Synthetic applications of aryl radical building blocks for cyclisation onto azoles

2-(2-Bromophenyl)ethyl groups have been used as building blocks in radical cyclisation reactions onto azoles to synthesise tri- and tetra-cyclic heterocycles. 2-(2-Bromophenyl)ethyl methanesulfonate was used to alkylate azoles (imidazoles, pyrroles, indoles and pyrazoles) for the synthesis of the radical precursors. Cyclisations of the intermediate aryl radicals yield new 6-membered rings attached to the azoles. The aryl radicals undergo intramolecular homolytic aromatic substitution onto the azole rings. Tributylgermanium hydride has been used with success to replace the toxic and troublesome tributyltin hydride. Initial studies show that the protocol can be used on solid phase resins. The molecular and crystal structures of methyl 5,6-dihydroimidazo[5,1-a]iso-quinoline-1-carboxylate and methyl 5,6-dihydroimidazo[2,1-a]isoquinoline-3-carboxylate were determined by X-ray crystallography.     

Epr and endor of free radicals formed during the aerobic oxidation of chlorogenic acid and of caffeic acid in strongly alkaline solution

The proton hyperline coupling constants in three free radicals which are formed during the aerobic oxidation of either chlorogenic acid or of caffeic acid in strongly alkaline solution have been measured using EPR and ENDOR spectroscopy and the three radicals thus characterised. Possible identities for the free radicals are discussed.     

Radical decomposition of <Emphasis Type="Italic">N,N</Emphasis>-bis-(3-chloro-1,4-naphthoquinon-2-yl) amine in basic conditions followed by EPR

EPR spectroscopy was used to assess the radicals produced upon basic decomposition of N,N-bis-(3-chloro-1,4-naphthoquinon-2-yl) amine (BClNQA). Three radicals have been trapped and identified: N-bis(3-chloro-1,4-naphthoquinone) hydrazine radical (6), 2-hydroxy-3-chloro-1,4-naphthoquinone anion radical (9) and 2-amino-3-chloro-1,4-naphthoquinone radical (8). The probable reaction mechanism, the structure of intermediates as well as the reaction profile are discussed.     

Unusual spin-trap chemistry for the reaction of hydroxyl radical with the carcinogen N-nitrosodimethylamine

The reaction of the potent carcinogen N-nitrosodimethylamine (NDMA) with hydroxyl radical generated via radiolysis was studied using EPR techniques. Attempts to spin trap NDMA radical intermediates with 3,5-dibromo-4-nitrosobenzene sulfonate (DBNBS) produced only unusual DBNBS radicals. One of these radicals was shown to be generated by both reaction of DBNBS with nitric oxide, and direct oxidation of DBNBS with an inorganic oxidant (^.Br^-₂). Another DBNBS radical was identified as a sulfite spin adduct resulting from the degradation of DBNBS by a NDMA reactive intermediate. In the absence of DBNBS, hydroxyl radical reaction with NDMA gave the dimethylnitroxide radical. Unexpectedly, addition of DBNBS to a solution containing dimethylnitroxide produced an EPR spectrum nearly identical to that of NDMA solutions with DBNBS added before radiolysis. A proposed mechanism accounting for these observations is presented.     

PHOTOCHEMICAL SENSITIZATION BY AZATHIOPRINE AND ITS METABOLITES. PART 3. A DIRECT EPR AND SPIN-TRAPPING STUDY OF LIGHT-INDUCED FREE RADICALS FROM 6-MERCAPTOPURINE AND ITS OXIDATION PRODUCTS

