Aromatic substitution by n-arylhydroxylamines—I : Formation of 8-amino-5,8′-iminobis(6-methoxyquinoline) by an intermolecular aromatic nitrene insertion reaction

Thermolysis of 8-hydroxylamino-6-methoxyquinoline at 65° in methanol gave 8-amino-5,8′-iminobis(6-methoxyquinoline), the same product being formed by thermolysis of 8-azido-6-methoxyquinoline as well as by deoxygenation of 6-methoxy-8-nitroquinoline with triethylphosphite in the presence of 8-amino-6-methoxyquinoline. Solvent effects were also consistent with the involvement of a nitrenoid species in these intermolecular aromatic substitutons. 8-Hydroxylaminoquinoline behaved in an analogous fashion but no iminobis compound was obtained from the corresponding 6-hydroxylaminoquinoline, indicating an internal interaction of the ring N atom with the 8-hydroxylamino function. Thermolysis of 8-hydroxylamino-6-methoxyquinoline in the presence of amines gave rise to o-diamines reconcilable with a nitrene intermediate.     

Synthesis of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinolines and some related ring systems

Reduction of amides of 8-amino-6-methoxyquinoline over platinum oxide in glacial acetic acid at room temperature affords 2-substituted-5,6-dihydro-8-methoxy-4H-imidazo [4,5,1-ij]-quinolines (I). The method could not be utilized for urea or carbamate derivatives of 8-amino-6-methoxyquinoline. 2-Amino derivatives of I were prepared through the chloro compound obtained from 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, (IV). Several related ring systems have also been prepared.     

Spectrophotometric studies on 5,7-dibromo-8-aminoquinoline chelates of some bivalent transition metals

The acid dissociation constant of 5,7-dibromo-8-amino-quinoline and the stability constant of 1:1 chelates of some bivalent transition metals were determined spectrophotometrically in 50% v v dioxan-water medium at an ionic strength of 0.50 at 25.0 +/- 0.1 degrees and compared with those of 8-aminoquinoline. The dissociation constant was found to be 7.54 x 10(-2) and the stability constants (log K(1)) were 2.3 (copper), 1.8 (nickel), 1.8 (zinc), 2.2 (cobalt) and 1.6 (cadmium), respectively. The dissociation constants are greater and the stability constants smaller than the corresponding values for 8-aminoquinoline and 8-quinolinol.     

Polyelectrolytes as new matrices for secondary ion mass spectrometry

Significant enhancements in ion yields in time-of-flight secondary ion mass spectrometry (TOF-SIMS) are observed when water-soluble analytes are mixed with a polyelectrolyte, e.g., poly(diallyldimethylammonium chloride) or poly(sodium 4-styrenesulfonate), and then deposited in the layer-by-layer method on a surface. This previously unobserved effect is demonstrated for 5-chloro-8-methoxyquinoline appended diaza-18-crown-6, 5-(2-aminoethoxy)methyl-5-chloro-8-methoxyquinoline appended diaza-18-crown-6, acridine, 9-anthracenecarboxylic acid, and ferrocenecarboxylic acid. By optical ellipsometry film thicknesses range from ca. 5-20 angstroms. X-ray photoelectron spectroscopy shows significantly less analyte in the polyelectrolyte-analyte films than in the neat analytes. However, TOF-SIMS generally shows significant enhancements in ion yields from the polyelectrolyte films compared with either the neat compounds or the compounds solubilized with acid or base and then dried on a surface. These significant enhancements in ion yields also appear to extend to analyte fragments and cationized molecular species. Some enhancement is also observed for dried droplets of analytes mixed with a polyelectrolyte on surfaces.     

Spectral, electrical conductivity and biological activity properties of some new azopyrimidine derivatives and their complexes

The electronic absorption spectra of 5-(o-substituted phenylazo)-6-amino-2-thiouracils and 6-(o-substituted phenylazo)-5-aminouracils containing different substituents are studied at different pH's. The dissociation constants are evaluated and discussed. Phenomenon of tautomerism is more supported by (1)H NMR and (13)C NMR spectra. The electrical conductivity of some ligands and their Co(II), Ni(II) and Cu(II) complexes in the temperature range 293-150K favoured their semiconducting properties where the metal ion forms a bridge to facilitate the flow of the current. The biological activity of some ligands and their complexes are tested against a number of Gram-positive and Gram-negative bacteria. The results showed that some of the compounds have a well considerable activity against some of the organisms.     

Structure of 5-Amino-4-Arylazopyrazoles in Ethanolic Aqueous Media

The structure and tautomerism of 5-amino-4-arylazopyrazoles (2a-f) are investigated in aqueous media. In solutions of pH>5 these compounds exist as ring N—1 protonated species. At pH>10 they afford anions which are stabilized by delocalization of the negative charge in the ring as well as on the arylazo moiety. Controlled potential electrolysis and polarographic analysis indicate that 2a-f are reduced via a four electron reduction process to triaminopyrazole and the corresponding substituted aniline derivative. A mechanism is suggested and discussed.     

