Stable Nitroxyl Radicals Research Articles

Discovery and Exploitation of AZADO: The Highly Active Catalyst for Alcohol Oxidation

The oxidation of primary and secondary alcohols to the corresponding aldehydes (or carboxylic acids) or ketones is a fundamental transformation in organic synthesis. Stable organic nitroxyl radicals as represented by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (1) have been used extensively to catalyze the oxidation of a number of alcohol substrates employing environmentally benign co-oxidants such as bleach (NaOCl) or PhI(OAc)2. Although TEMPO oxidation is better known as a method for selective oxidation of primary alcohols to the corresponding aldehydes, the TEMPO-based method is not very efficient for the oxidation of structurally hindered secondary alcohols. We designed and synthesized 2-azaadamantane N-oxyl [AZADO (11)] and 1-Me-AZADO (20), a structurally less hindered class of nitroxyl radical. AZADOs were found to exhibit excellent catalytic activity enabling oxidation of a variety of alcohols with which TEMPO exhibits poor reactivity. Based on structure-activity relationships (SAR) employing AZADO (11), 1-Me-AZADO (20), 1,3-dimethyl-AZADO (33), 9-azabicyclo[3.3.1]nonane-N-oxyl [ABNO (34)] and 9-azanoradamantane N-oxyl [Nor-AZADO (37)], we concluded that the α-methyl group flanked nearby the nitroxyl group affects the reactivity for the oxidation of sterically hindered alcohols and the azaadamantane skeleton contributes to the high turnover of the catalyst. The highly active nature of AZADOs spurred us to exploit their further use in alcohol oxidations. A facile, green, one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability has been developed by employing an expedient catalytic system consisting of the oxoammonium salt [1-Me-AZADO(+)X(-) (X=Cl, BF4)]/NaClO2. The synthetic use of AZADOs and the related nitroxyl radicals/oxoammonium salts-based methods for alcohol oxidation have been demonstrated in several total syntheses of natural products. We also describe the development of a Nor-AZADO (37)/DIAD/AcOH method that offers exceptionally mild and highly chemoselective oxidation of alcohols.

The kinetics and mechanism of reactions of aliphatic stable nitroxyl radicals with alkyl and peroxide radicals during styrene oxidation

A kinetic study (EPR, microvolumometry), quantum-chemical analysis (DFT B3LYP/6-31G*), and kinetic simulation of the antioxidant activity of aliphatic stable nitroxyl radicals during styrene oxidation was performed. The key reactions constituting the detailed mechanism of the process were analyzed. It was shown that the inhibiting action of nitroxyl radicals was caused by their reaction not only with alkyl radicals but also with substrate peroxy radicals, which resulted in the regeneration of nitroxyl radicals in chain-termination steps.

Use of Electron Paramagnetic Resonance Spectroscopy to Study Dielectric Properties of Liquids

The signal response of an EPR active species is attenuated by the medium it is in. Keeping all other parameters the same, the higher the dielectric constant of the medium, the lower the EPR signal response. This behavior is problematic in studying EPR active species in high dielectric media but can be capitalized upon to monitor changes in the dielectric constant or estimate the dielectric constant of the medium. Using a coaxial EPR cell design, the EPR signal of a stable nitroxyl radical compound (2,2,6,6-tetramethyl-piperidin-1-oxyl radical) in a low dielectric constant solvent in an inner tube is attenuated by the solvent present between the inner and outer tubes (jacket medium). The attenuation increases monotonically with an increase in the dielectric constant of the jacket medium. Calibration curves can be constructed using jacket media of known dielectric constants ranging from 2 to 80 and the dielectric constant of a sample used as the jacket medium can be estimated by interpolation. This technique is applied to estimate the dielectric constants and/or composition of mixed solvents and to monitor the rate of a reaction.

Antioxidant properties of the pollen exine polymer matrix

The antioxidant properties of exine polymer matrix which forms the outer layer of pollen grain wall were studied. The main component of this matrix is sporopollenin - a unique biopolymer resistant to mechanical and chemical damage. The samples of isolated exine, purified from soluble compounds, were studied with EPR using stable nitroxyl radical TEMPO and DMPO spin trap. At the same time, we analyzed changes in fluorescence of DCFH which detected ROS in the solution. It has been established that exine effectively reduces TEMPO radical and eliminates hydroxyl radical. Also, the fluorometric analysis demonstrated that the exine eliminated H2O2, and this ability significantly decreased after treatment of exine with feruloyl esterase or mild alkaline hydrolysis (1M NaOH), i.e. after hydrolysis of hydroxycinnamic acid esters. After harsh hydrolysis (4M NaOH, 170 degrees C) of ethers bonds a large amount of hydroxycinnamic acids has been released, and exines have lost their antioxidant capacity almost completely. The obtained results point to the ability of extracellular polymer matrix of the exine to eliminate free radicals and H2O2 during crucial periods of male gametophyte development. The participation of ferulic acid and, possibly, of other hydroxycinnamic acids of sporopollenin in these processes has been demonstrated.

