Profluorescent nitroxides: Sensors and stabilizers of radical-mediated oxidative damage

In this study, three profluorescent nitroxides 1,1,3,3-tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO), 1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalene-2-yloxyl (TMAO) and 5-[2-(4-methoxycarbonyl-phenyl)-ethenyl]1,1,3,3-tetramethylisoindoline-2-yloxyl (MeCSTMIO) were tested as probes for radical-mediated damage in polypropylene arising from both UV and thermally initiated sources. These nitroxides possess a very low fluorescence quantum yield due to quenching by the nitroxide group; however, when the free-radical moiety is removed by reaction with alkyl radicals (to give an alkoxyamine), strong fluorescence is observed. The results obtained from this profluorescent nitroxide trapping technique compare favourably with other methods of monitoring degradation, provided the appropriate probe is chosen for the conditions of oxidation, signalling an indication of damage well before other techniques show any response. The technique was also applied to the monitoring of crosslinked polyester coating resins. Differentiation in the oxidative stability of the resins was evident after as little as 200 min where other monitoring techniques require up to 300 h of accelerated degradation. This highlights the sensitivity of this method as well as demonstrating the scope of this technique to assess polymer stability.     

In situ nitroxide‐mediated polymerization of styrene promoted by the N‐tert‐butyl‐α‐isopropylnitrone/bpo pair: ESR investigations

The styrene polymerization initiated by benzoyl peroxide (BPO) in the presence of N‐tert‐butyl‐α‐isopropylnitrone as nitroxide precursor is well‐controlled provided that a prereaction between the nitrone and BPO is carried out in suitable conditions prior to polymerization at a higher temperature. Electron spin resonance (ESR) spectroscopy was implemented to probe the nitroxides formed during both steps, that is, the prereaction and polymerization, and to get crucial information regarding the structure of the nitroxides responsible for the polymerization control. ESR studies combined with first principles calculations have evidenced that nitroxides observed during the prereaction in the presence of styrene and during the polymerization steps consist of a mixture of two macronitroxides. One is formed by the addition of a growing polystyrene chain to the nitrone as would be expected. However, the second one results from the addition of a polystyrene chain to tert‐butyl nitroso that is in situ formed presumably by decomposition of the first macronitroxide type. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

N‐(2‐Hydroxypropyl)methacrylamide (HPMA) Copolymer‐Linked Nitroxides: Potential Magnetic Resonance Contrast Agents

N‐(2‐Hydroxypropyl)methacrylamide (HPMA) copolymer‐linked nitroxides were synthesized as macromolecular contrast agents for MR imaging. Molar relaxivities of HPMA copolymer‐linked nitroxides increased linearly in proportion to the number of nitroxides attached per gram of copolymer. HPMA copolymer‐linked nitroxides with 15, 20 and 30 mol‐% nitroxide exhibited higher relaxivities than gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA). These results demonstrate the potential of HPMA copolymer‐linked nitroxides as MR contrast agents for solid tumors.

Structure of HPMA copolymer‐linked nitroxides.     

Stable Bicyclic Functionalized Nitroxides: The Synthesis of Derivatives of Aza-nortropinone–5-Methyl-3-oxo-6,8-diazabicyclo[3.2.1]-6-octene 8-oxyls

In recent decades, bicyclic nitroxyl radicals have caught chemists’ attention as selective catalysts for the oxidation of alcohols and amines and as additives and mediators in directed C-H oxidative transformations. In this regard, the design and development of synthetic approaches to new functional bicyclic nitroxides is a relevant and important issue. It has been reported that imidazo[1,2-b]isoxazoles formed during the condensation of acetylacetone with 2-hydroxyaminooximes having a secondary hydroxyamino group are recyclized under mild basic catalyzed conditions to 8-hydroxy-5-methyl-3-oxo-6,8-diazabicyclo[3.2.1]-6-octenes. The latter, containing a sterically hindered cyclic N-hydroxy group, upon oxidation with lead dioxide in acetone, virtually quantitatively form stable nitroxyl bicyclic radicals of a new class, which are derivatives of both 2,2,6,6-tetramethyl-4-oxopiperidine-1-oxyl (TEMPON) and 3-imidazolines.     