Studies on triazolo- and imidazo- [4.5-f]Quinolines

Oxidation of 5-arylazo-6-aminoquinoline with copper sulphate in pyridine gives the corresponding 2-aryltriazolo[4.5-f]quinolines. Condensation of halogenated nitrobenzenes with triazolo- [4.5-f]quinoline yields the corresponding 2- and 3-derivatives. Imidazo[4.5-f]quinoline behaves similarly and furnishes the 3-derivative. NMR, IR and UV spectra of several of the products are discussed.     

Mechanisms of the reactions of substituted iso-quinoline and quinoline N-oxides with arenesulfonyl chlorides

The rearrangements of substituted iso-quinoline and quinoline N-oxides with arenesulfonyl chlorides have been carried out to clarify the mode of migration of the arenesulfonoxy group by means of both ¹⁸O tracer and kinetic experiments. In the rearrangements of N-arenesulfonoxy-iso-carbostyril and carbostyril, the main migration route of the arenesulfonoxy group is via the solvent separated ion pair path with a minor portionpassing throug step appears to be N---O bond cleavage. For 1-amino-iso-quinoline N-oxide the migration of tosyloxy group to 1-amino-4-tosyloxyiso-quinoline through the oxygen-bridged ion pair pathway is so fast that the presence of the anhydro base cannot be detected. Reaction of 2-aminoquinoline N-oxide to afford 2-amino-6-tosyloxyquinoline which involves migration to a distant position proceeds rapidly, apparently through the solvent separated ion pair path.     

The potential use of 6-amino-5-methoxy(methyl)-2,3-dimethyl-and 6-amino-5-methoxy(methyl)-1,2,3-trimethyl-indoles in the synthesis of pyrrolo[2,3-f]quinolines

The reaction of 6-amino-2,3-dimethyl-and 6-amino-1,2,3-trimethyl-5-methoxy(methyl)indoles with 4,4,4-trifluoroacetoacetic ester and of 6-amino-5-methoxy-1,2,3-trimethylindole also with other β-dicarbonyl compounds has been studied. It was found that all of the amines investigated undergo condensation readily to form the corresponding enamines while the possible subsequent cyclization to give pyrrolo[2,3-f]quinolines was found only for the condensation product of 6-amino-2,3,5-trimethylindole with 4,4,4-trifluoroacetoacetic ester. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp 97–103, January, 2006.     

Kinetics and equilibria of proton exchange in the lowest excited singlet states of 8-methoxyquinoline and 8-methoxyquinaldine: analysis of some complex fluorimetric titration curves

The determination of the rate constants for proton exchange in the lowest excited singlet states of 8-methoxyquinoline and 8-methoxyquinaldine from the pH dependences of their fluorescence spectra is complicated by overlap of the spectra of the conjugate acids and bases of both compounds and by the enhancement of 8-methoxyquinoline fluorescence at high pH by a process apparently unrelated to proton exchange. The fluorimetric titration data are analyzed in ways which compensate for these difficulties and the kinetic parameters of excited-state proton exchange determined. Qualitative relationships between the parameters of excited-state proton exchange, electronic structure and steric factors are considered.     

Application of Free-Wilson matrices to the analysis of the tautomerism and aromaticity of azapentalenes: a DFT study

The tautomerism and aromaticity of 44 neutral and the corresponding 60 protonated azapentalenes were studied. The tautomerism was based on the calculated relative energies of the different tautomers, from two to three and nine nitrogen atoms. The aromaticity was estimated from the NICS values of both rings of azapentalenes. The possible relationship between both properties was assessed. The calculation was carried out at the B3LYP/6-311++G^∗∗ computational level. MEP and NBO analysis were carried out on the studied compounds.     

The mobility and ion structure of protonated aminoazoles

The reduced mobility of protonated pyrazole derivatives was measured by ion mobility spectrometry (IMS) in air, nitrogen, and carbon dioxide, at temperatures between 150 and 250°C. It was found that the mobility of protonated 5-amino-1-phenylpyrazole was higher than that of its 3- and 4-isomers. This was attributed to the fact that in the 5-isomer the preferred site of protonation is on the endocyclic nitrogen, which leads to delocalization of the ionic charge, and thus to a diminished interaction with the drift gas molecules. On the other hand, protonated 5-amino-1-methylpyrazole has a slightly lower mobility than its isomers, which is indicative of a different protonation mechanism.     

Ring-chain tautomerism of the thiosemicarbazones of substituted benzaldehydes and acetophenones in acid media

Ring-chain tautomerism between the protonated form of the thiosemicarbazone and the 5-amino-2,3-dihydro-1,3,4-thiadiazolium cation is characteristic for thiosemicarbazones and 4-methylthiosemicarbazones of substituted benzaldehydes and acetophenones in CF₃COOH solutions.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.12, pp. 1689–1697, 1992.     

Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands

The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines as ligands for SH3 domains--so far the only reported examples of entirely small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are 6-substituted compounds. In this article, the synthesis of several new 2-aminoquinolines, including 5-, 6- and 7-substituted compounds, for Tec SH3 domain ligand binding studies is presented. As a part of the synthetic investigation, the utility of different methods for the synthesis of 2-aminoquinolines was explored and potentially powerful methods were identified for the synthesis of 2-aminoquinolines with diverse functionality. Of the compounds prepared, the 5-substituted-2-aminoquinolines generally bound with similar affinities to unsubstituted 2-aminoquinoline, whilst the 7-substituted compounds generally bound with similar or lower affinity than unsubstituted 2-aminoquinoline. However, the 6-substituted-2-aminoquinolines generally bound with significantly higher affinity than unsubstituted 2-aminoquinoline. In addition, one 6-substituted-N-benzylated-2-aminoquinoline was also tested for SH3 binding and some evidence for the formation of additional contacts at other regions of the SH3 domain was found. These results provide new and useful SAR information that should greatly assist with the challenge of developing high affinity small-molecule ligands for the SH3 domains.     

Fluorescence quenching of acridinium and 6-methoxyquinolinium ions by Pb2+, Hg2+, Cu2+, Ag+ and hydrogen sulphide

The quenching of the fluorescene of cationic derivatives of 6-methoxyquinoline and acridine by various heavy metal cations and hydrogen sulphide ion have been studied in detail. Stern—Volmer constants were determined and quenching was found to be exclusively dynamic, except for the hydrogen sulphide ion, which acts as both a dynamic and static quencher. The highly efficient static quenching process is interpreted in terms of nucleophilic attack of hydrogen sulphide to the 9-position of acridinium ion, thereby destroying the conjugated system of the fluorophore.     

Blackbody infrared radiative dissociation of bradykinin and its analogues: energetics, dynamics, and evidence for salt-bridge structures in the gas phase

Blackbody infrared radiative dissociation (BIRD) spectra of singly and doubly protonated bradykinin and its analogues are measured in a Fourier-transform mass spectrometer. Rate constants for dissociation are measured as a function of temperature with reaction delays up to 600 s. From these data, Arrhenius activation parameters in the zero-pressure limit are obtained. The activation parameters and dissociation products for the singly protonated ions are highly sensitive to small changes in ion structure. The Arrhenius activation energy (E(a)) and pre-exponential (or frequency factor, A) of the singly protonated ions investigated here range from 0.6 to 1.4 eV and 10(5) to 10(12) s(-1), respectively. For bradykinin and its analogues differing by modification of the residues between the two arginine groups on either end of the molecule, the singly and doubly protonated ions have average activation energies of 1.2 and 0.8 eV, respectively, and average A values of 10(8) and 10(12) s(-1), respectively, i.e., the presence of a second charge reduces the activation energy by 0.4 eV and decreases the A value by a factor of 10(4). This demonstrates that the presence of a second charge can dramatically influence the dissociation dynamics of these ions. The doubly protonated methyl ester of bradykinin has an E(a) of 0.82 eV, comparable to the value of 0.84 eV for bradykinin itself. However, this value is 0.21 +/- 0.08 eV greater than that of singly protonated methyl ester of bradykinin, indicating that the Coulomb repulsion is not the most significant factor in the activation energy of this ion. Both singly and doubly protonated Lys-bradykinin ions have higher activation energies than the corresponding bradykinin ions indicating that the addition of a basic residue stabilizes these ions with respect to dissociation. Methylation of the carboxylic acid group of the C-terminus reduces the E(a) of bradykinin from 1.3 to 0.6 eV and the A factor from 1012 to 105 s(-1). This modification also dramatically changes the dissociation products. Similar results are observed for [Ala(6)]-bradykinin and its methyl ester. These results, in combination with others presented here, provide experimental evidence that the most stable form of singly protonated bradykinin is a salt-bridge structure.     

Synthesis of novel fluorinated 4-aminoquinoline derivatives

New 4-aminoquinolines having a -CF₂CH-(heteroaryl)-OH moiety are obtained in moderate yields from the electrochemical catalyzed reaction of the corresponding 4-amino-3-chlorodifluoroacetyl-2-methoxyquinoline in the presence of heteroaryl aldehydes. A one-pot intramolecular zinc mediated aromatic nucleophilic substitution also gave access to novel difluorinated 5-aminodihydropyrano[2,3-b]quinolin-4-ones.     

