Probing the Crystal Structure Landscape by Doping: 4‐Bromo, 4‐Chloro,and 4‐Methylcinnamic Acids

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4‐bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4‐methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4‐chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl‐doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of π???π interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.     

2′,4′‐Di­hydroxy‐3‐methoxy‐α,β‐di­hydro­chalcone and 2′,4‐di­hydroxy‐α,β‐di­hydro­chalcone: supramolecular structures formed by O—H⋯O,C—H⋯O and stacking interactions

The crystal structures of 2′,4′‐di­hydroxy‐3‐methoxy‐α,β‐di­hydro­chalcone, C₁₆H₁₆O₄, and 2′,4‐di­hydroxy‐α,β‐di­hydro­chalcone, C₁₅H₁₄O₃, have been determined. In both compounds, the structure consists of two nearly planar six‐membered aromatic rings connected by a propanal chain, which is bent in the methoxy compound and almost straight in the other compound. In the crystal structures, the molecular units of both compounds are linked by O—H⋯O hydrogen bonds to form infinite one‐dimensional chains. Hydro­gen bonds and C—H⋯O contacts in the crystal structures were studied by topological analysis of charge density based on Hartree–Fock calculations. Almost all of the investigated C—H⋯O contacts should be characterized as weak hydrogen bonds.     

2,6‐Di­phenyl­pyridine‐4‐carboxyl­ic acid

The distinctive feature of the crystal structure of 2,6‐di­phenyl­pyridine‐4‐carboxyl­ic acid, C₁₈H₁₃NO₂, is the formation of intermolecular O—H?O hydrogen bonds that lead to the formation of centrosymmetric cyclic dimers with R(8) topology. Molecules related by translation along the b axis exhibit strong π–π stacking of aromatic rings, with an average interplanar distance of 3.3 Å.     

4‐Carboxypiperidinium 1‐carboxycyclobutane‐1‐carboxylate

The title salt, C₆H₁₂NO₂⁺·C₆H₇O₄⁻ or ISO⁺·CBDC⁻, is an ionic ensemble assisted by hydrogen bonds. The amino acid moiety (ISO or piperidine‐4‐carboxylic acid) has a protonated ring N atom (ISO⁺ or 4‐carboxypiperidinium), while the semi‐protonated acid (CBDC⁻ or 1‐carboxycyclobutane‐1‐carboxylate) has the negative charge residing on one carboxylate group, leaving the other as a neutral –COOH group. The –⁺NH₂– state of protonation allows the formation of a two‐dimensional crystal packing consisting of zigzag layers stacked along a separated by van der Waals distances. The layers extend in the bc plane connected by a complex network of N—H...O and O—H...O hydrogen bonds. Wave‐like ribbons, constructed from ISO⁺ and CBDC⁻ units and described by the graph‐set symbols C₃³(10) and R₃³(14), run alternately in opposite directions along c. Intercalated between the ribbons are ISO⁺ cations linked by hydrogen bonds, forming rings described by the graph‐set symbols R₆⁶(30) and R₄²(18). A detailed analysis of the structures of the individual components and the intricate hydrogen‐bond network of the crystal structure is given.     

2,6‐Di­phenylthiapyran‐4‐one

In the title compound, 2,6‐di­phenyl­thia­cyclo­hexan‐4‐one, C₁₇H₁₆OS, mirror site symmetry is retained by the mol­ecule in the solid state in the absence of C—H?X hydrogen bonds. The crystal structure is stabilized by van der Waals interactions, the shortest S?O and C?O contacts being 3.567 (2) and 3.512 (3) Å, respectively.     

具有U构型的二{1-甲硫基-1-[1-苯基-1-(1-苯基-3-甲基-5-氧代-4,5二氢吡唑-4-烯)-甲氨基]亚氨甲基}二硫醚的晶体结构

The reaction of 1-phenyl-3-methyl-4-benzoyl-2,5-dihydro-1H-pyrazol-5-one (PMBP) and methyldithiocarbazate (mdtc) in methanol results in formation of a yellow crystalline solid, adduct of 1-phenyl-3-methyl-4benzoyl-2,5-dihydro-lH-pyrazol-5-one and methyldithiocarbazate. When the yellow solids were dissolved in a mixture of methanol and ether (1:4), a red crystal, which is an oxidation product of the former, was obtained by allowing solvent to evaporate for a few days at room temperature. The X-ray analysis of the red crystal indicates that it is a novel disulfide with a special structure like a “U” conformation in the solid state.     

