Pyridine Synthon Research Articles

Scope and design of diversified supramolecular synthons of 5-hydroxyisophthalic acid: Crystallographic and theoretical investigations

The designed creation of cocrystals between 5-hydroxyisophthalic acid and diverse N-donor bases has been investigated by supramolecular synthon formations. The structures of four binary cocrystals are determined using single crystal X-ray diffraction technique. The resemblances and distinctions in supramolecular synthon structures have been analyzed and discussed. The interaction pattern changes with alteration in the structure and basicity of the N atoms of the respective bases. The acid···pyridine hetero-synthon, a supramolecular synthon between unlike functional groups, plays a major role in forming all the cocrystals. Apart from acid···pyridine synthon, hydroxyl···pyridine hetero-synthons are observed in HPA:DPE-I and HPA:DPE-I cocrystal. Whereas, acid···hydroxyl heterosynthons are found in HPA:AZO and HPA:TMP cocrystals. As hetero-synthons are energetically preferred regarding homosynthons, the latter is not observed in the structures. It is noticed that apart from strong O–H···N hydrogen bonds, comparatively weak C–H···O hydrogen bonds are also crucial in crystal packing and stability. DFT calculations along with Hirshfeld analysis have been performed to estimate the energetic characteristics of different interactions and crystal packing of the aforementioned cocrystals. Further, energetic characteristics of the synthons involving distinct non-covalent interactions, such as O–H···N, C–H···O and C–H⋯π interactions, are explored by intricate combination of computational methods i.e. QTAIM analysis and the non-covalent interaction (NCI) plot index.

Multicomponent solids of diclofenac with pyridine based coformers

The present study reports nine crystalline forms of diclofenac acid which include cocrystals, salts, salt-cocrystals and salt hydrates with pyridines and amines based coformers utilizing acid … pyridine synthon. All the solids were successfully prepared and structurally characterized through PXRD, ATR, DSC and single crystal XRD. The crystal structures were analyzed and discussed in terms of acid … pyridine heterosynthon. The conformation of diclofenac acid in the multicomponent solids reported in this paper is compared with its polymorphs. The structural chemistry of diclofenac acid (DIC) is discussed based on carboxylic acid … pyridine synthon in terms of DIC-coformer dimer or DIC-coformer-DIC trimers. The influence of pKa in dictating the final solid is also discussed.

Co-crystallization of anti-inflammatory pharmaceutical contaminants and rare carboxylic acid–pyridine supramolecular synthon breakdown

Co-crystallization of the pharmaceutical contaminants mefenamic acid and naproxen is reported; one co-crystal exhibits a rare carboxylic acid–pyridine synthon breakdown.

Crystal Engineering of Multicomponent Crystal Forms of p-Aminosalicylic Acid with Pyridine Based Coformers

This work reports detailed structural characterization of 13 new multicomponent solid forms of p-aminosalicylic acid (PAS) with various pyridine based compounds that include eight cocrystals, two salt cocrystals, two salts, and a salt hydrate. The structural chemistry of all solids of PAS with pyridine based coformers including those previously reported were analyzed in terms of PAS–coformer dimer or PAS–coformer–PAS trimer based on the carboxylic acid···pyridine synthon. The robustness of the carboxylic acid···pyridine synthon in the construction of a variety of multicomponent structures, the influence of solution composition and solvent in dictating the outcome of the crystallization event, and the applicability of the ΔpKa rule on a set of 32 PAS based multicomponent solids are also discussed.

Enhanced Bioavailability in the Oxalate Salt of the Anti-Tuberculosis Drug Ethionamide

Ethionamide (ETH) is an anti-tuberculosis (TB) Biopharmaceutics Classification System class II drug of poor aqueous solubility. The objective of the present study was to evaluate the solubility and bioavailability parameters of ETH cocrystals/salts with Generally Regarded as Safe (GRAS) coformers. Five cocrystals, namely, ETH–GLA (glutaric acid), ETH–ADP (adipic acid), ETH–SBA (suberic acid), ETH–SEBA (sebacic acid), ETH–FA (fumaric acid), and one salt ETH–OA (oxalic acid) were prepared by liquid-assisted grinding, and their structural characterization was carried out using spectroscopic, thermal, and powder X-ray diffraction techniques. The crystal structures of ETH–ADP, ETH–SBA, ETH–FA, and ETH–OA were confirmed by X-ray diffraction. The three cocrystal structures are sustained by the robust acid···pyridine synthon, while the ETH–OA salt has an ionic N–H···O hydrogen bond between carboxylate and pyridinium ions. The ETH–OA salt exhibited the highest dissolution compared to ETH (25 times), and its cocrys...

