Search

A series of novel 2-(trifluoromethyl)-2H/4H-chromene-3-carboxylate isomers 3 and 4 functionalized with diverse methoxybenzenes 2 at position 4 in compound 3 and position 2 in compound 4 were prepared in different proportions by nucleophilic substitution on ethyl 2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 in single step promoted by Indium (III) bromide (5 mol%) a Lewis acid. Regiospecific isomers 3k, 3l, 3m, and 3n prepared by using sterically bulk 1,3,5-trimethoxy benzene substrate 2e in this reaction. Further, isomers 3a and 4a independently on reaction with amines, only compound 3a could give Michael addition products 5a–c. All the compounds 3a–n, 4a–j, and 5a–c were screened for cytotoxic activity against four human cancer cell lines and found to show high activity at micromolar concentration. The compounds 4h and 5a–c showed promising cytotoxic activity against the tested cancer cell lines. Further, these compounds 4h and 5a–c were docked with protein (1SA0) on colchicine-binding site of β tubulin suggesting that tubulin inhibition could be the possible mechanism of action for these compounds.

Nine chalcones were prepared via Claisen-Schmidt condensation, and characterized by UV–vis, IR, 1H NMR, 13C NMR and mass spectrometry. One of the representative member 4-NDM-TC has been studied via single crystal XRD and the TGA/DTA technique. SHG efficiency and NLO susceptibilities of the chalcones have been evaluated by the Kurtz and Perry method and Degenerate Four Wave Mixing techniques respectively. 3-Cl-4′-HC was noted to possess SHG efficiency 1.37 times that of urea while 4-NDM-TC returned the highest third order NLO susceptibilities with respect to CS2. In silico studies help evaluate various physical parameters, in correlating the observed activities. In conclusion, the structure-activity relationship was derived based on the in silico and experimental results for the third order NLO susceptibilities.

Finite element simulation of the impact analysis of circular and rectangular water tanks subjected to projectile impact has been carried out using ANSYS Explicit Dynamics 15.0. Analyses were performed by considering both with water and without water for circular and rectangular water tanks. The different impact velocities considered in the present study were 50, 100, 200 and 400 kmph. The water tank is considered to be fixed at slab base. Due to the limitation on the maximum number of nodes in the academic version of ANSYS, finite element modelling of water tank has been carried out on a water tank of reduced capacity of 4400 L. The reduced tank has a height of 1.40 m and diameter as 2 m. The size of meshing is taken as 100 mm, and thickness of the base slab considered is 150 mm. Salient results such as total deformation, principal stresses, equivalent stresses, normal stresses and the directional deformation for both circular and rectangular tanks with water and without water cases for the different velocities were obtained. The comparison of the various results for the different cases was detailed. It is observed that with the use of finite element simulation, one can come to an optimized shape of the tank with least amount of internal stresses developed within.

Herein, a facile and efficient method for the preparation of allyl amides from the aldehyde of Baylis–Hillman adducts has been developed using a hydroxylamine/methanol system under a catalyst-free condition. The effects of solvents and temperature on the reaction and substituents on the phenyl ring have been examined. This method is best demonstrated by its advantages such as operational simplicity, moderate to excellent yields, short reaction time, and simple reaction procedure. Most importantly, the reaction proceeds smoothly in the absence of a catalyst and an external oxidant.

The subject of the study is the structure and conformation of 1″,4″-Dispiro-cyclohexane-6,6'-bis(benzothiazoline), a dispiro compound that has a cyclohexyl ring flanked by two benzothiazoline rings on either side. Using single crystal X-ray diffraction measurements, Infra-red absorption, and Raman spectroscopy techniques, it is found that the central cyclohexyl ring assumes the chair conformation and the sulfur, nitrogen atoms in both the benzothiazole rings are in the trans configurations. The experimental findings are further corroborated by geometry optimization and frequency calculations at B3LYP/6-311++G** level of theory using Gaussian 09 suite of program.

