Conjugate-Driven Electron Density Delocalization of Piperidine Nitroxyl Radical for Stable Aqueous Zinc Hybrid Flow Batteries.

Stable and soluble redox-active nitroxyl radicals are highly desired for high-capacity and long-life aqueous zinc hybrid flow batteries (AZHFBs). Here we report a "π-π" conjugated imidazolium and "p-π" conjugated acetylamino co-functionalized 2,2,6,6-tetramethylpiperidine-N-oxyl (MIAcNH-TEMPO) as stable catholyte for AZHFBs. The incorporation of double-conjugate substituents could delocalize the electron density of the N-O head and thus remarkably stabilize the radical and oxoammonium forms of TEMPO, avoiding the side reaction of ring-opening. Consequently, the applied MIAcNH-TEMPO/Zn AZHFB demonstrates the hardly time-dependent stability with a constant capacity retention of 99.95 % per day over 16.7 days at a high concentration catholyte of 1.5 M and high current density of 50 mA cm-2 . This proposed molecular engineering strategy based on electron density regulation of redox-active structures displays an attractive efficacy and thus represents a remarkable advance in high-performance AZHFBs.

Merging N-Hydroxyphthalimide into Metal-Organic Frameworks for Highly Efficient and Environmentally Benign Aerobic Oxidation.

Two highly efficient metal-organic framework catalysts TJU-68-NHPI and TJU-68-NDHPI have been successfully synthesized through solvothermal reactions of which the frameworks are merged with N-hydroxyphthalimide (NHPI) units, resulting in the decoration of pore surfaces with highly active nitroxyl catalytic sites. When t-butyl nitrite (TBN) is used as co-catalyst, the as-synthesized MOFs are demonstrated to be highly efficient and recyclable catalysts for a novel three-phase heterogeneous oxidation of activated C-H bond of primary and secondary alcohols, and benzyl compounds under mild conditions. Based on the high efficiency and selectivity, an environmentally benign system with good sustainability, mild conditions, simple work-up procedure has been established for practical oxidation of a wide range of substrates.

Low-frequency ESR studies on permeable and impermeable deuterated nitroxyl radicals in corn oil solution.

Low-frequency electron spin resonance studies were performed for 2 mM concentration of deuterated permeable and impermeable nitroxyl spin probes, 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl and 3-carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy in pure water and various concentrations of corn oil solution. The electron spin resonance parameters such as the line width, hyperfine coupling constant, g factor, rotational correlation time, permeability, and partition parameter were estimated. The broadening of line width was observed for nitroxyl radicals in corn oil mixture. The rotational correlation time increases with increasing concentration of corn oil, which indicates the less mobile nature of spin probe in corn oil mixture. The membrane permeability and partition parameter values were estimated as a function of corn oil concentration, which reveals that the nitroxyl radicals permeate equally into the aqueous phase and oil phase at the corn oil concentration of 50%. The electron spin resonance spectra demonstrate the permeable and impermeable nature of nitroxyl spin probes. From these results, the corn oil concentration was optimized as 50% for phantom studies. In this work, the corn oil and pure water mixture phantom models with various viscosities correspond to plasma membrane, and whole blood membrane with different hematocrit levels was studied for monitoring the biological characteristics and their interactions with permeable nitroxyl spin probe. These results will be useful for the development of electron spin resonance and Overhauser-enhanced magnetic resonance imaging modalities in biomedical applications.

Dynamic nuclear polarization studies on deuterated nitroxyl spin probes.

Detailed dynamic nuclear polarization and electron spin resonance studies were carried out for 3-carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, 3-carboxy-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl,3-methoxycarbonyl-2,2,5,5-tetramethy pyrolidine-1-oxyl nitroxyl radicals and their corresponding deuterated nitroxyl radicals, used in Overhauser-enhanced magnetic resonance imaging for the first time. The dynamic nuclear polarization parameters such as dynamic nuclear polarization (DNP) factor, longitudinal relaxivity, saturation parameter, leakage factor and coupling factor were estimated for deuterated nitroxyl radicals. DNP enhancement increases with agent concentration up to 3 mm and decreases above 3 mm. The proton spin-lattice relaxation time and the longitudinal relaxivity parameters were estimated. The leakage factor increases with increasing agent concentration up to 3 mm and reaches plateau in the region 3-5 mm. The coupling parameter shows the interaction between the electron and nuclear spins to be mainly dipolar in origin. DNP spectrum exhibits that the full width at half maximum values are higher for undeuterated nitroxyl radicals compared with deuterated nitroxyl radicals, which leads to the increase in DNP enhancement. The ESR parameters such as, the line width, line shape, signal intensity ratio, rotational correlation time, hyperfine coupling constant and g-factor were calculated. The narrow line width was observed for deuterated nitroxyl radicals compared with undeuterated nitroxyl radicals, which leads to the higher saturation parameter value and DNP enhancement. The novelty of the work permits clear understanding of the DNP parameters determining the higher DNP enhancement compared with the undeuterated nitroxyl radicals. Copyright © 2017 John Wiley & Sons, Ltd.