Methoxyquinoline-diethylenetriamine conjugate as a fluorescent zinc sensor

A 6-methoxyquinoline conjugated diethylenetriamine derivative, N,N'-bis(6-methoxy-2-quinolylmethyl)diethylenetriamine (6-MeOBQDIEN) has been synthesized and its fluorescent response toward zinc ion was investigated. In the presence of zinc ion, 6-MeOBQDIEN exhibits fluorescence (λ(ex) = 329 nm, λ(em) = 418 nm, φ = 0.039). The fluorescent intensity of the zinc complex of the compound is two times higher than the parent BQDIEN (φ = 0.021) under the same conditions. The crystal structure of 6-MeOBQDIEN-Zn complex shows that all five nitrogen atoms participate to the metal coordination in a distorted square-pyramidal geometry (τ = 0.145) with the aliphatic nitrogen in an apical position. Fluorescent microscopic analysis using 6-MeOBQDIEN reveals the zinc ion concentration change in living cells.     

Activation of 3-amino-1,2,4-benzotriazine 1,4-dioxide antitumor agents to oxidizing species following their one-electron reduction

The mechanism by which a benzotriazine 1,4-dioxide class of anticancer drugs produce oxidizing radicals following their one-electron reduction has been investigated using tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide, 1) and its 6-methoxy (6), 7-dimethylamino (7), and 8-methyl (8) analogues. By measuring the changes in absorption with pH, we found that the radical anions undergo protonation with radical pK(r) values of 6.19 +/- 0.05, 6.10 +/- 0.03, 6.45 +/- 0.04, and 6.60 +/- 0.04, respectively. The one-electron reduced species underwent a first-order reaction, with increased rate constants from 112 +/- 23 s(-)(1) for 1 to 777 +/- 12 s(-)(1)(6), 1120 +/- 29 s(-)(1) (7), and 825 +/- 89 s(-)(1) (8) at pH 7. No overall change in conductance was observed following the one-electron reduction of 6, and 8 at pH 4.5, consistent with the protonation of the radical anions, but a loss in conductance was seen for one-electron reduced 7 because of further protonation of the initially formed radical. This is assigned to the protonation of the dimethylamino group of the radical species, which has a pK(a) of 8.8 +/- 0.3. All conductance changes take place on a time-scale shorter than those of the above first-order reactions, which are not associated with the formation or loss of charged species. The absorption spectra present at the end of the unimolecular reactions were found to be similar to those formed immediately upon the one-electron oxidation of the respective substituted 3-amino-1,2,4-benzotriazine 1-oxides, and it is suggested that common benzotriazinyl radicals are formed by both routes. All these intermediate radicals underwent dismutation to produce final spectra matched by equal contributions of the parent compound and their respective substituted 3-amino-1,2,4-benzotriazine 1-oxides. By establishing redox equilibria between the intermediate radicals formed on the one-electron oxidation of the respective 3-amino-1,2,4-benzotriazine 1-oxides of the compounds and reference compounds, we found the one-electron reduction potential of the oxidizing radicals to range from 0.94 to 1.31 V. The benzotriazinyl radical of tirapazamine was found to oxidize dGMP and 2-deoxyribose with rate constants of (1.4 +/- 0.2) x 10(8) M(-)(1) s(-)(1) and (3.7 +/- 0.5) x 10(6) M(-)(1) s(-)(1), respectively.     

Mn(II) complexes of novel hexadentate AAZTA-like chelators: a solution thermodynamics and relaxometric study

Three novel chelators based on the 6-amino-6-methylperhydro-1,4-diazepine scaffold and possessing three pendant N-acetic or N-α-methylacetic acid have been synthesised. The ligands contain six donor atoms for complexation of Mn(II) ions and thus potentially leave an additional site for coordination of a water molecule. The protonation constants of the ligands and the stability constants of their complexes formed with Mn(II) ion were determined by pH-potentiometric titrations in 0.15 M NaCl solution at 25 °C and compared to those of the parent AAZTA ligand (AAZTA = 6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid). In spite of the similar value of the total basicity (Σlog K), the values of the stability constants of the Mn(II)AAZTA-like complexes are more than three orders of magnitude lower than that of MnAAZTA (log K(MnL) = 14.19). A detailed (1)H and (17)O NMR relaxometric study was carried out on the Mn(II) complexes in aqueous solution as a function of pH, temperature and magnetic field strength. The (1)H NMRD profiles of all the complexes show a similar shape, typical of low-molecular weight systems, but amplitudes that markedly differ to indicate a different degree of hydration. A similar behaviour is shown by the (17)O NMR transverse relaxation rates and chemical shift data as a function of temperature. The experimental data can be rationalised by considering the presence in solution of a mixture of two isomeric species differing in coordination number (7 and 6) and in the number (1 and 0) of bound water molecules. Whereas this type of coordination equilibrium has been previously reported for lanthanide(III) complexes, it is observed for the first time on Mn(II) chelates.