A simple, ecofriendly and one-pot three-component aqueous phase protocol is developed for the synthesis of functionalized spirooxindole derivatives by the reaction of isatin, β-nitrostyrene and benzyl amine/α-amino acids in water under microwave irradiation. The method allows the easy construction of a library of spirooxindoles in moderate to good yields with good diastereoselectivity starting from readily available precursors. In addition, all the synthesized compounds were screened for antimicrobial activity and the majority of compounds showed significant activity against Escherichia coli ATCC 10536, Candida tropicalis ATCC 750, Staphylococcus aureus ATCC25923 and Pseudomonas aeruginosa ATCC 15442.

A series of four novel funnel shaped triphenylamine core derivatized materials with various combinations of 3,6-di-tert-butyl-9H-carbazole as donors and benzo/pyrido[1,2,5]thiadiazole as peripheral acceptors were designed, synthesized and characterized. Optical and electrochemical studies revealed that increasing acceptor strength in the structure leads to a bathochromic shift in their absorption profile and stabilizes the lowest unoccupied molecular orbital (LUMO) energy level. Enhancement in the intensity of an intramolecular charge transfer transition with synergistic downshift of the highest occupied molecular orbital (HOMO) and LUMO levels was observed by increasing the number of acceptor units. Thermogravimetric analyses (TGA) indicated that the materials containing pyrido[1,2,5]thiadiazole (PTD) acceptor functionality have excellent thermal stability compared to the materials containing benzo[1,2,5]thiadiazole (BTD) functionality. The measurement of glass transition temperature (Tg) corroborated TGA results and the values were found to be in the range of 148–198 °C. X-ray analyses indicated that more twist in the structure leads to absorption in the high energy region and varying the number of electron donor and acceptor groups has an impact on the modulation of frontier energy levels. A power conversion efficiency of 2.21% for the molecule with PTD as an acceptor and bis-carbazole as donor was achieved for the preliminary photovoltaic devices under simulated AM 1.5 illumination (100 mW cm−2).

An expedient, eco-friendly and green-protocol has been developed for the synthesis of novel 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile derivatives via Knoevenagel/Michael/cyclisation reactions in one pot under catalyst-free conditions on aqueous media. These products exhibited UV-Vis absorption and photoluminescence properties.

A facile multicomponent synthesis of desirable medicinal scaffolds based on thiazoline, thiazolidinone and thiazolidinol derivatives has been disclosed. The synthesis employs the reaction of a primary amine and carbon disulphide in a microwave, to generate a symmetrical thiourea in situ. The subsequent addition of e.g. 3-bromo-1,1,1-trifluoropropan-2-one affords the desired product, in an efficient one-pot process.

A short and facile access to novel functionalized tetrahydroxanthenones via a DABCO-promoted tandem Knoevenagel condensation/hemiketalisation process from easily accessible substrates in a high yield. Tetrahydroxanthenones provide access to the stereo-controlled synthesis of triades or tetrades, which represent privileged structural motifs. Disubstituted tetrahydroxanthenones are generated as a mixture of diastereomers, favoring the formation of selective diastereomers. Unsymmetrical cyclic diketones give mixtures of regio isomers, favoring the formation of sterically less-hindered products.

A highly efficient method for the synthesis of 2-imino-4-(trifluoromethyl)thiazolidin-4-ol derivatives has been achieved by the one-pot, three-component reactions of primary amines, aryl isothiocyanates, and 3-bromo-1,1,1-trifluoropropanone. The reactions go via symmetrical and unsymmetrical thiourea intermediates. Subsequent reactions of the products allow the synthesis of various scaffolds, including isoxazoles, triazoles, and propargylamine derivatives.

A convenient and efficient method is described for the synthesis of alkoxy substituted 2H-chromens by l -proline catalyzed reaction of salicylaldehydes with diketone in alcohol. The method is applicable for various substituted salicylaldehydes and aliphatic as well as benzylic alcohols.

