Structural rationalisation of co-crystals formed between trithiocyanuric acid and molecules containing hydrogen bonding functionality

Crystallisation of trithiocyanuric acid (TTCA) from various organic solvents that have hydrogen bonding capability (acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, methanol and acetonitrile) leads to the formation of co-crystals in which the solvent molecules are incorporated together with TTCA in the crystal structure. Structure determination by single-crystal X-ray diffraction reveals that these co-crystals can be classified into different groups depending upon the topological arrangement of the TTCA molecules in the crystal structure. Thus, three different types of single-tape arrangements of TTCA molecules and one type of double-tape arrangement of TTCA molecules are identified. In all co-crystals, hydrogen-bonding interactions are formed through the involvement of N-H bonds of TTCA molecules in these tapes and the other molecule in the co-crystal. Detailed rationalisation of the structural properties of these co-crystals is presented.     

Detection of Significant Aprotic Solvent Effects on the Conformational Distribution of Methyl 4‐Nitrophenyl Sulfoxide: From Gas‐Phase Rotational to Liquid‐Crystal NMR Spectroscopy

The conformational equilibrium of methyl 4‐nitrophenyl sulfoxide (MNPSO) was experimentally investigated in the gas phase by using microwave spectroscopy and in isotropic and nematic liquid‐crystal solutions, in which the solvents are nonaqueous and aprotic, by using NMR spectroscopy; moreover, it was theoretically studied in vacuo and in solution at different levels of theory. The overall set of results indicates a significant dependence of the solute conformational distribution on the solvent dielectric permittivity constant: when dissolved in low‐polarity media, the most stable conformation of MNPSO proved to be strongly twisted with respect to that in more polar solvents, in which the conformational distribution maximum essentially coincides with that obtained in the gas phase. We discuss a possible explanation of this behavior, which rests on electrostatic solute–solvent interactions and is supported by calculations of the solute electric dipole moment as a function of the torsional angle. This function shows that the least polar conformation of MNPSO is located at a twist angle close to that of the conformational distribution maximum found in less‐polar solvents. This fact, associated with a relatively flat torsional potential, can justify the stabilization of the twisted conformation by the less‐polar solvents.     

Kitaigorodsky Revisited: Polymorphism and Mixed Crystals of Acridine/Phenazine

Non‐stoichiometric molecular mixed crystals have potential as functional materials, the properties of which can be tailored by rationally changing their composition. The guidelines for their preparation were summarized over thirty years ago by Alexander Kitaigorodsky. Here those principles are revised in light of new studies on the acridine/phenazine system, and solvent‐assisted grinding is presented as a convenient synthetic procedure to afford a more homogeneous product than traditional solvent‐evaporation methods. Finally, the proposed prerequisite of crystal isostructurality/isomorphicity for the pure compounds, which seems to be violated in the present case, is discussed.     

Conformational identity change of 3-methylbutanone from gaseous phase to solutions: An IR vibrational spectroscopy study

Infrared vibrational spectroscopy of 3-methylbutanone [Me(CO)iPr] leads to two conclusions: (1) The conformational identity is different in the gas phase and in various solvents. (2) In the gas phase, type B rovibrational structures are observed. Thus, the molecular symmetry isC ₅. The following interpretation is based upon a model which implicitly takes the solvent into account in the framework of an empirical calculation. The solvent increases the interconversion barrier between two enantiomers. As a consequence, the molecule changes conformation, moving from the stable conformation with bisected carbonyl seen in the gas phase, to a conformation with an eclipsed carbonyl in solutions.     

Hirshfeld surface analysis of sulfameter (polymorph III), sulfameter dioxane monosolvate and sulfameter tetrahydrofuran monosolvate,all at 296 K

