TEMPO Derivatives Research Articles

Colorimetric quantification of vancomycin by highly active nitroxyl radical compounds.

Nitroxyl radicals, represented by 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO), are highly stable organic free radicals with unique properties and are used as functional molecules in various fields. However, TEMPO had low reactivity and sometimes did not provide enough response. Therefore, highly active nitroxyl radical compounds have been developed in which bicyclo and tricyclo structures stabilize the radicals. In this study, we found that nortropine N-oxyl (NNO), a type of highly active nitroxyl radical, can oxidize the 2,2'-dihydroxybiphenyl structure under physiological conditions, and succeeded in the colorimetric quantification of vancomycin containing 2,2'-dihydroxybiphenyl moieties in the molecular structure. The reaction took only a few minutes to complete and could be confirmed with the naked eye, with a quantitative range of 10-100μM. High-performance analytical probes are expected to be developed that use highly active nitroxyl radical derivatives to replace TEMPO derivatives.

Honey-Derived Hydrochar Containing 2,2,6,6-tetramethylpiperidine-1-oxyl Free Radical for Degradation of Aqueous Organic Pollutants

The increasing demand for greener technologies in environmental remediation makes carbon materials from biomass and its derivatives some of the most attractive resources for a sustainable future. However, integrating these materials with stable free radicals remains challenging. This study presents a straightforward one-pot hydrothermal route using raw honey as the carbon source and 4-amino 2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO) as the free radical. The addition of TEMPO derivative initiates Maillard reactions between its amino group and the carbonyl groups of the carbohydrates in honey, resulting in the formation of a functionalized hydrochar with a spherical morphology (~ 8 μm). The presence of free radicals within the carbonaceous matrix was confirmed by electron spin resonance spectroscopy, supported by infrared spectroscopy, elemental analysis, thermal analysis, scanning electron microscopy, and X-ray photoelectron spectroscopy. The free radical content was estimated at 0.4 mmol∙g-1. The material effectively removed methylene blue, fluorescein, and doxorubicin from water in the presence of green oxidants like hydrogen peroxide and sodium hypochlorite. After 24 h, removal efficiencies reached 92% for doxorubicin, 73% for methylene blue, and 23% for fluorescein. Moreover, the hydrochar demonstrated good regeneration capability, maintaining its dye removal efficiency over several cycles.

Improved Electrosynthesis of Biomass Derived Furanic Compounds via Nitroxyl Radical Redox Mediation.

Biomass is an abundantly available, underutilized feedstock for the production of bulk and fine chemicals, polymers, and sustainable and biodegradable plastics that are traditionally sourced from petrochemicals. Among potential feedstocks, 2,5-furan dicarboxylic acid (FDCA) stands out for its potential to be converted to higher-value polymeric materials such as polyethylene furandicarboxylate (PEF), a bio-based plastic alternative. In this study, the sustainable, electrocatalytic oxidation of stable furan molecule 2,5-bis(hydroxymethyl)furan (BHMF) to FDCA is investigated using a variety of TEMPO derivative electrocatalysts in a mediated electrosynthetic reaction. Three TEMPO catalysts (acetamido-TEMPO, methoxy-TEMPO, and TEMPO) facilitate full conversion to FDCA in basic conditions with >90% yield and >100% Faradaic efficiency. The remaining three TEMPO catalysts (hydroxy-TEMPO, oxo-TEMPO, and amino-TEMPO) all perform intermediate oxidation of BHMF in basic conditions but do not facilitate full conversion to FDCA. On the basis of pH studies completed on all TEMPO derivatives to assess their electrochemical reversibility and response to substrate, pH and reversibility play significant roles in the catalytic ability of each catalyst, which directly influences catalyst turnover and product formation. More broadly, this study also highlights the importance of an effective and rapid electroanalytical workflow in mediated electrosynthetic reactions, demonstrating how voltammetric catalyst screening can serve as a useful tool for predicting the reactivity and efficacy of a catalyst-substrate electrochemical system.

Synthesis of Alkoxy-TEMPO Aminoxyl Radicals and Electrochemical Characterization in Acetonitrile for Energy Storage Applications

In this paper, we describe the synthesis and characterization of alkoxylated TEMPO, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, radicals with potential application in organic non-aqueous redox flow batteries. The behavior of a series of TEMPO derivatives with varying lengths of alkoxy chain is analyzed in acetonitrile solutions using electrochemical techniques, electron paramagnetic resonance (EPR) spectroscopy, and measurements of permeability through three different membranes. Electrochemical redox potentials are only weakly dependent on the substituent, but, in contrast, exchange current densities derived from the data do depend on the substitution. EPR lends further insight into these properties via the determination of hyperfine splitting constant and rotational correlation time. There is a negligible effect of the substituents on those parameters among the modified TEMPO radicals. Finally, permeation rates of modified TEMPO derivatives through membranes depend significantly on both the membrane and the substitution of TEMPO, providing insights into capacity fade measurements in the literature.