Temozolomide (TMZ) is an antitumor prodrug of broad spectrum antineoplastic activity. TMZ is stable in acidic medium (pH 7). In continuation of our efforts to design stable cocrystals of TMZ with partners such as organic acids (pKa 2–5) and a salt dihydrate with hydrochloric acid, we report herein TMZ cocrystals with amide coformers, e.g., isonicotinamide, nicotinamide, pyrazinamide, p-hydroxybenzamide, saccharin, and caffeine. TMZ exhibits polymorphs in the p-hydroxybenzamide cocrystal (synthon polymorphism). The occurrence of the stable conformation A of temozolomide and metastable conformation B (energy difference 1.44 kcal mol–1) in amide cocrystals is compared with the overall statistics in temozolomide cocrystal structures and polymorphs. The novel cocrystals were characterized by spectroscopic, X-ray diffraction, and thermal methods.

The X-ray crystal structure of temozolomide hydrochloride shows that the dihydrate salt contains one neutral temozolomide, one temozolomide-H+Cl−, one H3O+·Cl−, and three water molecules. This is the first crystallographic evidence of a protonated form of the antitumour drug temozolomide. The protonation of water O and imidazole N of the drug are rationalized by calculated pKas.

A simple, ecofriendly and one-pot three-component aqueous phase protocol is developed for the synthesis of functionalized spirooxindole derivatives by the reaction of isatin, β-nitrostyrene and benzyl amine/α-amino acids in water under microwave irradiation. The method allows the easy construction of a library of spirooxindoles in moderate to good yields with good diastereoselectivity starting from readily available precursors. In addition, all the synthesized compounds were screened for antimicrobial activity and the majority of compounds showed significant activity against Escherichia coli ATCC 10536, Candida tropicalis ATCC 750, Staphylococcus aureus ATCC25923 and Pseudomonas aeruginosa ATCC 15442.

The antitumor prodrug temo-zolomide (TMZ) decomposes in aque-ous medium of pH 7 but is relativelystable under acidic conditions. PureTMZ is obtained as a white powderbut turns pink and then brown, whichis indicative of chemical degradation.Pharmaceutical cocrystals of TMZwere engineered with safe coformerssuch as oxalic acid, succinic acid, sali-cylic acid, d,l-malic acid, and d,l-tarta-ric acid, to stabilize the drug as a coc-rystal. All cocrystals were character-ized by powder X-ray diffraction(PXRD), single crystal X-ray diffrac-tion, and FT-IR as well as FT-Ramanspectroscopy. Temozolomide cocrystalswith organic acids (pK a 2–6) werefound to be more stable than the refer-ence drug under physiological condi-tions. The half-life (T 1/2 ) of TMZ–oxalic and TMZ–salicylic acid mea-sured by UV/Vis spectroscopy in pH 7buffer is two times longer than that ofTMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ–succinic acid, TMZ–tartaric acid, andTMZ–malic acid also exhibiteda longer half-life (2.3, 2.5, and 2.8 h, re-spectively). Stability studies at 408Cand 75% relative humidity (ICH con-ditions) showed that hydrolytic degra-dation of temozolomide in the solidstate started after one week, as deter-mined by PXRD, whereas its cocrystalswith succinic acid and oxalic acid wereintact at 28 weeks, thus confirming thegreater stability of cocrystals comparedto the reference drug. The intrinsic dis-solution rate (IDR) profile of TMZ–oxalic acid and TMZ–succinic acid coc-rystals in buffer of pH 7 is comparableto that of temozolomide. Among thetemozolomide cocrystals examined,those with succinic acid and oxalic acidexhibited both an improved stabilityand a comparable dissolution rate tothe reference drug.Keywords: crystal engineering ·cocrystals · stability · temozolo-mide · X-ray diffraction2274

Nitrofurantoin (NF) drug is known to transform to a hydrate form in aqueous medium. The hydration stability and dissolution rate of a few cocrystals of NF were compared with that of its stable β polymorph and hydrate form II. Hydrogen bonding and molecular packing in the novel cocrystal structures were analyzed. Pharmaceutical cocrystals of NF with p-aminobenzoic acid (PABA) and urea showed superior physicochemical properties compared with the known L-arginine salt hydrate. All the solid-state adducts were characterized by single-crystal X-ray diffraction, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis. NF-PABA cocrystal was found to be superior among the compounds studied in terms of minimal transformation to NF hydrate and comparable dissolution rate to the reference drug.

