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4-Methylhippuric acid {systematic name: 2-[(4-methylbenzoyl)amino]ethanoic acid}, a p-xylene excreted metabolite with a backbone containing three rotatable bonds (R-bonds), is likely to produce more than one stable molecular structure in the solid state. In this work, we prepared polymorph I by slow solvent evaporation (plates with Z' = 1) and polymorph II by mechanical grinding (plates with Z' = 2). Potential energy surface (PES) analysis, rotating the molecule about the C-C-N-C torsion angle, shows four conformational energy basins. The second basin, with torsion angles near -73°, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57° matched molecules B of polymorph II. The energy barrier between these basins is 27.5 kJ mol-1. Superposition of the molecules of polymorphs I and II rendered a maximum r.m.s. deviation of 0.398 Å. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C(5) chains linked by N-H...O interactions along the a axis and C(7) chains linked by O-H...O interactions along the b axis. In polymorph II, two molecules (A with A or B with B) are connected by two acid-amide O-H...O interactions rendering R22(14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N-H...O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C-H...O and C-H...π, with contact distances close to the sum of the van der Waals radii. Electron density at a local level using the Quantum Theory of Atoms in Molecules (QTAIM) and the Electron Localization Function (ELF), or a semi-local level using noncovalent interactions, was used to rank interactions. Strong closed shell interactions in classical O-H...O and N-H...O hydrogen bonds have electron density highly localized on bond critical points. Weaker delocalized electron density is seen around the p-methylphenyl rings associated with dispersive C-H...π and H...H interactions.

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Both DNA barcoding and phylogenetic data of the studied botanical material suggested the existence a new population of Galphimia glauca. Their leaves afforded three new nor-3,4-seco-friedelanes named galphimines M-O, together with known galphimines D, E, G, and I. Galphimines M and N possess bicyclic orthoacetates which are the first examples of orthoesters found in the Malpighiaceae family, while galphimine O has a 27,20-δ-lactone moiety. The structures elucidation followed from spectroscopic means and the absolute configuration followed from single crystal X-ray diffraction analyses. Tests for antibacterial and antifungal activities of galphimines N and M showed no promising effects.

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Crystallographic, thermal and stability analyses are presented of three different anhydrated forms of bendamustine hydrochloride [(I), (III) and (IV)] and a fourth, monohydrated one (II). Since form (I) presents the higher melting point and the higher heat of fusion, according to the `heat of fusion' rule it should be the most stable in thermodynamic terms [Burger & Ramberger (1979). Mikrochim. Acta, 72, 259-271], though it is unstable in high-humidity conditions. The monohydrate structure (II), in turn, dehydrates by heating and topotactically transform into anhydrate (III). This latter form appears as less stable than anhydrate (I), to which it is linked via a monotropic relationship. For these three different forms, the crystal structure has been determined by single crystal X-ray diffraction. The crystal structures and molecular conformations of forms (II) and (III) are quite similar, as expected from the topotactic transformation linking them; furthermore, under high-humidity conditions, form (III) shows changes compatible with a transformation into form (II) within 24 h. The crystal structure of form (I) is different from the other two. The remaining polymorphic form (IV) could only be obtained as a powder, from which its crystalline structure could not be determined. The relative thermodynamic stability of the different crystalline forms was determined by differential scanning calorimetry and thermogravimetrical studies, and their stability under different humidity conditions analysed.

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Detailed literature inspections regarding the diterpenoids icetexone (1) and conacytone (3) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single-crystal X-ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kα graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate (2) and conacytone triacetate (4) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4, respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3-hydroxythymoquinone (6) and its tautomer 4-hydroxy-1,2-quinone 7, on 6-hydroxythymoquinone (8) and its tautomer ortho-quinone 9, and on icetexone (1) and the claimed natural occurring ortho-quinone tautomer romulogarzone (5) indicate that 2-hydroxy-1,4-quinones are more stable, by some 11-14 kcal/mol, than their 4-hydroxy-1,2-quinone tautomers, and therefore, romulogarzone (5) is inexistent.

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The naturally occurring eudesmanolide farinosin () is now fully characterized for the first time despite its original isolation almost half a century ago. The early assumed relative stereochemistry and absolute configuration were confirmed by vibrational circular dichroism together with evaluation of the Hooft X-ray parameters. The molecular conformation is very similar in the gas stage and in the solid state. Chirality 28:415-419, 2016. © 2016 Wiley Periodicals, Inc.

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Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer.

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Ethionamide (ETH), a Biopharmaceutics Classification System class II drug, is a second-line drug manufactured as an oral dosage form by Pfizer to treat tuberculosis. Since its discovery in 1956, only one reformulation was proposed in 2005 as part of the efforts to improve its solubility. Due to the limited scientific research on active pharmaceutical ingredients (APIs) for the treatment of neglected diseases, we focused on the development of an approachable and green supramolecular synthesis protocol for the production of novel solid forms of ETH. Initially, three salts were crystal engineered and supramolecular synthesized via slow evaporation of the solvent: a saccharinate, a maleate and an oxalate. The crystal structures of all salts were determined by single crystal X-ray diffraction. In sequence, mechanochemical protocols for them were developed, being the scale-up production of the maleate salt successfully reproducible and confirmed by powder X-ray diffraction. Finally, a more complete solid-state characterization was carried out for the ETH maleate salt, including thermal analysis, infrared spectroscopy, scanning electron microscopy and equilibrium solubility at different dissolution media. Although ETH maleate is thermodynamically less stable than ETH, the equilibrium solubility results revealed that this novel salt is much more soluble in purified water than ETH, thus being a suitable new candidate for future formulations.

