Cationcation hydrogen bonds in synephrine salts: a typical interaction in an unusual environment.

Hydrogen bonds between the same charge species have been labelled sometimes as pseudo, destabilizing or anti-electrostatic types as they fail to overcome the energetic destabilization, resulting from electrostatic repulsion between same charged species. They have also been proposed to be a result of coulombic compression caused by the attraction between counterions in the crystals. Such a hypothesis is faulty, which undermines the importance of hydrogen bonds in these cases. In this context, we report several cationcation species held together by the O-HO, N-HO and C-HO type hydrogen bonds observed in the crystalline salts of a nutraceutical compound (±)-p-synephrine. The hydrogen-bonded cationcation molecular pairs present in these salts were carefully analyzed using the quantum theory of atoms in molecules, non-covalent interaction plots, potential energy surface scans, and energy decomposition analysis. This study provides new insights into the nature and strength of the various types of hydrogen bonds present between the cationic molecular pairs and helps in delineating the role played by them in stabilizing the cationcation assembly. We also report a unique cationic dimer having water-mediated N-HO hydrogen bonds, which hold the two cationic charge centres at a very short intermolecular distance in the crystal. The analysis of the water-mediated cationic pair observed in this case revealed that the solvent can play a crucial role in reducing the coulombic repulsion between the two cations.

S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope.

A synthetic molecule S006-830, belonging to the class of thiophene-containing trisubstituted methanes, had shown good in vitro and in vivo bactericidal activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). The molecule had also shown good druglike pharmacokinetic properties. However, S006-830 is a racemic mixture of two enantiomers, one of which could possess a better pharmacological profile than the other. We purified both the enantiomers on a chiral column and observed that S-enantiomer has a significantly higher inhibitory and cidal activity against Mtb than the R-enantiomer. Action of S-S006-830 was "synergistic" for rifampicin and "additive" for isoniazid and ethambutol. The combination of S-S006-830 and rifampicin produced 100% kill of Mtb within 8 days. In a chemical proteomics approach using matrix-bound compound to pull down its target protein(s) from Mtb membrane, FabG4 (ß-ketoacyl CoA reductase, EC 1.1.1.100) emerged as the most likely target for S-S006-830. In target validation assays, the compound exhibited 2-fold higher inhibitory concentration for an Mtb construct overexpressing FabG4. In addition, it inhibited mycolic acid biosynthesis and formation of biofilms by Mtb. Molecular docking of S-S006-830 with FabG4 was consistent with the experimental data. These results support the development of S-S006-830 as a novel lead against tuberculosis.

Correction to "S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope".

[This corrects the article DOI: 10.1021/acsomega.7b01281.].

Synthesis of Octabromoperylene Dianhydride and Diimides: Evidence of Halogen Bonding and Semiconducting Properties.

A facile synthesis of octabromoperylene-3,4,9,10-tetracarboxylic dianhydride (Br8-PDA) (1), its diimides (Br8-PDIs) (2a-e), and bis-, tris-, and tetra-amino substituted diimides (5a-c) with six, five, and four remaining substitutable Br atoms, respectively, is reported. Octabromination results in facile chemical/electrochemical reduction, radical anion formation, and red-shifted optical properties. For the first time, diverse halogen-bonding interactions were identified in the PDA/PDI, which along with the attractive electronic features enhance the electron-transport characteristics compared to the di-/tetra-brominated PDIs (3/4).

Intermolecular atom-atom bonds in crystals - a chemical perspective.

Short atom-atom distances between molecules are almost always indicative of specific intermolecular bonding. These distances may be used to assess the significance of all hydrogen bonds, including the C-H⋯O and even weaker C-H⋯F varieties.

Crystal structure and prediction.

The notion of structure is central to the subject of chemistry. This review traces the development of the idea of crystal structure since the time when a crystal structure could be determined from a three-dimensional diffraction pattern and assesses the feasibility of computationally predicting an unknown crystal structure of a given molecule. Crystal structure prediction is of considerable fundamental and applied importance, and its successful execution is by no means a solved problem. The ease of crystal structure determination today has resulted in the availability of large numbers of crystal structures of higher-energy polymorphs and pseudopolymorphs. These structural libraries lead to the concept of a crystal structure landscape. A crystal structure of a compound may accordingly be taken as a data point in such a landscape.

Crystalline supramolecular nanofibers based on dehydrobenzoannulene derivatives.