Reaction of several resveratrol glycoside derivatives with hypochlorites in various media

The reactions of pterostilbenoside (trans-3,5-dimethoxystilben-4′-O-β-D-glucoside) and Ar–O–Tr derivatives of resveratroloside (3,5-dihydroxystilben-4′-O-β-D-glucoside) and pinostilbenoside (3-methoxy-5-hydroxystilben-4′-O-β-D-glucoside) with NaOCl and t-BuOCl in the presence of the stable nitroxyl radical TEMPO were studied in various media. It was found that the principal product of pterostilbenoside transformation was its 2,6-dichloroderivative, a part of which was oxidized to form 2,6-dichloropterostilbene glucuronide. Trityl ethers of resveratroloside and pinostilbenoside reacted with the hypochlorites to form mixtures of products.

Structure and properties of tempo-oxidized cotton fibers

In this paper, the influence of the catalytic oxidation using water soluble and stable nitroxyl radical 2,2?,6,6?-tetramethylpiperidine-1-oxyl (TEMPO) on structure and properties of cotton fibers was studied. In particular, the selective TEMPO-mediated oxidation has become very interesting way for introduction of functional groups into cellulose fibers with the aim to obtain oxycellulose fibers with specific properties. Unmodified and modified fibers were characterized in terms of weight loss values, introduced functional groups and crystallinity index. Also, oxidized fibers were characterized in terms of the sorption, morphological, and physico-mechanical properties. The TEMPO-oxidized cotton fibers show a minimum increase of fineness (from 1.32 to 1.28 dtex) and increase of crystallinity index (up to 91.9%), while the tensile strength of fibers decreases (up to 10.82 cN/tex). By the TEMPO-mediated oxidation of cotton fibers significant amount of carboxyl groups (up to 0.795 mmol/g cell) can be introduced into cellulose fibers. Introduced hydrophilic carboxyl groups increases the sorption properties of oxidized fibers, that can be used directly or for further chemical modification.

The origin of the radiobiological damage in cells stored in cryostatic conditions

The radiation induced free radical damage in Chinese hamster lung fibroblast V-79 cells stored in DMEM culture medium containing 10% DMSO has been investigated by matrix EPR spectroscopy in connection with the H2O/DMSO binary phase diagram. A major part of the indirect effect is due to radicals from the DMSO·3H2O phase in the freezing medium, which are released on warming in the temperature range between 130K and 160K, that is, far below the eutectic melting temperature (210K). The radicals trapped in the DMSO·3H2O phase react with oxygen above 160K giving reactive oxygen species (ROS) of the type of peroxyl radicals. A lower limit yield of 10–15% was calculated for this conversion. Scavenging experiments with a stable nitroxyl radical (tempol) have demonstrated that part of the DMSO·3H2O radicals escape by mutual recombination on melting and are therefore available for inducing indirect cell damage. The same experiments performed with pure frozen water have shown that OH radicals are not available for inducing cell damage. The EPR measurements performed on H2O/DMSO frozen mixtures suggest that the radiation induced radical forming process does not change when passing to the low dose range below 1Gy, in agreement with the linear model.

XPS spectra of free nitroxyl radicals and their electronic structure

The N(1s) and O(1s) XPS spectra of stable nitroxyl radicals and molecules with a related heterocycle structure: 4,4,5,5-tetramethyl-2-phenyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl, 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl, 4,4,5,5-tetramethyl-2-(2-hydroxyphenyl)-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl, 4,4,5,5-tetramethyl-2-(2-hydroxy-3-nitrophenyl)-4,5-dihydro-1Himidazole-3-oxide-1-oxyl, and 4,4,5,5-tetramethyl-2-phenyl-4,5-dihydro-1H-imidazole-3-oxide were studied. The possibility to apply X-ray electron spectra for investigation of the charge electron and spin density distribution on free radical atoms and at their coordination by a metal is considered.