Two succinic acid derivatives of 2‐ethyl‐6‐methylpyridin‐3‐ol

Crystals of bis(2‐ethyl‐3‐hydroxy‐6‐methylpyridinium) succinate–succinic acid (1/1), C₈H₁₂NO⁺·0.5C₄H₄O₄²⁻·0.5C₄H₆O₄, (I), and 2‐ethyl‐3‐hydroxy‐6‐methylpyridinium hydrogen succinate, C₈H₁₂NO⁺·C₄H₅O₄⁻, (II), were obtained by reaction of 2‐ethyl‐6‐methylpyridin‐3‐ol with succinic acid. The succinate anion and succinic acid molecule in (I) are located about centres of inversion. Intermolecular O—H...O, N—H...O and C—H...O hydrogen bonds are responsible for the formation of a three‐dimensional network in the crystal structure of (I) and a two‐dimensional network in the crystal structure of (II). Both structures are additionally stabilized by π–π interactions between symmetry‐related pyridine rings, forming a rod‐like cationic arrangement for (I) and cationic dimers for (II).     

2‐(Acridin‐9‐yl­imino)‐3‐di­methyl­amino‐1,3‐thia­zolidin‐4‐one

In the title compound, C₁₈H₁₆N₄OS, prepared by the reaction of 4‐(acridin‐9‐yl)‐1,1‐di­methyl­thio­semicarbazide with methyl bromo­acetate, the acridine and thia­zolidine ring systems are both non‐planar and, because of steric requirements, almost perpendicular, with a dihedral angle between their planes of 99.69 (6)°. C—H·O and C—H·π(arene) hydrogen bonds stabilize the crystal structure in the solid state.     

(E)‐2‐[(4‐Chlorophenyl)iminomethyl]‐5‐methoxyphenol and (E)‐2‐[(2‐chlorophenyl)iminomethyl]‐5‐methoxyphenol: X‐ray and DFT‐calculated structures

The crystal structures of the title 4‐chlorophenyl, (I), and 2‐chlorophenyl, (II), compounds, both C₁₄H₁₂ClNO₂, have been determined using X‐ray diffraction techniques and the molecular structures have also been optimized at the B3LYP/6‐31 G(d,p) level using density functional theory (DFT). The X‐ray study shows that the title compounds both have strong intramolecular O—H...N hydrogen bonds and that the crystal networks are primarily determined by weak C—H...π and van der Waals interactions. The strong intramolecular O—H...N hydrogen bond is evidence of the preference for the phenol–imine tautomeric form in the solid state. The IR spectra of the compounds were recorded experimentally and also calculated for comparison. The results from both the experiment and theoretical calculations are compared in this study.     

A solid‐state oxidation of 1,1,3,3‐tetramethylguanidinium 4‐methylbenzenesulfinate to 1,1,3,3‐tetramethylguanidinium 4‐methylbenzenesulfonate

The organic acid–base complex 1,1,3,3‐tetramethylguanidinium 4‐methylbenzenesulfonate, C₅H₁₄N₃⁺·C₇H₇O₃S⁻, was obtained from the corresponding 1,1,3,3‐tetramethylguanidinium 4‐methylbenzenesulfinate complex, C₅H₁₄N₃⁺·C₇H₇O₂S⁻, by solid‐state oxidation in air. Comparison of the two crystal structures reveals similar packing arrangements in the monoclinic space group P2₁/c, with centrosymmetric 2:2 tetramers being connected by four strong N—H...O=S hydrogen bonds between the imine N atoms of two 1,1,3,3‐tetramethylguanidinium bases and the O atoms of two acid molecules.     