A radical containing micellar probe for assessing esterase enzymatic activity with ultra-low field Overhauser-enhanced magnetic resonance imaging.

The ability to track altered enzyme activity using a non-invasive imaging protocol is crucial for the early diagnosis of many diseases but is often challenging. Herein, we show that Overhauser magnetic resonance imaging (OMRI) can be used to monitor enzymatic conversion at an ultra-low field (206 μT) using a highly sensitive "off/on" probe with a nitroxide stable radical containing ester, named T2C12-T80. This TEMPO derivative containing probe forms stable electron paramagnetic resonance (EPR) silent micelles in water that are hydrolysed by esterases, thus yielding narrow EPR signals whose intensities correlate directly with specific enzymatic activity. The responsiveness of the probe to tumours, facilitated by increased esterase activity, was initially determined by comparing EPR signals measured upon incubation with 3T3 (healthy fibroblasts used as control), HepG2 (human hepatoma) and Hs766T (human pancreatic cancer cells) cell lysates and then with Hs766T and 3T3 living cells. Next, Overhauser MR images were detected on a phantom containing the probe and the esterases to show that the approach is well suited for being translated to the in vivo detection at the earth's magnetic field. Regarding detection sensitivity, ultra-low field OMRI (ULF-OMRI) is beneficial over OMRI at higher fields (e.g. 0.2 T) since Overhauser enhancements are significantly higher and the technique is safe in terms of the specific absorption rate.

Theoretical terahertz spectroscopy of free radical solutes in solution: an EPR spin probe in water.

Free radical species are used as spin labels in electron paramagnetic resonance (EPR) spectroscopy of biomolecular systems in water, for instance in the frame of Overhauser dynamic nuclear polarization (ODNP) relaxometry to probe the local hydration water dynamics close to protein surfaces in aqueous environments. Widely used in this context are nitroxide spin probes such as TEMPO, PROXYL or MTSL derivatives. Here, we study the THz spectroscopy of HMI (2,2,3,4,5,5-HexaMethylImidazolidin-1-oxyl) in water at ambient conditions which has been recently investigated as to how its EPR properties depend on its solvation pattern in water. To enable theoretical THz spectroscopy of molecular radicals in solution, we have generalized well-established methodologies for THz spectral decomposition of closed-shell systems, namely the supermolecular solvation complex (SSC) and cross-correlation analysis (CCA) techniques, to open-shell polyatomic solute species in water. Based on this methodological advance, we have decomposed and assigned the THz response of HMI including its solvation shell by employing the generalized SSC and CCA methods to cope with the open-shell character of this free radical solute, in particular its unpaired electron localized at the nitroxy group. We reveal that the main modulations of the far-IR spectrum of HMI are dominated by the low-frequency intramolecular modes of the spin probe molecule itself while the solvation of its two hydrogen bonding sites contribute much less intensely in this spectral window. Finally, we have computed THz spectra of HMI with its local solvation water with an aim to provide a theoretical analogue of experimental THz difference spectroscopy. Beyond the specific case, our decomposition methodology that now is able to include open shells can be applied in future work to analyze the low-frequency vibrational response of the solvation shell of other free radicals in solution.

Two dysprosium complexes based on TEMPO radical derivative: synthesis, structures, magnetic and fluorescent properties

A new TEMPO derivative was synthesized and two Dy-radical complexes, [Dy(hfac)3(H2O)hmb-TEMPO] (1) and [Dy(hfac)3(hmb-TEMPO)2] (2, hmb-TEMPO = 4-((2-hydroxy-3-methoxybenzylidene)amino)-2,2,6,6-tetramethyl; hfac = hexafluoroacetylacetonate), were synthesized through reacting hmb-TEMPO radical and Dy(hfac)3 with 1:1 and 1:2 ratio, respectively. The structures of 1 and 2 were elucidated by single-crystal X-ray structural analysis. Both 1 and 2 feature mononuclear structures. Nonzero out-of-phase signals were observed for both Dy derivatives, indicating single-molecule magnet behavior. The room-temperature photoluminescence spectra of 1 and 2 exhibit strong emissions in the visible region.

