15805–15812). 1 Bond lengths and angles are similar for gas and crystal CCl₃SCN structures; however, the crystal structure presents different intermolecular interactions. These include halogen and chalcogen type interactions, the geometry of which was studied. Characteristic C‐Y???N angles (Y=Cl or S) close to 180° provide evidence for typical σ‐hole interactions along the halogen/chalcogen?carbon bond in N???Cl and N???S, intermolecular units.     

Acetone‐4‐methyl­thio­semicarbazone at 220 K

In the title compound, C₅H₁₁N₃S, the trans conformation is stabilized by a weak intramolecular N—H?N hydrogen bond. Unusually, one N—H bond is not involved in any hydrogen‐bond interactions and instead the mol­ecules form a one‐dimensional polymer via N—H?S intermolecular hydrogen bonds.     

Hydro­gen bonds and C—H⃛O interactions in N‐(2‐hydroxy‐1,1‐dimethyl­ethyl)benzamide at 150 K

The title compound, C₁₁H₁₅NO₂, crystallized in the centrosymmetric space group P2₁/n with one mol­ecule in the asymmetric unit. There is a single intermolecular hydrogen bond, in which the N_donor?O_acceptor distance is 3.0374 (11) Å and the N—H?O angle is 171.0 (12)°. The single intramol­ecular hydrogen bond has an O_donor?O_acceptor distance of 2.6279 (11) Å and an O—H?O angle of 161.8 (14)°. The four leading intermolecular C—H?O interactions have H?O distances ranging from 2.52 to 2.65 (2) Å and C—H?O angles ranging from 125.2 (9) to 143°. Chains of interactions form two‐dimensional networks.     

σ‐Hole Bond Versus Hydrogen Bond: From Tetravalent to Pentavalent N,P, and As Atoms

Ab initio calculations were performed on complexes of ZH₄⁺ (Z=N, P, As) and their fluoro derivatives, ZFH₃⁺ and ZF₄⁺, with a HCN (or LiCN) molecule acting as the Lewis base through the nitrogen electronegative center. It was found that the complexes are linked by the Z? H???N hydrogen bond or another type of noncovalent interaction in which the tetravalent heavy atom of the cation acts as the Lewis acid center, that is, when the Z???N link exists, which may be classified as the σ‐hole bond. The formation of the latter interaction is usually preferable to the formation of the corresponding hydrogen bond. The Z???N interaction may be also considered as the preliminary stage of the S_N2 reaction. This is supported by the observation that for a short Z???N contact, the corresponding complex geometry coincides with the trigonal‐bipyramidal geometry typical for the transition state of the S_N2 reaction. The Z???N interaction for some of complexes analyzed here possesses characteristics typical for covalent bonds. Numerous interrelations between geometrical, topological and energetic parameters are discussed. The natural bond orbital method as well as the Quantum Theory of “Atoms in Molecules” is applied to characterize interactions in the analyzed complexes. The experimental evidences of the existence of these interactions, based on the Cambridge Structure Database search, are also presented. In addition, it is justified that mechanisms of the formation of the Z???N interactions are similar to the processes occurring for the other noncovalent links. The formation of Z???N interaction as well as of other interactions may be explained with the use of the σ‐hole concept.     

Polymorphs and Polymorphic Cocrystals of Temozolomide

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4′‐bipyridine‐N,N′‐dioxide (BPNO), and solid‐state stability were studied. Apart from a known X‐ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3‐hydroxypyridine‐N‐oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N? H???N_imidazole and N? H???N_tetrazine interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZ?BPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen‐bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N–H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C?O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen‐bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen‐bond reorganization.     

