Bipul Sarma

Hydrogen bond synthon competition in the stabilization of theophylline cocrystals

Theophylline medications are used as bronchodilators that relax the muscles in the breathing tubes. Issues relating to the hydration behaviour and moisture stability of this drug are well-known. Seven new cocrystals of theophylline with phenols, and isomeric hydroxybenzoic acids are synthesized. Solvent assisted mechanochemical synthesis is employed in order to synthesize the cocrystal materials. Single crystal structures are obtained for all cocrystals and furthermore they are characterized thermally, spectroscopy and by powder X-ray diffraction. The hydrogen bonding and crystal packing features are examined and found to be comparable to reported cocrystals/salts of theophylline or its molecular analogues, i.e. caffeine and theobromine. The solubility of these cocrystals are determined using UV-vis spectroscopy and correlated with the hydrogen bond synthon energies computed on Gaussian using DFT. The occurrence probability of the hydrogen bond synthons are examined with the Cambridge Structural Database (CSD). An important observation is that the phenol coformers facilitate water assimilation in the crystalline lattice since they offer a weaker O–H⋯Nimidazole H bond synthon over the stronger COOH⋯Nimidazole H-bond available in hydroxybenzoic acid coformers. The presence of the –COOH group prevents water incorporation and provides added physical stability to the cocrystal at highly humid conditions. The results show the feasibility of cocrystal design of a drug to tune its physical properties based on hydrogen bond synthons.

Nickel(II), copper(II), and cobalt(II) complexes derived from a new unsymmetrical ONS donor Schiff base ligand: synthesis, characterization, crystal structure, and catalytic activities

Ni(II), Cu(II), and Co(II) complexes, ML2, with a new thioether containing ONS donors were synthesized, where L = deprotonated Schiff base. The analytical, spectral (FTIR, 1H NMR, and UV-vis), conductivity, and magnetic studies show that the metal complexes possess octahedral geometry and are non-electrolytes. The coordination mode of ligand, 1, and nickel(II) complex, NiL2, 2, was determined by single-crystal X-ray diffraction studies. Here, the nickel is coordinated to two oxygens, two nitrogens, and two sulfurs of two tridentate ligands with slightly distorted octahedral environment around nickel. The copper complex shows very good catalytic activities towards oxidation of organic thioethers to the corresponding sulfoxide predominantly using H2O2 as the oxidant. Graphical Abstract A series of Ni(II), Cu(II), and Co(II) complexes, ML2, of a new thioether containing ONS donors have been synthesized, where L = deprotonated Schiff base. The analytical, spectral (FTIR, 1H NMR, UV–vis), conductivity, and magnetic studies showed that the metal complexes possess octahedral geometry and are non-electrolytes. The structures of ligand as well as nickel(II) complex, NiL2, 2, were determined by single-crystal X-ray diffraction studies. The copper complex shows very good catalytic activities towards oxidation of organic thioethers to the corresponding sulfoxide predominantly using H2O2 as the oxidant.

Supramolecular networks of a H-shaped aromatic phenol host

X-Ray crystal structures of 1,4-di[bis(hydroxyphenyl)methyl]benzene and its solvates and cocrystals were analyzed for the occurrence of network architectures. From the simplest 1D ladder in EtOAc, DMSO and i-PrOH solvates of 1 (R1 = R2 = R4 = H, R3 = OH), doubly-interpenetrated 1D ladders in its guest-free form and 1D/2D-interpenetrated ladder networks in a cocrystal with phenazine were identified. The dioxane and DMSO solvates of 2 (R1 = R3 = OMe, R2 = OH, R4 = H), and the DMSO and toluene solvates of 4 (R1 = H, R2 = R4 = Me, R3 = OH) also adopt 1D ladder networks. Monomethyl phenol 3 (R1 = R2 = H, R3 = OH, R4 = Me) makes 2D grids of ladders that include nitromethane solvent in the channels. The hexagonal (6,3) net in the cocrystal of 1 with pyrazine-N,N′-dioxide is triply-interpenetrated in a 2D architecture. The DMF solvate of 3 is similar to 1·(PyzNO)2, except that the (6,3) nets are doubly-interpenetrated via Hopf links. An orthorhombic nitromethane solvate of 1 is 2D → 3D polycatenated with a degree of catenation (DOC) = 2/2, whereas the monoclinic polymorph of 1·(CH3NO2)2, as well as the chloroform inclusion structure of 4, adopt the rare (5,34) pentagonal net. Platonic (6,3) and Catalan (5,34) nets in the broader category of a uniform network topology were realized from H-shaped molecules 1–4 in different solvent inclusion and cocrystal structures. Finally, a cocrystal of 1 with quinoxaline forms a polyrotaxane 1D → 1D chain of Euclidean entanglement. Polythreaded rotaxane, pentagonal Catalan and 1D/2D interpenetrated nets are, as such, rare in organic molecular crystals. The role of the solvent/co-former in affording diverse supramolecular networks and entanglement modes are rationalized in the crystal structures.