The ability of the antibacterial agent sulfameter (SMT) to form solvates is investigated. The X‐ray crystal structures of sulfameter solvates have been determined to be conformational polymorphs. Both 1,4‐dioxane and tetrahydrofuran form solvates with sulfameter in a 1:1 molar ratio. 4‐Amino‐N‐(5‐methoxypyrimidin‐2‐yl)benzenesulfonamide (polymorph III), C₁₁H₁₂N₄O₃S, (1), has two molecules of sulfameter in the asymmetric unit cell. 4‐Amino‐N‐(5‐methoxypyrimidin‐2‐yl)benzenesulfonamide 1,4‐dioxane monosolvate, C₁₁H₁₂N₄O₃S·C₄H₈O₂, (2), and 4‐amino‐N‐(5‐methoxypyrimidin‐2‐yl)benzenesulfonamide tetrahydrofuran monosolvate, C₁₁H₁₂N₄O₃S·C₄H₈O, (3), crystallize in the imide form. Hirshfeld surface analyses and fingerprint analyses were performed to study the nature of the interactions and their quantitative contributions towards the crystal packing. Finally, Hirshfeld surfaces, fingerprint plots and structural overlays were employed for a comparison of the two independent molecules in the asymmetric unit of (1), and also for a comparison of (2) and (3) in the monoclinic crystal system. A three‐dimensional hydrogen‐bonding network exists in all three structures, involving one of the sulfone O atoms and the aniline N atom. All three structures are stabilized by strong intermolecular N—H...N interactions. The tetrahydrofuran solvent molecule also takes part in forming significant intermolecular C—H...O interactions in the crystal structure of (3), contributing to the stability of the crystal packing.     

Conformational analysis of trinucleotides containing a single abasic residue; mimics of DNA damage

The conformations of three deoxytrinucleotide analogues [d(TpXpT), where X = T, tetrahydrofuran (THF) or propyl (Pr)] were investigated using ¹H NMR spectroscopy as part of our studies of DNA‐base damage. The phosphorus‐decoupled ¹H NMR spectrum of each compound was simulated and values for the vicinal proton–proton coupling constants of the sugar ring hydrogens were extracted at several different temperatures, for use in conformational analyses. It was found that the south‐pucker preference of the sugar 3′ to the modification is increased whereas that of the 5′ is decreased relative to the puckers observed for the non‐modified system. The conformational change is <25%. This subtle effect may be sufficient for recognition by DNA repair enzymes. Copyright © 2003 John Wiley & Sons, Ltd.     

Phosphotungstic acid as a versatile catalyst for the synthesis of fragrance compounds by alpha-pinene oxide isomerization: solvent-induced chemoselectivity

The remarkable effect of the solvent on the catalytic performance of H3PW12O40, the strongest heteropoly acid in the Keggin series, allows direction of the transformations of alpha-pinene oxide (1) to either campholenic aldehyde (2), trans-carveol (3), trans-sobrerol (4 a), or pinol (5). Each of these expensive fragrance compounds was obtained in good to excellent yields by using an appropriate solvent. Solvent polarity and basicity strongly affect the reaction pathways: nonpolar nonbasic solvents favor the formation of aldehyde 2; polar basic solvents favor the formation of alcohol 3; whereas in polar weakly basic solvents, the major products are compounds 4 a and 5. On the other hand, in 1,4-dioxane, which is a nonpolar basic solvent, both aldehyde 2 and alcohol 3 are formed in comparable amounts. The use of very low catalyst loading (0.005-1 mol %) and the possibility of catalyst recovery and recycling without neutralization are significant advantages of this simple, environmentally benign, and low-cost method. This method represents the first example of the synthesis of isomers from alpha-pinene oxide, other than campholenic aldehyde, with a selectivity that is sufficient for practical usage.     

Conformational and electronic properties of a microperoxidase in aqueous solution: a computational study.

A theoretical study of the conformational properties of a small heme peptide in aqueous solution is carried out by classical, long-timescale molecular dynamics simulations. The electronic properties of this species, that is, the relative energies of its excited electronic states and the redox potential, are reproduced and related to the conformational behavior using the perturbed matrix method and basic statistical mechanics. Our results show an interesting coupling between the conformational transitions and the electronic properties. These investigations, beyond the biophysically relevant results addressing the long-standing question of the actual role of the enzyme structure on the enzyme activity, are also of some methodological interest since they offer a further computational perspective for including the electronic degrees of freedom into the modeling of rather complex molecular systems.     