Abstract Sunlight has been implicated in the high incidence of skin cancer found in patients receiving 6-mercaptopurine (PSH) in the form of its pro-drug azathioprine. In this study we have used EPR spectroscopy in conjunction with the spin-trapping technique to determine whether PSH and its metabolic or photochemical oxidation products generate highly reactive free radicals upon UV irradiation. When an aqueous anaerobic solution (pH 5 or 9) of PSH (pK₂= 7.7) and either 2-methyl-2-nitrosopropane (MNP) or nitromethane (NM) were irradiated (λ > 300 nm) with a Xe arc lamp, the corresponding purin-6-thiyl (PS^.) radical adduct and the reduced form of the spin trap (MNPIH’or CH₃N0₂) were observed. However, no radical adducts were detected when PSH and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were irradiated (λ= 320 nrn) in oxygen-free buffer. These findings suggest that PSH does not photoionize but that instead MNP and NM are reduced by direct electron transfer from excited state PSH, ^1,3(PSH)*. In aerobic solution, oxygen can act as an electron acceptor and the O₂*- and PS radicals are formed and trapped by DMPO. 6-Mercaptopurine did photoionize when irradiated with a Nd:YAG laser at 355 nm as evidenced by the appearance of the DMPO/H (e_eq+ H⁺) adduct, which decreased in intensity in the presence of N₂O. ^1,3(6-Mercap-topurine)* oxidized ascorbate, formate and reduced glutathione to the corresponding ascorbyl, CO₂.- or glutathiyl radicals. The photochemical behavior of 6-thioxanthine and 6-thiouric acid was similar to PSH. However, the excited states of these metabolic oxidation products exhibited stronger reducing properties than ^1,3(PSH)*. Photolysis of PSH photoproducts purine-6-sulfonate or purine-6-sulfinate resulted in homolysis of the C-S bond and the appearance of the SO₃′- and SO₂^?_-- radicals, respectively, which were detected by direct EPR. These studies demonstrate that UV irradiation of PSH, its photoproducts and metabolites generates a variety of free radicals that may be involved in the etiology of skin cancer induced by azathioprine.     

Single‐Line EPR Spectra from Radicals Encapsulated in Aggregates of Amphiphilic Block Copolymers with Hydrophobic Dendritic Pendants in Water

Summary: A water‐insoluble organic 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical is solubilized in aqueous solutions of aggregates of amphiphilic block copolymers with hydrophobic dendritic pendants. The number (100–200) of DPPH molecules solubilized in an aggregate, which is evaluated from UV‐visible absorption spectra, is in agreement with that of the DPPH radicals determined from electron paramagnetic resonance (EPR) spectroscopy. The DPPH radicals are stably solubilized without decomposition in the polymer aggregates. The radicals exhibit a single‐line EPR absorption, which is narrowed by the interspin interaction, and indicates the assembly formation of DPPH radicals in polymer aggregates. These results suggest the effective utilization of the DPPH radical as a spin‐probe indicator in aqueous solutions.

When DPPH is solubilized in aqueous solutions of NaAMPS‐b‐G2(n3), the polymer solutions become purple colored, which is characteristic of the DPPH radical.     

Structures,g-tensors,and hyperfine coupling constants of L-α-alanine radicals in radiation dosimetry: An ab initio molecular dynamics simulation study

Alanine is used as a transfer standard dosimeter for gamma ray and electron beam calibration. An important factor affecting its dosimetric response is humidity which can lead to errors in absorbed dose calculations. Ab initio molecular dynamics calculations were performed to determine the environmental effects on the electron paramagnetic resonance (EPR) parameters of L-α-alanine radicals in acidic and alkaline solutions. A new result, not dissimilar to the closed-shell amino acid molecule alanine, is that the non-zwitterionic form of the alanine radical is the stable form in the gas phase while the zwitterionic neutral alanine radical is not a stable structure in the gas phase. Geometric and EPR parameters of radicals in both gas and solution phases are found to be dependent on hydrogen bonding of water molecules with the polar groups and on dynamic solvation. Calculations on the optimized free radicals in the gas phase revealed that for the neutral radical, hydrogen bonding to water molecules drives a decrease in the magnitudes of g-tensor components g _xx and g _yy without affecting neither g _zz component nor the hyperfine coupling constants (HFCCs). The transfer from the gas to solution phase of the alanine radical anion is accompanied with an increase in the spin density on the carboxylic group's oxygen atoms. However, for the neutral radical, this transfer from gas to solution phase is accompanied with the decrease in the spin density on oxygen atoms. Calculated isotropic HFCCs and g-tensor of all radicals are in good agreement with experiment in both acidic and alkaline solutions.     