Supramolecular nanofibers (SNFs) composed of low-molecular-weight π-conjugated molecules exhibit attractive optical and electrical properties and are expected to be the next optoelectronic materials. In this work, five crystalline SNFs have been constructed from three dehydrobenzoannulene (DBA) derivatives. The DBAs were designed to assemble in one dimension in a strategy based on anisotropic crystal growth. The crystallinity of the SNFs allowed the molecular arrangements in the SNFs to be determined. Therefore the mechanism of construction and correlations between the molecular arrangements and optical and electrical properties could be considered. The results clearly indicate that the properties of the SNFs are affected by the chemical structures and molecular arrangements. Moreover, one of the SNFs exhibits a high charge-carrier mobility (Σµ=0.61 cm(2) V(-1) s(-1)) because of its crystallinity and appropriate molecular arrangement. This systematic experimental study based on a proposed strategy has provided information for improving the electrical properties of SNFs. This strategy will lead to highly functional SNFs.

Structural transformation between supramolecular nanofibers with drastic change of conductivity by heat and ultrasound.

Transformation with every fiber of its being: Dehydrobenzoannulene derivatives with a boomerang shape, dipole moment, and substituents that make diverse interactions enable the construction of stimuli-responsive nanofibers despite the lack of stimuli-responsive groups in these compounds. Interestingly, the supramolecular nanofibers obtained after ultrasonic treatment displayed an 80% decrease in conductivity as compared to untreated nanofibers. This is the first example of an electronic wire for which the conductivity can be controlled by ultrasound.

Triclabendazole: an intriguing case of co-existence of conformational and tautomeric polymorphism.

The crystal polymorphism of the anthelmintic drug, triclabendazole (TCB), is described. Two anhydrates (Forms I and II), three solvates, and an amorphous form have been previously mentioned. This study reports the crystal structures of Forms I (1) and II (2). These structures illustrate the uncommon phenomenon of tautomeric polymorphism. TCB exists as two tautomers A and B. Form I (Z'=2) is composed of two molecules of tautomer A while Form II (Z'=1) contains a 1:1 mixture of A and B. The polymorphs are also characterized by using other solid-state techniques (differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), PXRD, FT-IR, and NMR spectroscopy). Form I is the higher melting form (m.p.: 177 °C, ΔH(f) =≈105±4 J g(-1)) and is the more stable form at room temperature. Form II is the lower melting polymorph (m.p.:  166 °C, ΔH(f) =≈86±3 J g(-1)) and shows high kinetic stability on storage in comparison to the amorphous form but it transforms readily into Form I in a solution-mediated process. Crystal structure analysis of co-crystals 3-11 further confirms the existence of tautomeric polymorphism in TCB. In 3 and 11, tautomer A is present whereas in 4-10 the TCB molecule exists wholly as tautomer B. The DFT calculations suggest that the optimized tautomers A and B have nearly the same energies. Single point energy calculations reveal that tautomer A (in Form I) exists in two low-energy conformations, whereas in Form II both tautomers A and B exist in an unfavorable high-energy conformation, stabilized by a five-point dimer synthon. The structural and thermodynamic features of 1-11 are discussed in detail. Triclabendazole is an intriguing case in which tautomeric and conformational variations co-exist in the polymorphs.

Towards crystal structure prediction of complex organic compounds--a report on the fifth blind test.

Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.

Weak C-H···O hydrogen bonds in anisaldehyde, salicylaldehyde and cinnamaldehyde.

In situ cryocrystallization has been employed to grow single crystals of 4-methoxybenzaldehyde (anisaldehyde), C(8)H(8)O(2), 2-hydroxybenzaldehyde (salicylaldehyde), C(7)H(6)O(2), and (2E)-3-phenylprop-2-enal (cinnamaldehyde), C(9)H(8)O, all of which are liquids at room temperature. Several weak C-H···O interactions of the types C(aryl)-H···O, C(formyl)-H···O and Csp(3)-H···O are present in these related crystal structures.

Extending the supramolecular synthon based fragment approach (SBFA) for transferability of multipole charge density parameters to monofluorobenzoic acids and their cocrystals with isonicotinamide: importance of C-H···O, C-H···F, and F···F intermolecular regions.