Synthesis,structural analysis,spectral investigations,and DFT calculations of 1‐(3‐amino‐4‐thia‐1,2‐diazaspiro[4.11]hexadec‐2‐en‐1‐yl)ethan‐1‐one

1‐(3‐amino‐4‐thia‐1,2‐diazaspiro[4.11]hexadec‐2‐en‐1‐yl)ethan‐1‐one was synthesized and experimentally characterized by using FT‐IR, ¹H NMR, ¹³C NMR, and UV–Vis spectroscopy. The structure of the compound was confirmed by single‐crystal X‐ray diffraction. In the crystal structure, the molecules are linked by pairs of N‐H⋯N hydrogen bonds, forming centrosymmetric dimers with the graph‐set motif. The water molecule also plays an important role in the stabilization of the crystal structure, bridging the dimers to form a two‐dimensional supramolecular network. The molecular geometry, frontier molecular orbitals, vibrational frequencies, electronic properties, and molecular electrostatic potential were calculated using density functional theory (DFT) with the B3LYP/6‐311G(d,p) basis set. Geometric parameters, vibrational assignments, and electronic properties such as calculated energies, excitation energies, and oscillator strengths were compared with the experimental data, and it was seen that the theoretical results support the experimental parameters.     

Synthesis,Crystal Structure and Hydrolysis of a Novel Anhydrogalactosucrose: 2′‐Methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside

A novel anhydrogalactosucrose derivative 2′‐methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside ( 4 ) was prepared from 3,6:1′,4′:3′,6′‐trianhydro‐4‐chloro‐4‐deoxy‐galactosucrose ( 3 ) via a facile method and characterized by ¹H NMR, ¹³C NMR and 2D NMR spectra. The single crystal X‐ray diffraction analysis shows that the title molecule forms a two thee‐dimensional network structure by two kinds of hydrogen bond interactions [O(2) H(2)···O(7), O(5) H(5)···O(8)]. Its stability was investigated by acid hydrolysis reaction treated with sulfuric acid, together with the formation of 1,6‐Di‐O‐methoxy‐4‐chloro‐4‐deoxy‐β‐D‐galactopyranose ( 5 ) and 2,2‐Di‐C‐methoxy‐1,4:3,6‐dianhydromannitol ( 6 ). According to the result, the relative stability of the ether bonds in the structure is in the order: C(1) O C(5)≈C(3′) O C(6′)≈C(1′) O C(4′)>C(3) O C(6)≈C(1) O C(2′)>C(2′) O C(5′).     

The inner‐salt zwitterion,the dihydrochloride dihydrate and the dimethyl sulfoxide disolvate of 3,6‐bis(pyridin‐2‐yl)pyrazine‐2,5‐dicarboxylic acid

In the inner‐salt zwitterion of 3,6‐bis(pyridin‐2‐yl)pyrazine‐2,5‐dicarboxylic acid, (I), namely 5‐carboxy‐3‐(pyridin‐1‐ium‐2‐yl)‐6‐(pyridin‐2‐yl)pyrazine‐2‐carboxylate, [C₁₆H₁₀N₄O₄, (Ia)], the pyrazine ring has a twist–boat conformation. The opposing pyridine and pyridinium rings are almost perpendicular to one another, with a dihedral angle of 80.24 (18)°, and are inclined to the pyrazine mean plane by 36.83 (17) and 43.74 (17)°, respectively. The carboxy and carboxylate groups are inclined to the mean plane of the pyrazine ring by 43.60 (17) and 45.46 (17)°, respectively. In the crystal structure, the molecules are linked via N—H...O and O—H...O hydrogen bonds, leading to the formation of double‐stranded chains propagating in the [010] direction. On treating (Ia) with aqueous 1 M HCl, the diprotonated dihydrate form 2,2′‐(3,6‐dicarboxypyrazine‐2,5‐diyl)bis(pyridin‐1‐ium) dichloride dihydrate [C₁₆H₁₂N₄O₄²⁺·2Cl⁻·2H₂O, (Ib)] was obtained. The cation lies about an inversion centre. The pyridinium rings and carboxy groups are inclined to the planar pyrazine ring by 55.53 (9) and 19.8 (2)°, respectively. In the crystal structure, the molecules are involved in N—H...Cl, O—H...O_water and O_water—H...Cl hydrogen bonds, leading to the formation of chains propagating in the [010] direction. When (Ia) was recrystallized from dimethyl sulfoxide (DMSO), the DMSO disolvate 3,6‐bis(pyridin‐2‐yl)pyrazine‐2,5‐dicarboxylic acid dimethyl sulfoxide disolvate [C₁₆H₁₀N₄O₄·2C₂H₆OS, (Ic)] of (I) was obtained. Here, the molecule of (I) lies about an inversion centre and the pyridine rings are inclined to the planar pyrazine ring by only 23.59 (12)°. However, the carboxy groups are inclined to the pyrazine ring by 69.0 (3)°. In the crystal structure, the carboxy groups are linked to the DMSO molecules by O—H...O hydrogen bonds. In all three crystal structures, the presence of nonclassical hydrogen bonds gives rise to the formation of three‐dimensional supramolecular architectures.     