The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time (

Hydrogen-bond motifs for the supramolecular synthesis of sulfonamide−pyridine-N-oxide complexes were derived from the analysis of cocrystal structures of aryl sulfonamides and pyridine-N-oxides. The sulfonamide NH donor persistently interacts with the N-oxide acceptor via a N−H···O hydrogen bond, though the exact geometry of the motif, such as discrete (D), infinite chain C(4), cyclic motifs R42(8) or R22(4), varies from structure to structure. Surprisingly, the two-point R22(8) cyclic motif of N−H···O and C−H···O hydrogen bonds, analogous to the heterosynthon in carboxamide−pyridine-N-oxide cocrystals, was not observed in sulfonamide−N-oxide cocrystals. The utility of this model study is demonstrated by making cocrystals of Furosemide with 4,4′-bipyridine-N,N′-dioxide and isonicotinamide-N-oxide.

Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P21/n and P1 space groups. The conformationally flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol−1 energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are ∼4.5 kcal mol−1 less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol−1). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N−H···Cl hydrogen bonds and minimization of repulsive S═O···Cl interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the...

Two novel hydrate forms of norfloxacin (NF) were serendipitously obtained during cocrystallization with eugenol. NF 1.25 hydrate and 1.125 hydrate are isomorphous crystal structures in the P21/c space group, each with two symmetry-independent drug molecules, two full water molecules, and a third water of 0.5 and 0.25 partial occupancy, respectively. Water promoted proton transfer results in a shift from neutral to ionic hydrogen bonding between norfloxacin molecules in hydrate structures. The presence of eugenol additive gave novel NF hydrates of lower water stoichiometry, whereas crystallization in its absence gave the known NF dihydrate.

A facile multicomponent synthesis of desirable medicinal scaffolds based on thiazoline, thiazolidinone and thiazolidinol derivatives has been disclosed. The synthesis employs the reaction of a primary amine and carbon disulphide in a microwave, to generate a symmetrical thiourea in situ. The subsequent addition of e.g. 3-bromo-1,1,1-trifluoropropan-2-one affords the desired product, in an efficient one-pot process.

A short and facile access to novel functionalized tetrahydroxanthenones via a DABCO-promoted tandem Knoevenagel condensation/hemiketalisation process from easily accessible substrates in a high yield. Tetrahydroxanthenones provide access to the stereo-controlled synthesis of triades or tetrades, which represent privileged structural motifs. Disubstituted tetrahydroxanthenones are generated as a mixture of diastereomers, favoring the formation of selective diastereomers. Unsymmetrical cyclic diketones give mixtures of regio isomers, favoring the formation of sterically less-hindered products.

Hydrogen bond competition was studied in 21 X-ray crystal structures of N-X-phenyl-N′-p-nitrophenyl urea compounds (X = H, F, Cl, Br, I, CN, C≡CH, CONH2, COCH3, OH, Me). These structures are classified into two families depending on the hydrogen bond pattern: urea tape structures contain the well-known α-network assembled via N−H···O hydrogen bonds; however, in nonurea tape structures the N–H donors hydrogen bond with NO2 groups or solvent O acceptor atoms. Surprisingly, the urea C═O hardly accepts strong H bonds in nonurea type structures sustained by urea···nitro and urea···solvent synthons. The carbonyl group accepts intra- and intermolecular C−H···O interactions. The molecular conformation and H bonding motifs are different in the two categories of structures: the phenyl rings are twisted out of the urea plane in the tape motif, but they are coplanar in the nonurea category. Even though hydrogen bond synthon energy and urea carbonyl acceptor strength favor the N−H···O tape structure, the dominant patt...

The carboxamide-pyridine N-oxide heterosynthon is sustained by syn(amide)N-H...O-(oxide) hydrogen bond and auxiliary (N-oxide)C-H...O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide-N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide-N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine.quinoxaline N,N'-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N-H...O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius(2), COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 degrees C up to four weeks. Amide-N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H(2)O functional groups.