Electron spin resonance studies on deuterated nitroxyl spin probes used in Overhauser-enhanced magnetic resonance imaging.

The electron spin resonance studies were carried out for 2 mm concentration of 14 N-labeled and 15 N-labeled 3-carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, 3-carboxy-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl and their deuterated nitroxyl radicals using X-band electron spin resonance spectrometer. The electron spin resonance line shape analysis was carried out. The electron spin resonance parameters such as linewidth, Lorentzian component, signal intensity ratio, rotational correlation time, hyperfine coupling constant and g-factor were estimated. The deuterated nitroxyl radicals have narrow linewidth and an increase in Lorentzian component, compared with undeuterated nitroxyl radicals. The dynamic nuclear polarization factor was observed for all nitroxyl radicals. Upon 2 H labeling, about 70% and 40% increase in dynamic nuclear polarization factor were observed for 14 N-labeled and 15 N-labeled nitroxyl radicals, respectively. The signal intensity ratio and g-value indicate the isotropic nature of the nitroxyl radicals in pure water. Therefore, the deuterated nitroxyl radicals are suitable spin probes for in vivo/in vitro electron spin resonance and Overhauser-enhanced magnetic resonance imaging modalities. Copyright © 2017 John Wiley & Sons, Ltd.

Simultaneous evaluation of one-electron reducing systems and radical reactions in cells by nitroxyl biradical as probe.

In the present study, a novel probe for the simultaneous evaluation of one-electron reducing systems (electron transport chain) and one-electron oxidizing systems (free radical reactions) in cells by electron chemical detection was developed. Six-membered cyclic nitroxyl radicals (2,2,6,6-tetramethylpiperidine-1-oxyl; TEMPO series) are sensitive to one-electron redox systems, generating the hydroxylamine form [TEMPO(H)] via one-electron reduction, and the secondary amine form [TEMPO(N)] via one-electron oxidation in the presence of thiols. In contrast, the sensitivities of five-membered cyclic nitroxyl radicals (2,2,5,5-tetramethylpyrrolidine-1-oxyl; PROXYL series) to the one-electron redox systems are comparatively low. The electron chemical detector can detect 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), TEMPO(H) and PROXYL but not TEMPO(N). Therefore, nitroxyl biradical, TEMPO-PROXYL, as a probe for the evaluation of one-electron redox systems was employed. TEMPO-PROXYL was synthesized by the conjunction of 4-amino-TEMPO with 3-carboxyl-PROXYL via the conventional dicyclohexyl carbodiimide reaction. TEMPO-PROXYL, TEMPO(H)-PROXYL and TEMPO(N)-PROXYL were simultaneously quantified by HPLC with Coularray detection. Calibration curves for the quantification of TEMPO-PROXYL, TEMPO(H)-PROXYL and TEMPO(N)-PROXYL were linear in the range from 80 nm to 80 µm, and the lowest quantification limit of each molecule was estimated to be <80 nm. The relative standard deviations at 0.8 and 80 µm were within 10% (n = 5). Copyright © 2015 John Wiley & Sons, Ltd.

Nitroxyl-Radical-Catalyzed Oxidative Coupling of Amides with Silylated Nucleophiles through N-Halogenation.

A nitroxyl-radical-catalyzed oxidative coupling reaction between amines with an N-protecting electron-withdrawing group (EWG) and silylated nucleophiles was developed to furnish coupling products in high yields, thus opening up new frontiers in organocatalyzed reactions. This reaction proceeded through the activation of N-halogenated amides by a nitroxyl-radical catalyst, followed by carbon-carbon coupling with silylated nucleophiles. Studies of the reaction mechanism indicated that the nitroxyl radical activates N-halogenated amides, which are generated from N-EWG-protected amides and a halogenation reagent, to give the corresponding imines.

Practical aerobic oxidations of alcohols and amines with homogeneous copper/TEMPO and related catalyst systems.

Oxidations of alcohols and amines are common reactions in the synthesis of organic molecules in the laboratory and industry. Aerobic oxidation methods have long been sought for these transformations, but few practical methods exist that offer advantages over traditional oxidation methods. Recently developed homogeneous Cu/TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidinyl-N-oxyl) and related catalyst systems appear to fill this void. The reactions exhibit high levels of chemoselectivity and broad functional-group tolerance, and they often operate efficiently at room temperature with ambient air as the oxidant. These advances, together with their historical context and recent applications, are highlighted in this Minireview.

Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent.

Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development.

Impact of Nitroxyl Radicals on Photovoltaic Conversion Properties of Dye-Sensitized Solar Cells.

Nitroxyl radicals, characterized by unique redox properties, have been investigated for their potential influence on the photovoltaic conversion properties of dye-sensitized solar cells (DSSCs). In this study, we investigated the influence of nitroxyl radicals as donor sites in DSSCs. We observed that the redox activity of nitroxyl radicals significantly enhanced the photovoltaic conversion efficiency of DSSCs; this finding can offer new insights into the application of these radicals in solar energy conversion. Furthermore, we found that increasing the proportion of nitroxyl radicals improved the DSSC performance. Through a combination of experimental and analytical approaches, we elucidated the mechanism underlying this enhancement and highlighted the potential for more efficient DSSCs using nitroxyl radicals as key components. These findings provide new avenues for developing advanced DSSCs with improved performances and sustainability.