High performance liquid chromatography/electron spin resonance/mass spectrometry analyses of radicals formed in an anaerobic reaction of 9- (or 13-) hydroperoxide octadecadienoic acids with ferrous ions

The oxidation of linoleic acid yields isomeric acyl hydroperoxides. In order to clarify the relation between the lipid peroxide-derived radicals and the toxicity of the lipid peroxide, identification of the lipid-derived radicals is essential. In this paper, high performance liquid chromatography/electron spin resonance/mass spectrometry (HPLC/EPR/MS) analysis of the radicals was performed for the reaction mixture containing 9-hydroperoxy-(10E,12E)-octadeca-10,12-dienoic acid (9EE-OOH) [or 13-hydroperoxy-(9Z,11E)-octadeca-9,11-dienoic acid (13ZE-OOH)] under an aerobic condition or an anaerobic condition. Following radicals were identified from 9EE-OOH (or 13EZ-OOH) by using high performance liquid chromatography/electron spin resonance spectrometry (HPLC/EPR) and HPLC/EPR/MS: pentyl radical and isomers of epoxylinoleic acid radicals from 13EZ-OOH under an anaerobic condition; 7-carboxyheptyl radical and pentyl radical from 13EZ-OOH under an aerobic condition; 7-carboxyheptyl radical and pentyl radical from 9EE-OOH under an aerobic condition; 7-carboxyheptyl radical from 9EE-OOH under an anaerobic condition. These results showed that the formation of the respective radical species depends on oxygen concentration in the reaction mixtures to a great extent.     

Anodic oxidation of selenadiazoloquinolones in alkaline media

Newly synthesized derivatives of 6-oxo-6,9-dihydro[1,2,5]selenadiazolo[3,4-h]quinoline variously substituted at position 7 (R = H, COOH, COCH(3), CN, COOC(2)H(5) and COOCH(3)) are established in strongly alkaline aqueous solutions (0.1 M NaOH; pH ～ 13) as N(9)-deprotonated structures, but in less alkaline solutions (0.001 M NaOH; pH ～ 11) the N(9)-protonated oxo tautomeric forms dominate. Upon their anodic oxidation in alkaline solutions, the selenadiazole ring is replaced, forming instead the paramagnetic species analogous to the ortho semiquinone radical anions as monitored by in situ EPR spectroscopy. The quantum chemical calculations for two representative selenadiazoloquinolones (R = H and COOH) and their anodic oxidation products presented are in agreement with experiments.     

The oxidation and thermal transformations of macrooradicals in gamma irradiated cellulose

The secondary reactions of the oxidation and thermal transformations of gamma irradiated (at 77 K) and plasticized (with water) cellulose radicals were studied by 3 cm-and 2 mm-band EPR spectroscopy. The radiolysis of cotton cellulose was found to produce the H-C*=O formyl radical, and heating the irradiated samples to 190–200 K resulted in the formation of the ROO* peroxide radical. The EPR spectra of microcrystalline cellulose recorded at room temperature contained an individual triplet (α _β ^H = 2.5–2.7 mT) with an additional quadruplet structure (splitting 0.5–0.7 mT) from three γ-hydrogens. This triplet was interpreted as a signal of the primary radical at C4. The main direction of thermal transformations of primary radicals was synchronous reactions of the dehydration of the polycarbohydrate complex accompanied by the dissociation of the C-H, C-OH, and C-C bonds and elimination of H₂O, H₂, CO, and CO₂ with successive formation of allyl and then polyene radicals, which were a source of the growth of polyconjugated systems in macromolecules.     

EPR studies on H-abstractions/spin-trapping reactions of new 'magic blue' reagents with alcohols

The H-abstractions/spin-trapping reactions with primary, secondary and tertiary alcohols of new 'magic blue' reagents, namely, the blue F113 (CClF₂CCl₂F) solution containing bis{perfluoro[1-(2-fluorosulfonyl)ethoxy]ethyl} nitroxide (2) and perfluoro[1-nitroso-1-(2-fluorosulfonyl)ethoxy]ethane (3) both generated in the reaction of perfluoro[2-(2-fluorosulfonyl)ethoxy]propionyl peroxide (1) with sodium nitrite in F113 at room temperature, were studied by EPR. Based on the interpretation of the EPR spectra of the spin adducts, nitroxides, the region-selectivity of H-abstraction has been disclosed and the possible mechanistic paths of H-abstraction have also been discussed. EPR of H-abstraction by using 'magic blue' reagents can also be used for producing various hydroxyalkyl radicals from common alcohols.     