An extension of the supramolecular synthon-based fragment approach (SBFA) method for transferability of multipole charge density parameters to include weak supramolecular synthons is proposed. In particular, the SBFA method is applied to C-H···O, C-H···F, and F···F containing synthons. A high resolution charge density study has been performed on 4-fluorobenzoic acid to build a synthon library for C-H···F infinite chain interactions. Libraries for C-H···O and F···F synthons were taken from earlier work. The SBFA methodology was applied successfully to 2- and 3-fluorobenzoic acids, data sets for which were collected in a routine manner at 100 K, and the modularity of the synthons was demonstrated. Cocrystals of isonicotinamide with all three fluorobenzoic acids were also studied with the SBFA method. The topological analysis of inter- and intramolecular interaction regions was performed using Bader's AIM approach. This study shows that the SBFA method is generally applicable to generate charge density maps using information from multiple intermolecular regions.

Nature and strength of C-H···O interactions involving formyl hydrogen atoms: computational and experimental studies of small aldehydes.

Structural and electronic properties of C-H···O contacts in compounds containing a formyl group are investigated from the perspective of both hydrogen bonding and dipole-dipole interactions, in a systematic and graded approach. The effects of α-substitution and self-association on the nature of the formyl H-atom are studied with the NBO and AIM methodologies. The relative dipole-dipole contributions in formyl C-H···O interactions are obtained for aldehyde dimers. The stabilities and energies of aldehyde clusters (dimer through octamer) have been examined computationally. Such studies have an implication in crystallization mechanisms. Experimental X-ray crystal structures of formaldehyde, acrolein and N-methylformamide have been determined in order to ascertain the role of C-H···O interactions in the crystal packing of formyl compounds.

Quinoxaline: Z' = 1 form.

A new Z' = 1 crystal structure of quinoxaline (or 1,4-diaza-naphthalene), C(8)H(6)N(2), with one-fifth the volume of the earlier known Z' = 5 structure was obtained by means of an in situ cryocrystallization technique.

Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis.

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organisms. Our findings suggest that compound 10 "locks" DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.

Significant progress in predicting the crystal structures of small organic molecules--a report on the fourth blind test.

We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.

1,3-Difluoro-benzene.

The weak electrostatic and dispersive forces between C(δ+)-F(δ-) and H(δ+)-C(δ-) are at the borderline of the hydrogen-bond phenomenon and are poorly directional and further deformed in the presence of other dominant inter-actions, e.g. C-H⋯π. The title compound, C(6)H(4)F(2), Z' = 2, forms one-dimensional tapes along two homodromic C-H⋯F hydrogen bonds. The one-dimensional tapes are connected into corrugated two-dimensional sheets by further bi- or trifrucated C-H⋯F hydrogen bonds. Packing in the third dimension is controlled by C-H⋯π inter-actions.

1,2,3-Trifluoro-benzene.

In the title compound, C(6)H(3)F(3), weak electrostatic and dispersive forces between C(δ+)-F(δ-) and H(δ+)-C(δ-) groups are at the borderline of the hydrogen-bond phenomenon and are poorly directional and further deformed in the presence of π-π stacking inter-actions. The mol-ecule lies on a twofold rotation axis. In the crystal structure, one-dimensional tapes are formed via two anti-dromic C-H⋯F hydrogen bonds. These tapes are, in turn, connected into corrugated two-dimensional sheets by bifurcated C-H⋯F hydrogen bonds. Packing in the third dimension is furnished by π-π stacking inter-actions with a centroid-centroid distance of 3.6362 (14) Å.

Five varieties of hydrogen bond in 1-formyl-3-thiosemicarbazide: an electron density study.

In an attempt to investigate the putative S-H...N hydrogen bond, we have studied the title compound, 1-formyl-3-thiosemicarbazide, which was revealed in a CSD search as a crystal structure which might show such an interaction. However, a redetermination of the structure at room temperature and careful analysis showed that the earlier study [Saxena et al. (1991). Acta Cryst. C47, 2374-2376] on which the CSD search was based was in error and that the possibility of an S-H...N hydrogen bond is negated. The presence of five other varieties of hydrogen bond (N-H...O, N-H...S, N-H...N, C-H...O, C-H...S) in the crystal packing prompted us to redirect our efforts and to undertake a study of the charge-density distribution at 90 K. The topological analysis of these five varieties of hydrogen bond was carried out with Bader's quantum theory of ;atoms in molecules' and by applying Koch-Popelier's criteria. The analysis reveals that the hydrogen-bond strength is highest for N-H...O and lowest for C-H...S with N-H...S, N-H...N and C-H...O forming the middle order.

Misassigned C-H...Cu agostic interaction in a copper(II) ephedrine derivative is actually a weak, multicentred hydrogen bond.

Agostic interactions and weak hydrogen bonds to metal acceptors, M, are chemically and geometrically distinct, and this distinction must be maintained in the classification of new C-H...M interactions.