We show the requirement of Z‘ ≥ 2 for assembling an acid−pyridine trimer synthon in small, dissymmetric molecules. 5-Methylpyrazine-2,3-dicarboxylic acid (1) forms the rare O−H···N trimer synthon between three symmetry-independent molecules in a Kagome lattice. The two-dimensional layers organize in a chiral P65 crystal system stabilized by C−H···O helices.

A strong, cooperative O−H···O hydrogen bond network directs isostructurality in pyrazine tetracarboxylic acid, pyridine tetracarboxylic acid, and pyromellitic acid dihydrates. H2O and COOH groups reorganize their H bonding groups in an invariant network leading to Ow−H···N ⇔ C−H···Ow mimicry. The degree of similarity is related to the size of the multicenter synthon and the strength of the Oacid−H···Owater hydrogen bond.

Very short OH···O hydrogen bonds (O···O = 2.2−2.5 A) usually occur when the H-bond is stabilized by a negative or positive charge (OH···O-, O+H···O) or by resonance assistance (···OCCCOH···). We have characterized a very short intermolecular OacidH···Owater hydrogen bond in the title crystal structure, 1, by variable temperature neutron diffraction (O···O = 2.4751(11), 2.4765(10), 2.4807(12), and 2.4906(16) A at 20, 100, 200, and 293 K). The COOH donor is activated by π-cooperative hydrogen bonding (OacidH···OCacid), and the water-acceptor ability is enhanced by polarization assistance (σ-cooperative, OwH···Oacid, OwH···Npyrazine). The absence of proton migration in the temperature range 20−293 K to give ionic or tautomer forms rules out contribution from the charge- or resonance-assisted H-bonds in 1. The shortening of the OacidH···Ow hydrogen bond through synergistic π- and σ-cooperativity in the finite, neutral array I, named as a synthon-assisted hydrogen bond (SAHB), adds a new category to the curren...

Mono- and disubstituted chromenes with methoxy-, nitro-, chloro-, and bromo- groups as well as benzochromene are reacted with indole and N-methylindole.

Three component reaction of substrates (I) with amines and isothiocyanates affords thiazolidin-4-ols (IV).

A convenient and efficient method is described for the synthesis of alkoxy substituted 2H-chromens by l -proline catalyzed reaction of salicylaldehydes with diketone in alcohol. The method is applicable for various substituted salicylaldehydes and aliphatic as well as benzylic alcohols.

A series of 5-nitrofuran–triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC50 value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4'-bipyridine-N,N'-dioxide (BPNO), and solid-state stability were studied. Apart from a known X-ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3-hydroxypyridine-N-oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N--HN(imidazole) and N--HN(tetrazine) interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZBPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen-bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N-H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C==O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen-bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen-bond reorganization.

3,3‘-Bipyrroles 3 could be synthesized using a double Michael addition reaction involving diaroyl acetylene 1 and the appropriate 1,3-dicarbonyls 2 using ammonium acetate as a nitrogen source. The axial chirality of bipyrrole was anticipated from the X-ray crystal structure and DFT calculations and confirmed by separating the racemates on a chiral column and subsequent CD spectra of the enantiomers. The absolute configuration of the enantiomers was achieved by theoretical CD spectra calculation using the ZINDO method.

The higher Z′ polymorph has a shorter C–H⋯O interaction in 26 out of 38 crystal structures with two or more forms; these data suggest the dominance of stronger hydrogen bonds, or enthalpy, in the crystallization of multiple Z′ crystal structures.

Water molecules connect 6.5 × 4.5 A diameter rings in the X-ray crystal structure of 16-member tetrapeptide cyclo(Phe-Pro-Leu-Aha) (1) trihydrate. However, stereoisomer cyclo(D-Phe-Pro-Leu-Aha) (2) crystallized in anhydrate form. Structural differences in L- to D-amino acid exchanged cyclic peptides are analyzed.

The novel carboxamide-pyridine N-oxide synthon, sustained via N-H...O- hydrogen bonding and C-H...O interaction, is shown to assemble isonicotinamide N-oxide in a triple helix architecture and the same heterosynthon is exploited to synthesize cocrystals of barbiturate drugs with 4,4'-bipyridine N,N'-dioxide.