A Computational Study of Vicinal Fluorination in 2,3‐Difluorobutane: Implications for Conformational Control in Alkane Chains

A comprehensive conformational analysis of both 2,3‐difluorobutane diastereomers is presented based on density functional theory calculations in vacuum and in solution, as well as NMR experiments in solution. While for 1,2‐difluoroethane the fluorine gauche effect is clearly the dominant effect determining its conformation, it was found that for 2,3‐difluorobutane there is a complex interplay of several effects, which are of similar magnitude but often of opposite sign. As a result, unexpected deviations in dihedral angles, relative conformational energies and populations are observed which cannot be rationalised only by chemical intuition. Furthermore, it was found that it is important to consider the free energies of the various conformers, as these lead to qualitatively different results both in vacuum and in solvent, when compared to calculations based only on the electronic energies. In contrast to expectations, it was found that vicinal syn‐difluoride introduction in the butane and by extension, longer hydrocarbon chains, is not expected to lead to an effective stabilisation of the linear conformation. Our findings have implications for the use of the vicinal difluoride motif for conformational control.     

Recrystallization and shape control of crystals of the organic dye acid green 27 in a mixed solvent

Recrystallization of the unstructured dye acid green 27 (AG27) in a mixed solvent of alcohol (ethanol or methanol) and water was systematically studied. The results demonstrated that AG27 crystals with uniform sizes and controllable shapes can be produced by simply changing the volume ratio of ethanol (or methanol) and deionized water (DIW). Rodlike and shuttlelike AG27 crystals can be selectively synthesized. The XRD analyses revealed the periodic structures of the organic crystals. Furthermore, crystallization in another mixed solvent of N,N-dimethylformamide (DMF) and DIW results in the formation of longer fibers with high aspect ratio, which further validates the remarkable effects of mixed solvent on the shape of the AG27 crystals. This method of recrystallization in a mixed solvent is expected to facilitate the synthesis of other functional organic crystals with unusual shapes.     

Molecular Dynamics Simulations of Cellulose Oligomers: Conformational Analysis

Summary: The results of classical molecular simulations of cellulose oligomers are presented here. The conformations of the chains in the high temperature melt, room temperature quenched melt and gas phase are compared with respect to various geometrical parameters including square end‐to‐end distances, glycosidic link torsion correlations, ring puckering and hydrogen bonding. The cellulose oligomer melts were relaxed at 800 K with molecular dynamics, and then cooled down in three different ways to obtain dense amorphous systems at 500 K and at room temperature. The sample resulting from the quench (step) shows too much similarity with the melt at 800 K. The two other cooling schemes (ramp, 2ramps) give very similar results for all quantities investigated. The relevance of previous single molecule calculations with respect to the dense amorphous systems is called into question. Comparisons between the chains in the dense systems and those in the gas phase reveal that, even for these relatively short stiff chains, differences exist in the preferred conformations. At high temperatures, where both systems are in equilibrium, the distribution of square end‐to‐end distances are both fairly smooth, but the gas phase clearly prefers more compact conformations. At 300 K, the differences are exacerbated as the equilibrium distribution for the gas phase shows a high proportion of folded conformers, whereas the nonequilibrium quenched systems necessarily retain the extended envelope of the higher temperature. Differences are also evident in the puckering, the rotation of the hydroxymethyl groups and the pattern of hydrogen bonds.

The probability density distribution for the square end‐to‐end distance for octaose in the gas phase (light line) and in the dense phase (dark line) at 300 K.     

Conformational Control of Oligo(p‐phenyleneethynylene)s with Intrinsic Substituent Electronic Effects: Origin of the Twist in Pentiptycene‐Containing Systems

Dependence of the backbone planarity of oligo(p‐phenyleneethynylene)s (OPEs) on the intrinsic electronic character of substituents and on the nature of the solvent has been experimentally demonstrated with a series of center‐symmetrical five‐ring systems, pentiptycene‐pentiptycene‐arene‐pentiptycene‐pentiptycene, differing in the substituents on the central arene. In frozen 2‐methyltetrahydrofuran (MTHF), the adjacent pentiptycene units prefer to be in a mutually twisted orientation when the substituents are electron‐withdrawing (F and amido), resulting in a TPPT or TTTT conformation, whereas a planarized PPPP backbone is favored in the case of electron‐donating substituents (alkyl and alkoxy). The propensity to adopt the PPPP form is generally enhanced by replacing MTHF with either methylcyclohexane or mixed ethanol/methanol as solvent. These observations reveal that the twist between adjacent pentiptycene units in OPEs is a consequence of the electronic rather than steric effects of iptycenyl substituents. The electronic effect of iptycenyl substituents is manifested in decreased phenylene π polarizability as the net effect of both electron‐donating hyperconjugation and an electron‐withdrawing inductive effect. Variable‐temperature electronic absorption and emission spectroscopies are the critical tools for this work. Our findings provide important guidelines for conformational and electronic engineering of OPEs and for the design of novel iptycene‐based organic electronic materials.     