EPR analysis of the interacting properties and the degradation over time and irradiation of mastic resin used for painting protection

Mastic resin used as a covering film for painting protection was analyzed by electron paramagnetic resonance (EPR) spectroscopy, both as received and upon aging in sun-light. The effect of prolonged exposure to sun-light was mimicked by UV and, more so, by xenon lamp irradiation. Solid mastic presented EPR signals due to radicals trapped by PBN in solution. Data in the literature indicated the formation of acyl radicals (RCO·). These radicals preferentially dissolved in medium polarity solvents. The radical concentration in the solid mastic increased over time more than 50 times upon UV irradiation for 96 h and, even more, by xenon irradiation for 800 h. Also the PBN-trapped radicals in solution increased in concentration by irradiation. Small nitroxide radicals (TEMPO) interacted with a polar fraction of mastic dissolved in methanol, but mainly interacted with low polar mastic molecules in hydrophobic solvents. It was suggested, on the basis of both the PBN-spin trapping data and the TEMPO mobility variation in the solvents at different polarities, that terpenoid molecules partially polymerize by a radical mechanism to form low molecular weight products. A polyaromatic-radical (pyrene-TEMPO) and a biomolecule-radical (doxylcholestane) both interact weakly with mastic molecules in cyclohexane solutions. A positively charged surfactant radical (dimethylammonium-TEMPO bromide) was easily adsorbed onto the solid mastic surface suggesting that detergents are responsible for mastic degradation. In conclusion, this study provided information on the degradation mechanism of mastic resin and on its interacting ability towards external molecules and pollutants.     

Nitroxide Radicals of some N-Phenyl Substituted 1,4- and 1,2-Phenylenediamines

Summary.  Several N-phenyl substituted 1,4- and 1,2-phenylenediamines were oxidized using radicals and 3-chloroperbenzoic acid. EPR spectroscopy confirmed the generation of nitroxide radicals originating from the oxidation of the bridging -NH-group. No radical products suggesting the simultaneous reaction with the NH₂-group were observed. Only in the case of 1,4-phenylenediamine, a low concentration of nitroxide radical H–NO–C₆H₄–NH₂ was obtained. In o-aminodiphenylnitroxide the steric effect of the NH₂-group causes a partially asymmetrical spin density distribution in both phenyl rings. Corresponding author. E-mail: omelka@fch.vutbr.cz Received September 30, 2002; accepted October 4, 2002     

Imino- and bis-imino-pyridines with N-ter-butyl-N-aminoxyl group: synthesis, oxidation and use as ligand towards M ( Mn, Ni, Zn) and Gd

Imino- and bis-iminopyridine ligands bearing N-ter-butylhydroxy groups were synthesized by the condensation reaction between a N-ter-butylhydroxy substituted aniline and 2-formylpyridine, 2-acetylpyridine and 2,6-bis-acetylpyridine. The N-ter-butylaminoxy radicals obtained after oxidation using PbO₂ or Ag₂O were studied by EPR spectroscopy in solution. Indeed, complete decomposition was observed during isolation of these radical derivatives. The N-ter-butylhydroxy substituted ligands obtained were complexed with Mn²⁺, Ni²⁺, Zn²⁺ and Gd³⁺ salts; the obtained complexes were characterized and oxidized to give the aminoxy analogs, which were studied using IR, UV and EPR spectroscopies.     

Formation of a promazine radical and promazine 5‐oxide in the reaction of promazine with hydrogen peroxide: Mechanistic insight from kinetic and EPR measurements

The kinetics of the oxidation of promazine (PMZ) by hydrogen peroxide was studied in the presence of a large excess of H₂O₂ in acidic chloride media using UV–vis spectroscopy. The reaction proceeds via two consecutive steps. In the first step, oxidation leads to formation of a promazine radical. In the second step, the promazine radical is oxidized to promazine 5‐oxide. Electron paramagnetic resonance spectroscopy (EPR) results provide clear evidence for the formation of an intermediate promazine radical. Linear dependences of the pseudo‐first‐order rate constants (k₁ and k₂) on [H₂O₂] with a nonzero intercept were established for the first and the second process, respectively. The rate of the first stage of the reaction increased slightly with increasing concentration of O₂, indicating the role of the OH^? radicals on the redox process, which are transformed into the Cl radicals. The mechanism of the overall reaction is discussed on the basis of all these kinetic measurements. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 42: 1–9, 2010     