Cocrystals of the Tuberculosis Drug Isoniazid: Polymorphism, Isostructurality, and Stability

Isoniazid (INH) is a key drug ingredient in the fixed dose combination for the treatment of tuberculosis (TB). INH is highly soluble in aqueous medium and also stable in pure form, but it undergoes degradation when it is part of the FDC due to cross reactions. In continuation of our studies to improve the physiochemical properties of INH, we performed a cocrystal screen with pharmaceutically acceptable molecules selected from the generally regarded as safe (GRAS). Cocrystals with acidic conformers, such as vanillic acid (VLA), ferulic acid (FRA), caffeic acid (CFA), as well as with hydroxyl coformer resorcinol (RES), are reported. INH–VLA and INH–FRA are dimorphic, and INH–CFA is trimorphic. Form-1 of INH–FRA and INH–VLA are two-dimensional isostructural. All cocrystal structures are sustained by the expected acid–pyridine synthon, except the isostructural cocrystals which have the hydroxyl–pyridine synthon. The cocrystal forms were tested in accelerated ICH conditions of 40 °C and 75% RH for stability, and it was found that all the solid forms are stable for a test period of six months, except the INH–RES cocrystal. Slurry conditions and grinding experiments suggest that Form-2 of INH–FRA and INH–VLA have good stability, and Form-1 of INH–CFA is the most stable crystalline form of INH.

Different Hydrogen-Bonded Interactions in the Cocrystals of Nicotinamide with Two Aromatic Acids

Nicotinamide crystallizes with 3-hydroxy-2-naphthoic acid and 4-aminobenzoic acid to give rise to cocrystal 1 and 2, respectively. Cocrystal 1, [C11H8O3][C6H6N2O], crystallizes in the monoclinic space group C2/c with a = 25.810(4), b = 4.8932(5), c = 23.869(4) A, β = 107.078(8)o, V = 2881.6(7) A3, Z = 8, C17H14N2O4, M r = 310.30, D c = 1.431 g/cm3. Cocrystal 2, [C7H7NO2][C6H6N2O]·H2O, crystallizes in the triclinic space group P-1 with a = 7.214(5), b = 7.326(5), c = 13.484(11) A, α = 83.23(2), β = 77.189(18), γ = 80.35(2)o, V = 682.7(9) A3, Z = 2, C13H15N3O4, M r = 277.28, D c = 1.349 g/cm3. Similar carboxylic acid···pyridine synthon R 2 2 (7) can be observed in the two cocrystals. In 1, amide of nicotinamide forms a C(4) chain from the anti H to its carbonyl oxygen. In 2, the amide forms a R 2 2 (8) homodimer which is linked into 2D layer by water molecule through different hydrogen-bonding interactions. The 3D hydrogen-bonded structure results from a synthon R 4 2 (8) from amide, water and amino group of 4-aminobenzoic acid. Nicotinamide crystallizes with 3-hydroxy-2-naphthoic acid and 4-aminobenzoic acid to give rise to cocrystal 1 and 2, respectively. Similar carboxylic acid···pyridine synthon R 2 2 (7) can be observed in the two cocrystals. In 1, amide of nicotinamide forms a C(4) chain from the anti H to its carbonyl oxygen. The syn H is accepted by hydroxyl oxygen of 3-hydroxy-2-naphthoic acid to form an infinite C 2 2 (12) chain. In 2, the amide forms a R 2 2 (8) homodimer which is linked into 2D layer by water molecule through different hydrogen-bonding interactions. The 3D hydrogen-bonded structure results from a synthon R 4 2 (8) from amide, water and amino group of 4-aminobenzoic acid.

4,4'-Bipyridine-5-fluoro-isophthalic acid (1/1).

Co-crystallization of 5-fluoro­isophthalic acid (H2fip) with 4,4′-bipyridine (bipy) leads to the formation of the title compound [(H2fip)(bipy)], C8H5FO4·C10H8N2, with an acid–base molar ratio of 1:1. The acid and base subunits are arrange alternately in the crystal structure, displaying a wave-like tape motif via inter­molecular O—H⋯N and C—H⋯O hydrogen bonds [carbox­yl–pyridine synthon of R 2 2(7) hydrogen-bond notation], which are further combined into a two-dimensional architecture through C—H⋯F inter­actions involving the bipy and H2fip mol­ecules.

Packing incentives and a reliable N–H⋯N–pyridine synthon in co-crystallization of bipyridines with two agrochemical actives

The co-crystallization of agrochemical actives thiophanate-methyl and thiophanate-ethyl with 2,2′-bipyridine, 4,4′-bipyridine and 1,2-bis(4-pyridyl)ethane was investigated with conventional crystallization, the slurry method and liquid-assisted grinding. Co-crystals of both thiophanates with all bipyridines were found and the structures solved with single crystal X-ray diffraction. Whereas the 2,2′-bipyridine co-crystals seem to form because of a combination of weak interactions, and in the case of the thiophanate-methyl, partly because of close packing incentives, the 4,4′-bipyridine and 1,2-bis(4-pyridyl)ethane co-crystals form mainly because of a favourable N–H⋯N–pyridine hydrogen bonding synthon.