The first polymorph in the family of nucleobases: a second form of cytosine

A new polymorph of cytosine, C₄H₅N₃O, is reported half a century after the report of its first known crystal structure [Barker & Marsh (1964). Acta Cryst. 17 , 1581–1587]. Cytosine thus provides the first polymorphic example in the category of parent nucleobases. The new form, denoted (Ib), was observed unexpectedly during an attempt to cocrystallize cytosine with catechol. Form (Ib) crystallizes in the orthorhombic centrosymmetric space group Pccn with two molecules in the asymmetric unit. The previously known form, denoted (Ia), crystallizes in the orthorhombic noncentrosymmetric space group P2₁2₁2₁. The cytosine molecule is planar in both forms. Hydrogen‐bonding interactions are also similar for both forms. Infinite one‐dimensional ribbons composed of cytosine base‐pair dimers in R₂²(8) arrangements are observed in both (Ia) and (Ib). However, the way that the ribbons are packed differs in (Ia) and (Ib). This appears to guide the centrosymmetric versus noncentrosymmetric space‐group selection through the formation of an inversion‐related motif in polymorph (Ib) and a helical propagation in polymorph (Ia). A few selected polymorphic systems have been gathered from the Cambridge Structural Database to understand possible structural features responsible for achiral molecules adopting centro‐ and noncentrosymmetric space groups.     

Expanding the structural landscape of niclosamide: a high Z′ polymorph,two new solvates and monohydrate HA

Three new crystalline phases are reported for the drug niclosamide [5‐chloro‐N‐(2‐chloro‐4‐nitrophenyl)‐2‐hydroxybenzamide], C₁₃H₈Cl₂N₂O₄. A new high‐Z′ polymorph (denoted Form II) is described, with four molecules in the asymmetric unit in the space group P2/n. The structure exhibits pseudosymmetry, including local translations and screw‐type operations. The niclosamide molecules are linked by O—H...O hydrogen bonds into chains, and the chains are packed so that the molecules form face‐to‐face (stacking) and end‐to‐end interactions within layers perpendicular to the chains. There are two different layer arrangements, giving a structure that is relatively complex. In the acetone and acetonitrile solvates, the incorporated solvent molecules accept hydrogen bonds from the OH groups of niclosamide, and the niclosamide molecules are stacked in a face‐to‐face manner. In the acetone solvate, C₁₃H₈Cl₂N₂O₄·C₃H₆O, V‐shaped arrangements are formed in which the nitrobenzene ends of the niclosamide molecules are brought into face‐to‐face contact. In the acetonitrile solvate, C₁₃H₈Cl₂N₂O₄·CH₃CN, stacking occurs by translation along a short axis (ca 3.8 Å) and the crystals are frequently observed to be twinned by twofold rotation around that axis. The acetonitrile molecules occupy channels in the structure. A complete structure is provided for niclosamide monohydrate, C₁₃H₈Cl₂N₂O₄·H₂O, polymorph H_A, obtained by Rietveld refinement against laboratory powder X‐ray diffraction data. It has been suggested that this compound is related to the methanol solvate of niclosamide [Harriss, Wilson & Radosevljevic Evans (2014). Acta Cryst. C 70 , 758–763], but it is found that the two are not fully isostructural: they contain isostructural two‐dimensional layers, but the layers are arranged differently in the two structures. This suggests that H_A may have the potential for polytypism, and features in the Rietveld difference curve indicate that a polytype fully isostructural with the methanol solvate might be present.     