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The new 3-methyl-2-trifluoromethylchromone (1) and 3-bromomethyl-2-trifluoromethylchromone (2) compounds were synthesized and characterized by vibrational (IR, Raman), UV-Vis and NMR ((1)H, (13)C and (19)F) spectroscopy and MS spectrometry. The crystal structures of 1 and 2 were determined by X-ray diffraction methods. Both compounds crystallize in the monoclinic P21/c space group with Z=4 molecules per unit cell. The structures were solved from 1423 (1) and 1856 (2) reflections with I>2σ (I) and refined by full-matrix least-squares to agreement R1-values of 0.0403 (1) and 0.0554 (2). Because of π-bonding delocalization, the organic molecular skeletons are planar and the molecular bonding structures can be described by formally single, double and resonant bonds. In 2, the CF3 group revealed a strong rotational disorder around the CCF3 bond, which could be explained in terms of four split positions with about uniform angular distribution. The vibrational, electronic and NMR, spectra were discussed and assigned with the assistance of DFT calculations.

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Dos nitro-regioisómeros de la moléculacis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina fueronpreparados vía una síntesis one-pot de tres componentes basada en lareacción de cicloadición imino Diels-Alder catalizada por BF3.OEt2. Sucompleta caracterización estructural se llevó a cabo usando la técnicade difracción de rayos-X de monocristal y métodos espectroscópicos.La pureza de los productos y la composición de las mezclas de reacciónfueron monitoreadas por cromatografía en capa fina (CCD). Losproductos fueron aislados y purificados usando cromatografía encolumna. Las sustancias fueron identificadas usando resonancia magnéticanuclear (RMN) y espectrometría de masas (EM). Los datos para lacaracterización por difracción de rayos-X fueron colectados usando undifractómetro Bruker AFC7S Mercury con radiación de Mo-Kα (λ =0.71073Å) a temperatura ambiente. Las estructuras de los regio-isómerosfueron confirmadas por 1H RMN y 13C RMN y la estructura cristalinafue estudiada usando la difracción de rayos-X de monocristal. El análisisespectroscópico (RMN, EM y difracción de rayos-X) mostró una completacaracterización y permitió establecer la correcta estereoquímica para elanillo tetrahidroquinolínico. El empaquetamiento molecular en el cristalpara el regioisómero 5-nitro 4 es producto de la combinación de enlaces dehidrógeno intermoleculares e interacciones de van der Waals, mientras queen el 7-nitro regioisómero 3 el empaquetamiento se debe principalmente ainteracciones intermoleculares débiles de tipo van der Waals y N—H••• π...

Here we synthesized two nitro regioisomersof cis-4-(4-methoxyphenyl)-3-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline via the “one pot” three-componentimino Diels-Alder reaction catalyzed by BF3.OEt2and completed its structural characterization using thesingle crystal X-ray diffraction technique and otherspectroscopic methods. To monitor the purity of theproducts and the composition of the reaction mixtureswe used thin layer chromatography, and isolated andpurified the products by column chromatography. Thenusing nuclear magnetic resonance (NMR) and massspectrometry (MS) identified the substances. We collectedX-ray diffraction data for crystal characterization byusing a Bruker AFC7S Mercury diffractometer with Mo-Kα radiation (λ = 0.71073Å) at room temperature. Thestructures of these regioisomers were confirmed by 1HNMR and 13C NMR studies and studied their crystalstructure using single crystal X-ray diffraction technique.The spectroscopy analyses (NMR, GC-MS and X-raydiffraction) provided a complete characterizationand enabled the correct stereochemistry for thetetrahydroquinoline ring. We determined the molecularpacking for the 5-nitro regioisomer 4 is the product ofthe combination of intermolecular hydrogen bonds andvan der Waals interactions, while for 7-nitro regioisomer3 is mainly due to weak intermolecular van der Waalsinteractions and N—H··· π...

Dois nitro regioisómeros da molécula cis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina foram preparados através de umasíntese de um só recipiente de três componentes com base na reacçãode imino Diels-Alder cicloadição catalisada BF3.OEt2 e sua completacaracterização estrutural foi realizada usando a técnica de difracçãocristalografia de raios X, e outros métodos espectroscópicos. A purezado produto e a composição das misturas reaccionais foram monitorizadaspor cromatografia em camada fina (CCD). Os produtos foram isoladose purificados utilizando cromatografia em coluna. As substâncias foramidentificadaos por ressonância magnética nuclear (RMN) e espectrometriade massa (EM). Os dados para caracterização por difração de raios Xforam coletados usando um Bruker AFC7S Mercury difratômetro comMo-Ka radiação (λ = 0,71073Å) à temperatura ambiente. As estruturasdosa regioisómeros foram confirmadaos por 1H RMN e 13C RMN aestrutura de cristal foi investigada usando difracção de raios X de cristalúnico. As análises espectroscópicas (RMN, EM e difracção de raios-X)demonstraram uma completa caracterização e permitiramu estabelecer aestereoquímica correcta de anel tetrahidroquinolínico. O empacotamentomolecular no cristal para 5-nitro regioisómero 4 é derivado de umacombinação de ligações de hidrogénio intermoleculares e interacções devan der Waals, e ao 7-nitro regioisómero 3 embalagens é principalmentedevido a interacções intermoleculares fracas do tipo van der Waals e N-H• • • π...

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