Fluorinated nitroxides as ESR probes of solvation

Some newly synthesized fluorinated nitroxides, such as t-butyl perfluoroalkyl nitroxides Bu^tN(O) R_f (R_f=CF₃, 5; C₂F₅, 6; n-C₃F₇, 7) and s-butyl perfluoroacyl nitroxides Bu^sN(O) COR_f (R_f=CF₃, 9; n-C₃F₇, 10) have been employed as ESR probes of solvation in different common organic solvents. In aprotic solvents, the measured a_N values for each of the nitroxyl probes show a linear correlation with the cybotactic polar solvent parameters E_T (Dimroth) and Z (Kosowar), i.e. a_N=bE_T+c, and a_N=b′Z+c′. The physical significance for the slope (b or b′), the slope×E_T or slope×Z, the extrapolated intercept on a_N axis, c or c′, are linked, respectively, to the sensitivity of a specific nitroxide toward solvation, the magnitude of the overall solvation effect on the a_N value, and the intrinsic a_N value of each nitroxide in the ideal gaseous state. The intercept on the a_N axis may also serve as a new measure of electronegativity for perfluoroalkyl groups, CF₃, C₂F₅, n-C₃F₇, and perfluoroacyl groups, CF₃CO, n-C₃F₇CO. In protic solvents, i.e. alcohols and carboxylic acids, however, a_N values of all the probes, kept almost no change with the increase in E_T and Z. Furthermore, the plots of a_N versus non-cybotactic solvent constants, such as dipolar moment (μ) and dielectric constant (ε), all show random variations.     

EPR studies on H-abstraction from p-substituted benzaldehydes by new “Magic Blue” reagents and correlation analysis of aN values of ω-fluorosulfonylperfluoroalkyl p-substituted benzoyl nitroxides

New “Magic Blue” reagent, namely, the blue solution in F113 (CClF₂CCl₂F) containing H-abstracting agent bis[ω-fluorosulfonylperfluoroalkyl] nitroxide R_FN(O)R_F2 and ω-fluorosulfonylperfluoronitrosoalkane spin trap R_FNO 3 both generated in the reaction of ω-fluorosulfonylperfluorodiacyl peroxide [FO₂SCF₂CF₂OCF(CF₃)CF₂OCF(CF₃)COO]₂1 with sodium nitrite in F113 (CClF₂CCl₂F) at room temperature, reacted with a series of p-substituted benzaldehydes 4 via regio-selective abstraction of the formyl hydrogen followed by spin trapping of the acyl radical intermediate 5, thus led to the formation of stable spin adducts ω-fluorosulfonylperfluoroalkyl p-substituted benzoyl nitroxides 6. The correlation analyses of a_N values of nitroxides 6 with various substituent constants disclose that the polar effects are the major factors varying the spin density on the nitroxyl-nitrogen while the effect through spin-delocalization is felt slightly.     

EPR study of nitroxides formed from the reaction of nitric oxide with photolyzed amides

Free radicals generated from UV irradiation of simple aliphatic amides in anaerobic and nitric oxide (NO)‐saturated liquid mixtures or solutions gave EPR spectra of nitroxides. The application of isotopic effects to EPR spectra and the generation of radicals by transient radical attack on substrate molecules or by photolysing amine or acetoin were used to help identify photochemically produced radicals from the amides. The aliphatic amides used were formamide, acetamide and their N‐methyl‐ or deuterium‐substituted derivatives. Transient radicals used to attack the amides via hydrogen‐atom abstraction were generated from the initiator AIBN or AAPH. The observation of various nitroxides indicates the reactivity of NO for trapping acyl, carbamoyl and other carbon‐centered radicals. Possibly mechanistic pathways diagnosed with this trap are proposed. Copyright © 2003 John Wiley & Sons, Ltd.     

Profluorescent nitroxides: Thermo-oxidation sensors for stabilised polypropylene

The profluorescent nitroxide, 1,1,3,3-tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO) was investigated as a probe for the radical-mediated degradation of stabilised polypropylene. TMDBIO has been previously shown to be a sensitive probe for free-radical degradation during the thermo-oxidation of unstabilised polypropylene. Here we report on the effect that adding hindered phenol or phosphite stabilisers to polypropylene has on the free-radical sensing ability of TMDBIO during thermo-oxidation. In addition, novel dual-functional, hindered phenol containing profluorescent nitroxides, 5-[2-(4-hydroxy-3,5-di-tert-butylphenyl)ethenyl]-1,1,3,3-tetramethylisoindolin-2-yloxyl (HSTMIO) and its derivatives were investigated as probes for the radical-mediated degradation of polypropylene. These dual-functional probes were shown to be efficient stabilisers for polypropylene during thermo-oxidation at 150 °C in oxygen and sensors of thermo-oxidation during its early stages, in the so-called “induction period”.     