An X‐ray crystallographic and density functional theory study of (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one

The Schiff base enaminones (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₃H₁₇NO₄S, (I), and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₅H₂₁NO₂, (II), were studied by X‐ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C—C=C—N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino–phenol group canted relative to the rest of the molecule; the twist about the N(enamine)—C(aryl) bond leads to dihedral angles of 40.5 (2) and −116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N—H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one‐dimensional hydrogen‐bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H—O hydrogen bond, and consequently also forms a one‐dimensional hydrogen‐bonded chain. The DFT‐calculated structures [in vacuo, B3LYP/6‐311G(d,p) level] for the keto tautomers compare favourably with the X‐ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol⁻¹ lower in energy than the enol tautomers for (I) and (II), respectively.     

1,4,4‐Tri­methyl‐9‐phenyl‐8‐oxa‐9‐aza­bi­cyclo­[3.2.2]­non‐6‐en‐2‐one

The structure of the adduct of eucarvone with nitro­so­benzene, C₁₆H₁₉NO₂, is reported. The [3.2.2] bicyclic system corresponds to two seven‐membered rings in boat and distorted chair conformations and a six‐membered ring that adopts a distorted boat conformation. No conjugation is observed between the phenyl group and the N—O system. The packing is directed mainly by a C?O hydrogen bond, C—H?O‐(1 ? x, ?y, z) and by intermolecular C—H?π interactions.     

Multipole refinement of 2‐(indol‐3‐yl)‐1,1,3,3‐tetramethylthiouronium nitrate

The cation of the title compound, C₁₃H₁₈N₃S⁺·NO₃⁻, consists of two subunits, viz. a planar indole moiety and a nonplanar thiouronium moiety. An isolated intermolecular hydrogen bond connects the cation with the nitrate anion. The crystal packing is additionally characterized by short intermolecular contacts between parallel indole systems. A topological analysis of the electron density revealed C—S single bonds and partial double bonding in the N—C—N group.     

3,5‐Di­methyl‐1,3,5‐oxadi­azane‐2,4,6‐trione: short intermolecular contacts determining the crystal packing

In the title compound, C₅H₆N₂O₄, the mol­ecules lie across a crystallographic mirror plane. The compound lacks traditional hydrogen‐bond donors, and hence crystals are held together by unusual C=O⋯O, O⋯C and weak C—H⋯O interactions, forming layers. Adjacent layers are arranged in an antiparallel manner, yielding an ABA layer sequence. The intermolecular contacts are quite short; a topological analysis of charge density based on density‐functional‐theory calculations was used for consideration of these short contacts and indicated a strong attractive bonding closed‐shell interaction between these atoms in the crystal structure.     

1‐Benzoyl‐3‐[(2‐benzylsulfanyl)phenyl]thiourea

In the title compound, C₂₁H₁₈N₂OS₂, a strong intramolecular N—H...O hydrogen bond [N...O = 2.642 (3) Å] between the amide N atom and the benzoyl O atom forms an almost planar six‐membered ring in the central part of the molecule. In the crystal, molecules are packed through weak N—H...S interactions. Intra‐ and intermolecular hydrogen bonds and van der Waals interactions are the stabilizing forces for the crystal structure.     

Crystallographic study of self‐organization in the solid state including quasi‐aromatic pseudo‐ring stacking interactions in 1‐benzoyl‐3‐(3,4‐dimethoxyphenyl)thiourea and 1‐benzoyl‐3‐(2‐hydroxypropyl)thiourea