A CoMFA analysis with conformational propensity: An attempt to analyze the SAR of a set of molecules with different conformational flexibility using a 3D-QSAR method

CoMFA analysis, a widely used 3D-QSAR method, has limitations to handle a set of SAR data containing diverse conformational flexibility since it does not explicitly include the conformational entropic effects into the analysis. Here, we present an attempt to incorporate the conformational entropy effects of a molecule into a 3D-QSAR analysis. Our attempt is based on the assumption that the conformational entropic loss of a ligand upon making a ligand-receptor complex is small if the ligand in an unbound state has a conformational propensity to adopt an active conformation in a complex state. For a QSAR analysis, this assumption was interpreted as follows: a potent ligand should have a higher conformational propensity to adopt an `active-conformation'-like structure in an unbound state than an inactive one. The conformational propensity value was defined as the populational ratio, N<sub>active</sub>/N<sub>stable</sub>, of the number of energetically stable conformers, N<sub>stable</sub>, to the number of `active-conformation'-like structures, N_active. The latter number was calculated by counting the number of conformers that satisfied the structural parameters deduced from the active conformation. A set of SAR data of imidazoleglycerol phosphate dehydratase inhibitors containing 20 molecules with different conformational flexibility was used as a training set for developing a 3D structure-activity relationship by a CoMFA analysis with the conformational propensity value. This resulted in a cross-validated squared correlation coefficient of the CoMFA model with the conformational propensity value (R ² _cross = 0.640) higher than that of the standard CoMFA model (R ² _cross = 0.431). Then we evaluated the quality of the CoMFA models by predicting the inhibitory activity for a new molecule.     

Theoretical studies of molecular conformation. II: Application of the SIBFA procedure to molecules containing carbonyl and carboxylate oxygens and amide nitrogens

The SIBFA procedure (Sum of Interactions Between Fragments computedAb initio, Ref [1]) is extended to the study of the conformational behavior of representative molecules containing amide nitrogens and carbonyl and carboxylate oxygens. The molecules studied are C- and N-ethylammonium formamide, C- and N-ethanol-formamide, ethylammonium formate and ethanolformate. The cases investigated include interactions of the types which occur between functional groups in proteins or ionophores. The accuracy of the procedure, assessed by comparing the results to those of correspondingab initio SCF computations, is very satisfactory. An application of the procedure to study the conformation of the glycyl and alanyl dipeptides as a function of the backbone torsional angles and is presented.     

Photodynamics of a PV Trimer in High‐Viscosity Solvents and in PMMA Films: A New Insight into Energy Transfer versus Conformational Relaxation in Conjugated Polymers

Non‐Stokes–Einstein relaxation : The rate constant of conformational relaxation of a phenylenevinylene trimer (see picture) in different solvents is proportional to η^?α, with α values decreasing from close to unity (low viscosity) to zero at sufficiently high solvent viscosity. This behaviour is attributed to the flexible methylbutyl side chains of the trimer, which partially screen the solvent friction.

     

Synthesis, Crystal Structure and Conformational Analysis of(E)-5-Methoxy-2-((4-methoxyphenylimino)methyl)phenol

The title compound,(E)-5-methoxy-2-((4-methoxyphenylimino)methyl)phenol(C15H15NO3),crystallizes in monoclinic,space group P21/c with a=9.4361(6),b=10.6212(5),c=12.9338(9),β=93.064(5)o,V=1294.41(14)3,Z=4,Dc=1.320 g/cm3,F(000)=544,Rint=0.116,T=296 K,μ=0.09 mm-1,the final R=0.051 and wR=0.148 for 1836 observed reflections with I2σ(I).An extensive two-dimensional network of C-H…O hydrogen bonds and π-ring interactions are responsible for the crystal stabilization.Intermolecular hydrogen bonds and C-H…π interactions produce R22(14),R44(30) and R44(31) rings.In addition to the molecular geometry from X-ray experiment,the molecular geometry of the title compound in the ground state has been calculated using the semi-empirical(AM1 and PM3) and density functional theory method(DFT)(B3LYP) with 6-31G(d) basis set.To determine the conformational flexibility,molecular energy profile of the title compound was obtained by semi-empirical(PM3 and AM1) and DFT/B3LYP calculations with respect to the selected degree of torsional freedom,which varied from -180° to +180° in a step of 10°.     

Remarkable enhancement of photo-allylation of aromatic carbonyl compounds with a hypervalent allylsilicon reagent by donor molecules

Photo-allylation of various aromatic carbonyl compounds with a penta-coordinated allylsiliconate reagent was remarkably accelerated by the addition of a donor molecule. As the oxidation potential of the allylsiliconate was significantly decreased in the presence of a donor molecule, the more efficient photo-induced electron transfer from the allylsiliconate to the excited substrate was enabled by the hexa-coordination of the silicon atom.