Electrochemical Characterization of Stable Nitroxyl Radical, Intermediaries in the Synthesis of 3-Methacryloylamin-PROXYL

Nitroxyl radicals have suited into materials used as anodes in lithium secondary batteries due to their stability and reversibility during the redox process. In the literature there is a wide range of such compounds, where changes in the size of the molecule and the substituent, provide variation of the redox E°. This paper presents the electrochemical characterization of three compounds obtained during the synthesis of 3-methacryloylamin-PROXYL, 4-oxo-TEMPO (2), 3-bromo-4-oxo-TEMPO (4) and 3-carbamoyl-PROXYL (5). Cyclic voltammetry and direct and double pulse chronoamperometry were used, with a glassy carbon electrode in a 0.1M Bu4NPF6 solution in acetonitrile. The oxidation of these radicals is a quasireversible process in which the species involved are stable. The E1/2 and diffusion coefficients (D) for the three free radical species were evaluated.

Electrochemical oxidation of 1-chloro(bromo)-2,2,6,6-tetramethylpiperidines

Electrochemical oxidation of 1-haloamines of the 2,2,6,6-tetramethylpiperidine series results in the formation of relatively stable radical-cations, detected by the methods of cyclic voltammetry and ESR spectroscopy. The final products of electrochemical oxidation of these haloamines are stable nitroxyl radicals.

Spin statistical factor in the reactions of excess electron scavenging by stable nitroxyl radicals

Spin statistical factor in the reactions of excess electron scavenging by stable nitroxyl radicals

The photolysis in polymer matrices of dyes containing a benzothioxanthene chromophore linked with a hindered amine

Novel dyes based on a benzothioxantheneimide chromophore covalently linked with a sterically hindered amine (HAS) were prepared and their light stability was tested in polymer matrices. The following dyes: 2-(2,2,6,6-tetramethyl-4-piperidyl)-thioxantheno[2,1,9-dej]isoquinoline-1,3-dione (BTXINH) and N-alkoxy derivative 2-(1-(1′-phenylethoxy)-2,2,6,6-tetramethyl-4-piperidyl)-thioxantheno[2,1,9-dej] isoquinoline-1,3-dione (BTXINOR) were prepared. For comparison the parent dye without HAS structural unit benzothioxanthene-3,4-dicarboxylic anhydride and the N-alkyl derivative 2-(1-dodecyl)-thioxantheno[2,1,9-dej]isoquinoline-1,3-dione (BTXID) and the stable nitroxyl radical 2-(1-oxo-2,2,6,6-tetramethyl-4-piperidyl)-thioxantheno[2,1,9-dej]isoquinoline-1,3-dione (BTXINO) were also tested. Their spectral properties, absorption and fluorescence have been examined in polystyrene (PS), poly(methyl methacrylate) (PMMA), poly(vinyl chloride) (PVC) and in isotactic polypropylene (PP). The light stability of these dyes and model compounds were examined in thin polymer films. The photolysis rate was monitored by UV spectroscopy and for all additives under study it was in the range 10 −4–10 −3 h −1. The rate of decomposition was the lowest for the parent amine BTXINH in PMMA, PS and PVC. The rate constants of photolysis are about 10 times higher for all adducts and the lowest rate of decomposition in PP matrix was observed for BTXINOR. A distinct stabilization effect of HAS structural unit on the dye decomposition was not observed. The light stability of the dyes was more influenced by the selection of the polymer. The photolysis proceeds rather fast in PP, and moderately in PS and PVC compared to PMMA.

Asymmetric Synthesis of the Bioprotective Agent JP4-039

JP4-039 is a stable nitroxyl radical that is capable of crossing lipid bilayer membranes and scavenging reactive oxygen species, such as the superoxide radical anion. It concentrates in the mitochondria where it inhibits hydro­peroxidation of the lipid cardiolipin. JP4-039 is ­being developed for the amelioration of radiation damage. The enantiomer of JP4-039 and five ­analogues were also prepared.

Structure and characteristics of chitosan cobalt-containing hybrid systems, the catalysts of olefine oxidation

Cobalt-containing hybrid organo-inorganic materials based on the chitosan-SiO2, chitosan-Al2O3, and chitosan-cellulose systems were obtained. The surface structure and processes that occur during the formation of metal-containing materials, the catalytic properties of which were studied in the oxidation reactions of alkene, were investigated by EPR spectroscopy using a stable pH-sensitive nitroxyl radical, 4-dimethylamino-2-ethyl-5,5-dimethyl-2-(pyridin-4-yl)-2,5-dihydro-1H-imidazole-1-oxyl, as the adsorbed probe molecules.

Investigation of the structure of chitosan hybrid systems by pH-sensitive nitroxyl radical

Hybrid organo-inorganic materials based on the chitosan-SiO2, chitosan-Al2O3, and chitosancellulose systems are prepared. The structure of the surface is studied by means of EPR spectroscopy using the stable pH-sensitive nitroxyl radical, 4-dimethylamino-2-ethyl-5,5-dimethyl-2-pyridine-4-yl-2,5-dihydro-1H-imidazole-1-oxyl as adsorbed probe molecules, and the processes that occur during the formation of hybrid materials are considered.