Hydrogen-bond networks in the binary complexes of trigonal molecules with 4,4′-bipyridine

A 1:1 binary salt and a cocrystal of two chemically different trigonal symmetric donor molecules, 2,4,6-trimethyl-1,3,5-benzenetricarboxylic acid (MTAH3) and 2,4,6-tris(4-hydroxyphenoxy)-1,3,5-triazine (HPT) with 4,4′-bipyridine (bipy) have been synthesized and the crystal structures have been studied. The MTAH3·bipy salt shows an unprecedented parallel interpenetrated 3D bookshelf type of structure aided by C(8) type O–H⋯O and acid⋯pyridine O–H⋯N interactions. The HPT·bipy complex has a 2D → 3D parallel polycatenated pcu net aided by the usual hydroxy⋯pyridine synthon and supported by a C–H⋯O interaction. Both the complexes exhibit the formation of 3D structures from trigonal donors, contrary to the fact that trigonal species generally are being considered to be candidates for construction of 2D networks.

Rational Design and Synthesis of Porous Organic−Inorganic Hybrid Frameworks Constructed by 1,3,5-Benzenetriphosphonic Acid and Pyridine Synthons

1,3,5-Benzenetriphosphonic acid, H6BTP, 1,3,5-[(HO)2OP]3C6H3, was reacted hydrothermally with copper salts in the absence and presence of 4,4'-bipyridine (bpy) and 4,4'-trimethlyenedipyridine (tbpy) in a 1:1 molar ratio leading to three new organic-inorganic hybrid frameworks. Compound 1, {Cu6[C6H3(PO3)3]2(H2O)8} x 5.5 H2O, has three different copper ions that are interconnected by the highly charged [1,3,5-(PO3)3C6H3]6- anionic moieties. These moieties self-assemble through tetra-copper units to give a cagelike motif with two benzene rings parallel to each other at a distance of 3.531 A which extend along the a axis and link with a grouping of four-coordinated copper units in the b axis direction to give the cross-linked layered structure. In compound 2, Cu{C6H3[PO(OH)O]2[PO(OH)2]}(C10H8N2), the copper ions are in square pyramidal geometries and are interconnected via chelating and bridging BTP ligands into layers which are further cross-linked by bpy ligands into a pillared layered architecture. Compound 3, {Cu2C6H3[PO(OH)O]2[PO3](C13H14N2)} x 3 H2O x 0.5 HCON(CH3)2, contains tetra-copper units that are linked by BTP ligands and further linked by tbpy linkers in the c axis direction to produce a large channel-sized 3D framework.

Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals

Linear, zigzag tapes and flat, corrugated sheet structures are described in binary cocrystals 1–9 of some di- and tricarboxylic acids with 4,4′-bipyridine bases and isonicotinamide. Carboxylic acid⋯pyridine O–H⋯N, its proton transfer form N+–H⋯O−, carboxamide dimer N–H⋯O, and extended motifs are present in these crystal structures. Our results show modular expansion of carboxylic acid dimer in neutral cocrystals with pyridine type bases. Even as the structures of these aggregates can be understood from the molecular constituents in a straightforward manner, the nature of acid⋯pyridine synthon, i.e. neutral or ionic, is difficult to anticipate from their ΔpKa values. We modify the ΔpKa (pKa conjugate acid of pyridine base – pKa carboxylic acid) rule in COOH–pyridine cocrystals: ΔpKa 3.75 results in proton migration to the ionic interaction N+–H⋯O−. Proton transfer results in the assembly of a supramolecular 3-connected node of cyclohexane tricarboxylate and these anions form chair cyclohexane or parquet grid sheets in 10 and 11. The length of bipyridinium cation plays a role in the overall structure. A novel approach to three-component adducts is crystallization of 1,3cis,5cis-cyclohexane tricarboxylic acid with 4,4′-bipyridine and 4,4′-bipyridine-N-oxide bases of different strengths, which results in a ternary cocrystal 12 sustained via O–H⋯N and O–H⋯O− hydrogen bonds.

Production of Pyridine Synthons by Biotransformations of Benzene Precursors and Their Cyclization with Nitrogen Nucleophiles

Biotransformation of benzene and derivatives has been used to accumulate meta-ring fission products of several catechols, including catechol, 3- and 4- methylcatechols, and 3- (trifluoromethyl) catechol. Dilute solutions of these yellow highly absorbing products were used to examine reaction conditions that affect their facile cyclizations with nitrogen nucleophiles, principally NH3. The effects of NH4+/NH3 concentration, pH and temperature on the non-enzymic cyclizations of 2-hydroxymuconic semialdehyde to 2-picolinate and its substituted derivatives have been characterised. As expected, the enzymic product from 3-(trifluoromethyl) catechol cyclised 20 times more slowly than that from 3-methylcatechol under identical reaction conditions. Most of the biological and chemical transformations were studied in very dilute solutions for the convenience of optical absorbance measurements. Because of the known sensitivity of the spectral shifts and extinction coefficients to minor changes in pH between 4 and 8 bo...

Synthesis of potential anticancer agents. Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines.

Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with alpha-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated hydrochloric acid regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and disulfide linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with alpha-halo ketones either in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3-, and 2,2,3-substituted ethyl (5-amino-2H-pyridol[4,3-b][1,4]thiazin-7-yl)carbamates 9. The effects of these pyridooxazines and pyridothiazines upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 leukemia were determined.