The effect of 1,3-diphenylisobenzofuran on the photo-oxidative degradation of cis-1,4-polybutadiene

1,3-Diphenylisobenzofuran (DPBF) is easily photo-oxidized by two mechanisms viz free radical oxidation and singlet oxygen oxidation. The final products of DPBF oxidation by these two mechanisms are the same. Using light in the range 280–480 nm, DPBF is an effective sensitizer of photooxidative degradation of polybutadiene in the solid and in solution. In a system with methylene blue (MB) in methanol-benzene solution (0.5:9.5) where free radicals from MB and ¹O₂ are formed during irradiation with visible light, DPBF is oxidized by both ¹O₂ and free radical mechanisms. DPBF cannot stop free radical degradation of PB initiated by MB radicals in MB-methanol-benzene solution. These results show that the DPBF is an ineffective stabilizer for polydienes against ¹O₂ and free radical oxidation. It rather acts as a sensitizer for photo-oxidation of polydienes.     

Characterization of titanium dioxide photoactivity following the formation of radicals by EPR spectroscopy

In order to find ways to characterize oxygen-saturated aqueous TiO₂ suspensions, the formation of photo-induced free radicals was followed by EPR spectroscopy, using as indicators N-oxide and nitrone spin trapping agents, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), 3,3,5,5-tetramethyl-1-pyrroline N-oxide (TMPO), α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POB N), 4-(N-methylpyridyl)-N-tert-butylnitrone (MePyBN), as well as semi-stable free radicals, 4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl (TEMPOL), cation radical of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), diammonium salt (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH). DMPO and TMPO are efficiently oxidized to the EPR-silent products via radical in termediates. Conversely, the nitrone spin traps (POBN and MePyBN) showed selective formation of hydroxyl radical spin adducts upon continuous irradiation of oxygenated TiO₂ suspensions. Their concentrations increased proportionally with the amount of photocatalyst and irradiation time. The EPR spectrum of the semi-stable free radicals TEMPOL, ABTS^·+ or DPPH is gradually eliminated during irradiation, and this system represents a simple technique for the evaluation of TiO₂ activity.     

EPR spectra and structure of the chlorotrifluoroethylene and bromotrifluoroethylene radical anions

EPR spectra attributable to the halogenotrifluoroethylene radical anions have been generated by electron attachment in solid solutions at low temperatures. The spin density distribution in these radicals strongly suggests that the unpaired electron occupies a σ^* orbital, a conclusion which is supported by CNDO/2 calculations.     

On the nature of radicals formed in methanol catalytic oxidation

The quantum-chemical calculations of the hydroxymethyl radical •CH₂OH were performed for the first time and a theoretical EPR spectrum of this radical was constructed. The formation of the hydroxymethyl radical in the reaction of methanol oxidation is thermodynamically favorable. The shape and parameters of the constructed spectrum differed from those for radicals experimentally detected in the catalytic oxidation of methanol using the matrix isolation method. However, they are consistent with the spectrum ascribed to the EPR spectrum of •CH₂OH observed in the direct photolysis of methanol. This result allows one to refine the identification of the nature of radicals formed in the catalytic reaction of methanol oxidation.     

Radical anions of nitrobenzothiazoles: EPR study of conjugative properties of benzothiazolyl systems

The electrochemical reduction in DMSO of the five isomers of nitrobenzothiazole (NBTZ) gave quite persistent radical anions that could be easily characterised by EPR spectroscopy. By contrast, the chemical reduction in alkaline solution, that is by t-BuOK in DMSO or by glucose and MeOK in MeOH, presented some problems with 6- and 4-NBTZ, and in the case of 2-NBTZ did not provide any detectable paramagnetic species. The internal consistency of coupling constants of the nitrobenzothiazole radical anions is in good agreement with the conjugative properties of the various benzothiazolyl systems and allows rectifying a recent EPR characterisation of 6-NBTZ radical anion.