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.     

4‐(4‐Chloro­benzyl­ideneamino)‐1,5‐dimethyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐one and 4‐(2‐chloro­benzyl­idene­amino)‐1,5‐dimethyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐one

The two title compounds, both with formula C₁₈H₁₆ClN₃O, are structurally similar Schiff bases derived from the condensation of 4‐chloro­benzaldehyde or 2‐chloro­benzaldehyde with 4‐amino­anti­pyrine in methanol solution. As expected, both compounds adopt trans configurations about the central C=N bonds. In the crystal structure of the 4‐chloro analogue, mol­ecules are linked through weak C—H⋯O hydrogen bonds, forming chains running along the a axis. In the crystal structure of the 2‐chloro analogue, mol­ecules are linked through weak C—H⋯O and C—H⋯Cl hydrogen bonds, forming layers parallel to the ab plane.     

Conformational polymorphism of (E,E)‐N,N′‐bis(4‐nitrobenzylidene)benzene‐1,4‐diamine

Two polymorphs of (E,E)‐N,N′‐bis(4‐nitrobenzylidene)benzene‐1,4‐diamine, C₂₀H₁₄N₄O₄, (I), have been identified. In each case, the molecule lies across a crystallographic inversion centre. The supramolecular structure of the first polymorph, (I‐1), features stacking based on π–π interactions assisted by weak hydrogen bonds involving the nitro groups. The second polymorph, (I‐2), displays a perpendicular arrangement of molecules linked via the nitro groups, combined with weak C—H...O hydrogen bonds. Both crystal structures are compared with that of the carbon analogue (E,E)‐1,4‐bis[2‐(4‐nitrophenyl)ethenyl]benzene, (II).     

(4S,5S)‐4‐[(1R)‐1,2‐Di­hydroxy­ethyl]‐5‐tri­decyl‐1,3‐oxazolidin‐2‐one

The title compound, C₁₈H₃₅NO₄, is a new bioactive amphiphilic lipid with a cis‐substituted 1,3‐oxazolidin‐2‐one head group. In the crystal structure, the mol­ecules form intercalating bilayers in which the oxazolidinone head groups are joined together by hydrogen bonds into chains.     

2‐(4‐Hydroxy­phenyl)‐4,4‐dimethyl‐2‐oxazoline: X‐ray and density functional theory study

In the crystal structure of the title compound, C₁₁H₁₃NO₂, there are strong inter­molecular O—H⋯N hydrogen bonds which, together with weak intra­molecular C—H⋯O hydrogen bonds, lead to the formation of infinite chains of mol­ecules, held together by weak inter­molecular C—H⋯O hydrogen bonds. A theoretical investigation of the hydrogen bonding, based on density functional theory (DFT) employing periodic boundary conditions, is in agreement with the experimental data. The cluster approach shows that the influence of the crystal field and of hydrogen‐bond formation are responsible for the deformation of the 2‐oxazoline ring, which is not planar and adopts a ⁴T₃ (^C3T_C2) conformation.     