Spatiotemporal imaging of redox status using in vivo dynamic nuclear polarization magnetic resonance imaging system for early monitoring of response to radiation treatment of tumor.

In general, the effectiveness of radiation treatment is evaluated through the observation of morphological changes with computed tomography (CT) or magnetic resonance imaging (MRI) images after treatment. However, the evaluation of the treatment effects can be very time consuming, and thus can delay the verification of patient cases where treatment has not been fully effective. It is known that the treatment efficacy depends on redox modulation in tumor tissues, which is an indirect effect of oxidizing redox molecules such as hydroxyl radicals and of reactive oxygen species generated by radiation treatment. In vivo dynamic nuclear polarization-MRI (DNP-MRI) using carbamoyl-PROXYL (CmP) as a redox sensitive DNP probe enables the accurate monitoring of the anatomical distribution of free radicals based on interactions of electrons and nuclear spin, known as Overhauser effect. However, spatiotemporal response of the redox status in tumor tissues post-irradiation remains unknown. In this study, we demonstrate the usefulness of spatiotemporal redox status as an early imaging biomarker of tumor response after irradiation using in vivo DNP-MRI. Our results highlight that in vivo DNP-MRI/CmP allowed us to visualize the tumor redox status responses significantly faster and earlier compared to the verification of morphological changes observed with 1.5 T MRI and cancer metabolism (Warburg effect) obtained by hyperpolarized 13C pyruvate MRS. Our findings suggest that the early assessment of redox status alterations with in vivo DNP-MRI/CmP probe may provide very efficient information regarding the effectiveness of the subsequent radiation treatment.

Synergistic catalysis within core-shell Fe3O4@SiO2 functionalized with triethylene glycol (TEG)-imidazolium ionic liquid and tetramethylpiperidine N-oxyl (TEMPO) boosting selective aerobic oxidation of alcohols.

HYPOTHESIS: It is expected that incorporation of 2, 2, 6, 6-tetra-methyl piperidine-N-oxyl radical (TEMPO) and an imidazolium bromide bearing hydrophilic triethylene glycol (TEG) groups on Fe3O4@SiO2 core-shell may not only result in a novel highly water-dispersible/magnetically separable multi-functional catalyst system for metal-free aerobic oxidation of alcohols, which operates through a synergistic relay pathway, but it could potentially provide a strong platform for simultaneous separation and recycling of all components. EXPERIMENTS: The catalyst was prepared by anchoring TEMPO moieties onto a magnetic core-shell Fe3O4@SiO2 functionalized with an ionic liquid bearing TEG groups. The materials was characterized using transmission electron microscopy, Fourier transform infrared spectroscopy, nitrogen adsorption-desorption isotherms, thermal gravimetric analysis, and elemental analysis. The performance of the catalyst was evaluated and quantitatively measured in the aerobic oxidation of alcohols in water. FINDINGS: The catalyst exhibited excellent and stable colloidal dispersion in water and high performance in the aerobic oxidation of various types of alcohols under metal- and halogen-free reaction conditions. As hypothesized, strong synergistic effect between functionalized components was seen in the described reaction. The catalyst displayed excellent dual-adjustable-selectivity in the oxidation of primary alcohols to either the corresponding aldehydes or carboxylic acids by tuning the reaction solvent and/or reaction time and excellent recycling behavior through a "double-separation-strategy".

Artifact suppression in electron paramagnetic resonance imaging of (14)N- and (15)N-labeled nitroxyl radicals with asymmetric absorption spectra.

This article describes an improved method for suppressing image artifacts in the visualization of (14)N- and (15)N-labeled nitroxyl radicals in a single image scan using electron paramagnetic resonance (EPR). The purpose of this work was to solve the problem of asymmetric EPR absorption spectra in spectral processing. A hybrid function of Gaussian and Lorentzian lineshapes was used to perform spectral line-fitting to successfully separate the two kinds of nitroxyl radicals. This approach can process the asymmetric EPR absorption spectra of the nitroxyl radicals being measured, and can suppress image artifacts due to spectral asymmetry. With this improved visualization method and a 750-MHz continuous-wave EPR imager, a temporal change in the distributions of a two-phase paraffin oil and water/glycerin solution system was visualized using lipophilic and hydrophilic nitroxyl radicals, i.e., 2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy (16-DOXYL stearic acid) and 4-hydroxyl-2,2,6,6-tetramethylpiperidine-d17-1-(15)N-1-oxyl (TEMPOL-d17-(15)N). The results of the two-phase separation experiment verified that reasonable artifact suppression could be achieved by the present method that deals with asymmetric absorption spectra in the EPR imaging of (14)N- and (15)N-labeled nitroxyl radicals.