1‐Benzoylthioureas contain both carbonyl and thiocarbonyl functional groups and are of interest for their biological activity, metal coordination ability and involvement in hydrogen‐bond formation. Two novel 1‐benzoylthiourea derivatives, namely 1‐benzoyl‐3‐(3,4‐dimethoxyphenyl)thiourea, C₁₆H₁₆N₂O₃S, (I), and 1‐benzoyl‐3‐(2‐hydroxypropyl)thiourea, C₁₁H₁₄N₂O₂S, (II), have been synthesized and characterized. Compound (I) crystallizes in the space group P , while (II) crystallizes in the space group P 2₁/c . In both structures, intramolecular N—H…O hydrogen bonding is present. The resulting six‐membered pseudo‐rings are quasi‐aromatic and, in each case, interact with phenyl rings via stacking‐type interactions. C—H…O, C—H…S and C—H…π interactions are also present. In (I), there is one molecule in the asymmetric unit. Pairs of molecules are connected via two intermolecular N—H…S hydrogen bonds, forming centrosymmetric dimers. In (II), there are two symmetry‐independent molecules that differ mainly in the relative orientations of the phenyl rings with respect to the thiourea cores. Additional strong hydrogen‐bond donor and acceptor –OH groups participate in the formation of intermolecular N—H…O and O—H…S hydrogen bonds that join molecules into chains extending in the [001] direction.     

Density functional theory and topological analysis on the hydrogen bonding interactions in cysteine‐thymine complexes

Hydrogen bonding interactions between amino acids and nucleic acid bases constitute the most important interactions responsible for the specificity of protein binding. In this study, complexes formed by hydrogen bonding interactions between cysteine and thymine have been studied by density functional theory. The relevant geometries, energies, and IR characteristics of hydrogen bonds (H‐bonds) have been systematically investigated. The quantum theory of atoms in molecule and natural bond orbital analysis have also been applied to understand the nature of the hydrogen bonding interactions in complexes. More than 10 kinds of H‐bonds including intra‐ and intermolecular H‐bonds have been found in complexes. Most of intermolecular H‐bonds involve O (or N) atom as H‐acceptor, whereas the H‐bonds involving C or S atom usually are weaker than other ones. Both the strength of H‐bonds and the structural deformation are responsible for the stability of complexes. Because of the serious deformation, the complex involving the strongest H‐bond is not the most stable structures. Relationships between H‐bond length (ΔR_X‐H), frequency shifts (Δv), and the electron density (ρ_b) and its Laplace (?²ρ_b) at bond critical points have also been investigated. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Probing the relationships between molecular conformation and intermolecular contacts in N,N‐dibenzyl‐N′‐(furan‐2‐carbonyl)thiourea

In the crystal structure of the title compound, C₂₀H₁₈N₂O₂S, molecules are linked by bifurcated C—H...O hydrogen‐bond interactions, giving rise to chains whose links are composed of alternating centrosymmetrically disposed pairs of molecules and characterized by R₂²(10) and R₂²(20) hydrogen‐bonding motifs. Also, N—H...S hydrogen bonds form infinite zigzag chains along the [010] direction, which exhibit the C(4) motif. Hirshfeld surface and fingerprint plots were used to explore the intermolecular interactions in the crystal structure. This analysis confirms the important role of C—H...O hydrogen bonds in the molecular conformation and in the crystal structure, providing a potentially useful tool for a full understanding of the intermolecular interactions in acylthiourea derivatives.     

A first‐principles investigation of the hydrogen bond interaction and the sensitive characters in cis‐1,3,4,6‐tetranitrooctahydroimidazo‐[4,5‐d]imidazole

A theoretical study of structural and electronic properties of cis‐1,3,4,6‐tetranitrooctahydroimidazo‐[4,5‐d]imidazole (BCHMX) crystal is performed using density functional theory. The band structure, the total density of states, the atomic orbit projected density of states (PDOS) of C, N, O, and H, and Mulliken population analysis are discussed. The study by analyzing the PDOS shows that the structure of BCHMX crystal possesses C? H···O intra‐ and intermolecular hydrogen bonding. There are hydrogen bonds between H₃‐1s and O₅‐2p orbits, H₂‐1s and O₆‐2p orbits of intramolecules and between H₂‐1s and O₁‐2p orbits of intermolecules. The reasons for the smaller impact sensitivity compared with β‐1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocane and 1,3,5‐trinitro‐1,3,5‐triazinane are also explored from the band gap in the crystal and the weakest bond dissociation energy in single molecule. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011