Two New Nitronyl Nitroxide Radicals and Their Complexes with M（hfac）2 [M=Co（II）, Ni（ll）, Mn（ll）]： Syntheses,Crystal Structures,and Magnetic Characterizations

Two new nitronyl nitroxides with amido units L1 and L2 were synthesized and characterized. Reactions of L1 and L2 with M（hfac）2 [hfac=hexafluoroacetylacetonate, M=Co（II）, Ni（II）, Mn（II）] afforded five hetero-spin complexes LiCo（hfac）2, LlNi（hfac）2, L2Co（hfac）2, L2Ni（hfac）2 and L2Mn（hfac）2. The crystal structures and magnetic characterizations of L1, L2 and their metal complexes LM（hfac）2 were described and discussed. Crystal structural analysis shows that both the carbonyl oxygen and the nitroxide oxygen are coordinated to the metal ions. Strong antiferromagetic coupling between the nitronyl nitroxides and metal ions were observed for all the five LM（hfac）2 complexes.     

1,3-Dipolar cycloaddition in the synthesis of pyrazolyl-substituted nitronyl nitroxides

A new approach to the synthesis of polyfunctional pyrazolyl-substituted nitronyl nitroxides was developed based on the presynthesized pyrazole derivatives prepared by 1,3-dipolar cycloaddition. The structures of the resulting mono-and biradicals were confirmed by X-ray diffraction. Dedicated to Academician A. L. Buchachenko on the occasion of his 70th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2105–2116, September, 2005.     

End‐group fidelity in nitroxide‐mediated living free‐radical polymerizations

In this study, new nitroxides based on the 2,2,5‐trimethyl‐4‐phenyl‐3‐azahexane‐3‐oxy skeleton were used to examine chain‐end control during the preparation of polystyrene and poly(t‐butyl acrylate) under living free‐radical conditions. Alkoxyamine‐based initiators with a chromophore attached to either the initiating fragment or the mediating nitroxide fragment were prepared, and the extent of the incorporation of the chromophores at either the initiating end or the propagating chain end was determined. In contrast to 2,2,6,6‐tetramethyl piperidinoxy (TEMPO), the incorporation of the initiating and terminating fragment into the polymer chain was extremely high. For both poly(t‐butyl acrylate) and polystyrene with molecular weights less than or equal to 70,000, incorporations at the initiating end of greater than 97% were observed. At the terminating chain end, incorporations of greater than 95% were obtained for molecular weights less than or equal to 50,000. The level of incorporation tended to decrease slightly at higher molecular weights because of the loss of the alkoxyamine propagating unit, which had important consequences for block copolymer formation. These results clearly show that these new α‐H nitroxides could control the polymerization of vinyl monomers such as styrene and t‐butyl acrylate to an extremely high degree, comparable to anionic and atom transfer radical polymerization procedures. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4749–4763, 2000     

Nitroxide decomposition: Implications toward nitroxide design for applications in living free‐radical polymerization

Nitroxides bearing an α‐hydrogen decompose upon heating in a bimolecular reaction. A new mechanism is proposed for the decomposition of t‐butylisopropylphenyl nitroxide (TIPNO) involving the formation of a head‐to‐tail dimer, single electron transfer to form an oxammonium salt, epimerization to the corresponding nitrone, and elimination to form a conjugated oxime. This mechanism may provide insights into designing new nitroxides for use in controlled polymerization. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 697–717, 2006     

C2-Symmetric nitroxides and their potential as enantioselective oxidants

The synthesis and evaluation of four C₂-symmetric nitroxides are presented. The nitroxides were evaluated for their ability to mediate the oxidation of several alcohols and found to have good catalytic activity. One enantioenriched nitroxide was found to kinetically resolve selected secondary alcohols with very modest selectivities.     

Nitroxide partitioning between styrene and water

Research into nitroxide‐mediated radical polymerization (NMRP) performed in emulsions and miniemulsions has progressed significantly over the past several years. However, our knowledge of the conditions during polymerization (e.g., the nitroxide concentrations in the aqueous and organic phases) is incomplete, and as such we have yet to achieve a clear understanding of the mechanisms involved in these processes. To better understand the conditions present in heterogeneous NMRP, we measured the partition coefficients of 2,2,6,6‐tetramethylpiperidinyl‐1‐oxy (TEMPO), 4‐hydroxy‐TEMPO, and 4‐amino‐TEMPO between styrene and water from 25 to 135 °C. Experiments were performed in a 250‐mL Parr reactor that was equipped for the simultaneous sampling of the aqueous and organic phases. Aqueous‐phase and organic‐phase nitroxide concentrations were measured with ultraviolet–visible spectrophotometry. Experiments were also performed at 135 °C in the presence of hexadecane (costabilizer), polystyrene, and sodium dodecylbenzenesulfonate (surfactant) to determine the effects of the miniemulsion polymerization recipe ingredients on the partitioning of TEMPO and 4‐hydroxy‐TEMPO. On the basis of the measured partition coefficients (expressed as the ratio of the nitroxide concentration in the organic phase to the nitroxide concentration in the aqueous phase), 4‐hydroxy‐TEMPO was the most hydrophilic of the nitroxides investigated, followed by 4‐amino‐TEMPO and TEMPO. Hexadecane, polystyrene, and sodium dodecylbenzenesulfonate did not have a significant influence on the partitioning of these nitroxides at 135 °C. Experiments with ethylbenzene instead of styrene demonstrated that thermally generated radicals were not responsible for the observed temperature effects on the measured partition coefficients. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1081–1089, 2001     