Nitroxides: Versatile Reporters and Reactants

Stable nitroxyl radicals are important tools in chemistry, biophysics, biology, and materials science. Their stability and the sensitivity of their EPR spectra to the local environment make them valuable molecular probes. This review seeks to give an overview of the developments in the field of nitroxide spin probes and their various applications, with the main focus on the pH-sensitive imidazoline nitroxide family.

Modification of the structure of plasmatic membranes of the liver by the action of α-tocopherol in vitro

The effect of the natural antioxidant alpha-tocopherol in a broad concentration range (10(-4) - 10(-25) M) on the viscosity characteristics and thermally induced structural transitions of a lipid bilayer of plasma membranes of murine hepatocytes in vitro has been studied. Changes in the rigidity of surface (approximately Abb) of the lipid bilayer were measured on a Bruker EMX EPR spectrometer (Germany) by the method of spin probes. Stable nitroxyl radicals of 5- and 16-doxylstearic acid, localized at different depth in the membrane served as spin probes. It was shown that the concentration dependence of the effect of alpha-tocopherol is linear and polymodal with three statistically significant increases in three ranges of its concentration: (1) in the range of traditional physiological concentrations 10(-4)-10(-9) M, (2) in the range of superlow doses 10(-9) - 10(-17) M, and (3) in the range of "imaginary" concentrations 10(-17) - 10(-25) M. The mechanisms of action of alpha-tocopherol in each of the three ranges are discussed. When studying the temperature dependences of viscous characteristics, a new thermally induced structural transition in the range of "physiological" temperatures 309-313 K for those alpha-tocopherol concentrations (including superlow ones) to which the maxima on the dose dependence curves at constant temperature of 293 K corresponded.

9-Azanoradamantane N-Oxyl (Nor-AZADO): A Highly Active Organocatalyst for Alcohol Oxidation

A highly active organocatalyst for alcohol oxidation has been developed. 9-Azanoradamantane N-oxyl (Nor-AZADO 4), constituting an unhindered, stable nitroxyl radical, exhibits superior catalytic activity to 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and AZADOs in the oxidation of alcohols to their corresponding carbonyl compounds.

Synthesis of amphiphilic block copolymers bearing stable nitroxyl radicals

AbstractWe present here the synthesis of two kinds of amphiphilic block copolymers, a diblock copolymer MPEG‐b‐PTAm and a triblock copolymer MPEG‐b‐PLA‐b‐PTAm, which can self‐assemble into micelles with nitroxyl radicals‐containing PTAm segment in the core. The structure of the block copolymers was characterized by 1H NMR and GPC. Dynamic laser light scattering and transmission electron microscopy were used to study the micellar behavior of the two block copolymers in aqueous solution. The micelles carrying nitroxyl radicals in the core can generate electron paramagnetic resonance, which is stable for a period of time up to 8 min even in the presence of reducing reagent such as ascorbic acid. The enhanced stability against the reducing agent was ascribed to the inaccessibility of the nitroxyl radical core placed in the interior of the micelles. Combined with the biocompatibility, these micelles were promising to be used as the EPR probes for bioimaging in vivo. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010

ChemInform Abstract: Intramolecular Quenching of Excited Singlet States by Stable Nitroxyl Radicals.

Absorbance and steady-state and time-resolved fluorescence measurements were employed to examine the mechanism(s) of excited singlet state quenching by nitroxides in a series of nitroxide-fluorophore adducts. This work establishes the following: (1) the absorption and emission energies of the fluorophores are unaffected by the presence of the nitroxide substituent(s), and the residual emission that is observed from the adducts arises from the locally excited singlet of the fluorophore, not from charge recombination; (2) rate constants for intramolecular quenching by the nitroxides (k{sub q}) are high (10{sup 8}-10{sup 10} s{sup {minus}1}) and decrease significantly with increasing nitroxide to fluorophore distance-however, relatively high rates of quenching (>10{sup 8} s{sup {minus}1}) are observed over distances as great as 12 {angstrom}; (3) Foerster energy transfer does not contribute significantly to the quenching due to the low values for the spectral overlap integrals; (4) the K{sub q}'s do not increase proportionally to the solvent-dependent increases in the Dexter overlap integral, indicating that energy transfer by the Dexter mechanism is not responsible for the quenching; (5) the values of k{sub q} show no obvious correlation with the calculated free energies for photoinduced electron transfer, suggesting that this quenching pathway is also unimportant; (6) for hematoporphyrin-nitroxide adducts,more » which contain a fluorophore whose singlet energy is below that of the first excited state energy of the nitroxide (thus precluding energy transfer), significant rates of quenching are still observed.« less