Nickel(II), copper(II), cobalt(II), and palladium(II) complexes with a Schiff base: crystal structure, DFT study and copper complex catalyzed aerobic oxidation of alcohol to aldehyde

Ni(II), Cu(II), Co(II), and Pd(II) complexes were synthesized with a Schiff base containing thioether with ONS donors chelating to the metal center. The ligand and complexes were characterized by elemental analysis, FT-IR, 1H-NMR, UV–visible spectroscopy and magnetic studies. The crystal structures of the ligand and its Ni(II) and Pd(II) complexes were determined by single-crystal X-ray diffraction analysis. Structures revealed that the ligand chelated with Ni(II) and Pd(II) center in slightly distorted octahedral and slightly distorted square planar fashion, respectively. DFT studies of the Pd(II) complex revealed that the calculated structural parameters are very close with the experimentally observed data. The Cu(II) complex shows very good catalytic activity toward the conversion of alcohol to aldehyde under aerobic oxidation with ammonium persulfate.

Synthesis of anti-2,3-dihydro-1,2,3-trisubstituted-1H-naphth [1,2-e][1,3]oxazine derivatives via multicomponent approach

A series of anti-2,3-dihydro-1,2,3-trisubstituted-1H-naphth [1,2-e][1,3]oxazine derivatives 6 were exclusively obtained in high yields for the first time through multicomponent reactions (MCRs) of 2-naphthol, aromatic aldehydes and electron rich primary amines in ethanol at room temperature using CCl3COOH as catalyst. The same reaction could be conducted effectively in solvent-free medium at 100 °C. The stereochemistry of the two hydrogens connected to C-2 and C-4 (1,3) positions of the oxazine ring are identified as anti-orientation by single crystal XRD, COSY and NOESY analysis.

Tetrakis(4-sulfophenyl)methane dodecahydrate. Reversible and selective water inclusion and release in an organic host

Infinite water helices and discrete H2O–H2O–SO3H hydrogen bond aggregates occupy 19% unit cell volume in different channels of the title host tecton. The cooperative nature of H2O–SO3H H bonds and inter-connected channels correlate with higher Tonset of O4 and O5 water molecules at 149 °C compared to release of O6 H-bonded water helix from parallel channels at 114 °C. The zeolite-like organic host shows reversible water uptake and dehydration in successive heat–cool–heat cycles.

Crystal structures of mirtazapine molecular salts

A few molecular salts of the anti-depressant drug R/S-Mirtazapine with organic carboxylic acids, its HCl salt, and Mirtazapine hemihydrate were crystallized and characterized by X-ray diffraction, IR and Raman spectroscopy, and thermal analysis. Whereas Mirtazapine base sublimed above ambient conditions its molecular salts do not show any sublimation even at elevated temperatures. Crystal structure analysis showed that proton transfer in the hemiadipate salt occurs contrary to the ΔpKa rule. A strong ionic two-point synthon of N+–H⋯O− and C–H⋯O−hydrogen bonds is a recurring motif in Mirtazapinium carboxylate crystal structures.

Influence of germination conditions on malting potential of low and normal amylose paddy and changes in enzymatic activity and physico chemical properties

Malting potential of two rice cultivar i.e. low (12.5%) (LR) and normal (20.2%) amylose paddy (NR) were evaluated under different germination conditions (25-40°C for 120h). Based on malting potential, 30 and 35°C germination temperatures were found suitable. Enzymes (amylolytic and α-amylase) activity increased at both temperatures for LR and NR whereas NR exhibited higher activity. NR malted rice showed higher starch degradation (64 and 74 times) when compared to LR (58 and 62 times) at 30 and 35°C respectively leading to formation of reducing sugar and lowering of viscosity. During germination of LR and NR significant morphological and structural changes were observed as evident from pin-holes and eroded surface in micrographs, decreased % crystallinity and FTIR peaks. Outcome of present study concluded that the amylose amylopectin ratio played an important role during germination and NR paddy was found more suitable for malting at 30 and 35°C.

Ruthenium(II)‐Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction

The first decarbonylative insertion of an alkyne through C-H/C-C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh3 to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.

Pyridine N-oxides as coformers in the development of drug cocrystals

Pyridine N-oxides were synthesized via a convenient method and exploited in the preparation of drug cocrystals. Drugs associated with aqueous solubility issues such as propofol, ferulic acid, sulfathiazole, p-aminobenzoic acid etc. were used as the representative active ingredients to engineer pharmaceutical solids of a desired phase. In this study, 4,4′-bipyridine-N,N′-dioxide was picked as the cocrystal former. The types of supramolecular heterosynthons exhibited by the binary systems of N-oxide·drugs were analyzed. The formation of hydrogen bond synthons such as COOH–pyridine N-oxide, OH or NH–pyridine N-oxide was found to be robust and followed the trend observed in the Crystal Structure Database. These synthons were further correlated with the ameliorated properties of the drugs, which was supported by experiments, DFT studies and Hirshfeld surface analysis. This has been a goal in drug development.