Synthesis of New Tetraethyl(N-alkyl-1-aminoethan-1,1-diyl)bisphosphona-tes and ESR Analysis of Chemical Exchange of Derived Nitroxides of Acyclic Aminobisphosphonates

The synthesis and the full characterization of two new linear bisphosphonates (tetraethyl(N-tert-butyl-1-aminoethan-1,1-diyl)bisphosphonate and tetraethyl(N-sec-butyl-1-aminoethan-1,1-diyl)bisphosphonate), and the first analysis of the ESR spectra of the corresponding nitroxides is reported. The preliminary results of theoretical calculations on model compounds suggest a small B₀ (in the McConnell equation). The results of bisphosphonate ester and bisphosphonic acid are similar. The discrepancies of P coupling for the diphosphorus compound stems from B₂ that is different when the dihedral angle is larger than 90°.     

金属-自由基分子基铁磁体的设计合成进展

金属一自由基分子基铁磁体的设计和合成，是近年发展起来的新课题，本文介绍这一课题的研究现状与发展趋势。     

Synthesis,crystal structure and magnetic properties of a new complex containing Cu(I) and radicals, [Cu(imme2py)2](ClO4)

A new complex, [Cu(imme2py)₂](ClO₄) (imme2py?=?2-(2′-(6′-methylpyridyl))-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxyl) has been synthesized and structurally characterized by X-ray diffraction methods. It crystallizes in the orthorhombic crystal system, space group P ₂₁₂₁₂₁ . The structure consists of [Cu(imme2py)₂]⁺ cations and chloride anions. The coordination geometry about Cu(I) is tetrahedral with the four coordination sites being occupied by four nitrogen atoms. Magnetic measurements show intramolecular antiferromagnetic interactions between the imino nitroxides.     

具有光控功能的两种氮氧自由基体系磁偶合作用的理论研究

采用密度泛函结合对称性破损态(DFT-BS)方法, 通过计算具有光控磁性分子开关功能的二氮氧自由基二芳基乙烯化合物的磁偶合常数, 合理解释了其分子结构发生开环和闭环变化时, 分子磁性发生的改变．同时设计了二氮氧自由基二甲基二氢化芘分子光控开环和闭环模型, 并用同样的方法计算了模型分子的磁偶合常数, 发现这些模型分子的磁行为类似于二氮氧自由基二芳基乙烯化合物, 有可能也具有光控磁性分子开关功能．     

A Simple Method of Synthesis of 3-Carboxy-2,2,5,5-Tetraethylpyrrolidine-1-oxyl and Preparation of Reduction-Resistant Spin Labels and Probes of Pyrrolidine Series

Stable free radicals are widely used as molecular probes and labels in various biophysical and biomedical research applications of magnetic resonance spectroscopy and imaging. Among these radicals, sterically shielded nitroxides of pyrrolidine series demonstrate the highest stability in biological systems. Here, we suggest new convenient procedure for preparation of 3-carboxy-2,2,5,5-tetraethylpyrrolidine-1-oxyl, a reduction-resistant analog of widely used carboxy-Proxyl, from cheap commercially available reagents with the yield exceeding the most optimistic literature data. Several new spin labels and probes of 2,2,5,5-tetraethylpyrrolidine-1-oxyl series were prepared and reduction of these radicals in ascorbate solutions, mice blood and tissue homogenates was studied.     

Analysis of the magnetic coupling in nitroxide organic biradicals

The magnetic coupling in organic biradicals has been analyzed by means of ab initio wave function-based methods. Attention is focused on the coupling between the spin moments localized on the NO-groups in meta and para phenylene-bridged nitroxides, and bis(nitronyl) nitroxide and bis(imino) nitroxide biradicals. The leading mechanisms governing the coupling have been isolated by means of class-partitioned CI calculations. It was found that the mechanisms of the coupling in the para and meta phenylene-bridged nitroxides are similar to that found in transition metal complexes, while for the other biradicals the dominance of other mechanisms (like the spin polarization) imposes restrictions on the computational strategy to be followed to best estimate the coupling.