Conformational study of (Z)‐5‐(4‐chlorobenzylidene)‐2‐[4‐(2‐hydroxyethyl)piperazin‐1‐yl]‐3H‐imidazol‐4(5H)‐one in different environments: insight into the structural properties of bacterial efflux pump inhibitors

The 2‐amine derivatives of 5‐arylidene‐3H‐imidazol‐4(5H )‐one are a new class of bacterial efflux pump inhibitors, the chemical compounds that are able to restore antibiotic efficacy against multidrug resistant bacteria. 5‐Arylidene‐3H‐imidazol‐4(5H )‐ones with a piperazine ring at position 2 reverse the mechanisms of multidrug resistance (MDR) of the particularly dangerous Gram‐negative bacteria E. coli by inhibition of the efflux pump AcrA/AcrB/TolC (a main multidrug resistance mechanism in Gram‐negative bacteria, consisting of a membrane fusion protein, AcrA, a Resistant‐Nodulation‐Division protein, AcrB, and an outer membrane factor, TolC). In order to study the influence of the environment on the conformation of (Z )‐5‐(4‐chlorobenzylidene)‐2‐[4‐(2‐hydroxyethyl)piperazin‐1‐yl]‐3H‐imidazol‐4(5H )‐one, ( 3 ), two different salts were prepared, namely with picolinic acid {systematic name: 4‐[(Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1H‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium pyridine‐2‐carboxylate, C₁₆H₂₀ClN₄O₂⁺·C₆H₄NO₂⁻, ( 3 a )} and 4‐nitrophenylacetic acid {systematic name: 4‐[(Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1H‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium 2‐(4‐nitrophenyl)acetate, C₁₆H₂₀ClN₄O₂⁺·C₈H₆NO₄⁻, ( 3 b )}. The crystal structures of the new salts were determined by X‐ray diffraction. In both crystal structures, the molecule of ( 3 ) is protonated at an N atom of the piperazine ring by proton transfer from the corresponding acid. The carboxylate group of picolinate engages in hydrogen bonds with three molecules of the cation of ( 3 ), whereas the carboxylate group of 4‐nitrophenylacetate engages in hydrogen bonds with only two molecules of ( 3 ). As a consequence of these interactions, different orientations of the hydroxyethyl group of ( 3 ) are observed. The crystal structures are additionally stabilized by both C—H…N [in ( 3 a )] and C—H…O [in ( 3 a ) and ( 3 b )] intermolecular interactions. The geometry of the imidazolone fragment was compared with other crystal structures possessing this moiety. The tautomer observed in the crystal structures presented here, namely 3H‐imidazol‐4(5H )‐one [systematic name: 1H‐imidazol‐5(4H )‐one], is also that most frequently observed in other structures containing this heterocycle.     

Synthesis and Spectral Properties of 4‐(2,5‐Dimethoxyphenylmethelene)‐2‐phenyl‐5‐oxazolone (DMPO)

An interesting flourophore, 4‐(2,5‐dimethoxyphenylmethelene)‐2‐phenyl‐5‐oxazolone (DMPO) was synthesized by mixing an equivalent molar quantity of hippuric acid and 2,5‐dimethoxybenzaldehyde in acetic anhydride in the presence of anhydrous sodium acetate. The absorption and fluorescence characteristics of 4‐(2,5‐dimethoxy‐phenylmethelene)‐2‐phenyl‐5‐oxazolone (DMPO) were investigated in different solvents. DMPO dye exhibits red shift in both absorption and emission spectra as solvent polarity increases, indicating change in the dipole moment of molecules upon excitation due to an intramolecular charge transfer interaction. The fluorescence quantum yield depends strongly on the properties of the solvents, which was attributed to positive and negative solvatokinetic effects. A crystalline solid of DMPO gave strong excimer like emission at 630 nm due to the excitation of molecular aggregates. This is expected from the idealized crystal structure of the dye that belongs to the B‐type class of Steven's Classification. DMPO displayed fluorescence quenching by triethylamine via nonemissive exciplex formation.