A family of mono-nuclear lanthanide-radical complexes: Synthesis, structures, magnetic and fluorescent properties

Two new rare earth complexes based on TEMPO derivative namely [Ln(hfac)3(H2O)hmb-TEMPO] (Ln = Gd 1, Tb 2; hmb-TEMPO = 4-((2-hydroxy-3-methoxybenzylidene) amino)-2,2,6,6-tetramethyl; hfac = hexafluoroacety lacetonate) were successfully synthesized through reacting hmb-TEMPO radical and Ln(hfac)3. Single-crystal X-ray diffraction reveals that 1 and 2 are isostructural complexes in which the LnIII ion is surrounded nine oxygen atoms and displayed distorted tricapped trigonal prism geometry. Magnetic studies show that antiferromagnetic interactions dominate in complex 1. Nonzero out-of-phase signals were observed for complex 2, indicating single-molecule magnet behavior. The low-temperature photoluminescence spectrum of complex 2 were investigated and discussed in detail.

Application of Highly Active TEMPO Derivatives for Electrochemical Analysis

Application of Highly Active TEMPO Derivatives for Electrochemical Analysis

Thermodynamic Evaluation on Alkoxyamines of TEMPO Derivatives, Stable Alkoxyamines or Potential Radical Donors?

AbstractIn this work, the bond dissociation energy (BDE) values, including BDE(O−X) and BDE(N−O), for 129 alkoxyamines (XRT) of TEMPO derivatives were predicted, and the evaluations on stabilities of alkoxyamines, reactivities of alkoxyamines as radical donors and reactivity of TEMPO as various radical scavenger are well compared and discussed based on the predicted BDE values from the view of thermodynamic driving forces. Without a doubt, the wide and valuable BDE values are helpful for chemists better understand the thermodynamic properties and kinetic behaviors of alkoxyamines and TEMPO in chemical reactions and drug metabolism in vivo and promoting the rapid development and application of novel alkoxyamines.

Proton-detected solution-state NMR at 14.1 T based on scalar-driven 13C Overhauser dynamic nuclear polarization

Overhauser dynamic nuclear polarization (ODNP) NMR of solutions at high fields is usually mediated by scalar couplings that polarize the nuclei of heavier, electron-rich atoms. This leaves 1H-detected NMR outside the realm of such studies. This study presents experiments that deliver 1H-detected NMR experiments on relatively large liquid volumes (60 ∼ 100 μL) and at high fields (14.1 T), while relying on ODNP enhancements. To this end 13C NMR polarizations were first enhanced by relying on a mechanism that utilizes e--13C scalar coupling interactions; the nuclear spin alignment thus achieved was then passed on to neighboring 1H for observation, by a reverse INEPT scheme relying on one-bond JCH-couplings. Such 13C →1H polarization transfer ported the 13C ODNP gains into the 1H, permitting detection at higher frequencies and with higher potential sensitivities. For a model solution of labeled 13CHCl3 comixed with a nitroxide-based TEMPO derivative as polarizing agent, an ODNP enhancement factor of ca. 5x could thus be imparted to the 1H signal. When applied to bigger organic molecules like 2-13C-phenylacetylene and 13C8-indole, ODNP enhancements in the 1.2-3x range were obtained. Thus, although handicapped by the lower γ of the 13C, enhancements could be imparted on the 1H thermal acquisitions in all cases. We also find that conventional 1H–13C nuclear Overhauser enhancements (NOEs) are largely absent in these solutions due to the presence of co-dissolved radicals, adding negligible gains and playing negligible roles on the scalar e-→13C ODNP transfer. Potential rationalizations of these effects as well as extensions of these experiments, are briefly discussed.

TEMPO-mediated late stage photochemical hydroxylation of biaryl sulfonium salts.

The late stage photochemical hydroxylation of biaryl sulfonium salts was enabled with a TEMPO derivative as a simple oxygen source, in metal free conditions. The scope and mechanism of this exceptionally simple synthetic method, which constructs important arylated phenols from aromatic C-H bonds, are herein discussed.

A Stable, Low Permeable TEMPO Catholyte for Aqueous Total Organic Redox Flow Batteries

AbstractAqueous organic redox flow batteries (AORFBs) are highly attractive for large‐scale energy storage because of their nonflammability, low cost, and sustainability. (2,2,6,6‐Tetramethylpiperidin‐1‐yl)oxyl (TEMPO) derivatives, a class of redox active molecules bearing air‐stable free nitroxyl radicals and high redox potential (>0.8 V vs NHE), has been identified as promising catholytes for AORFBs. However, reported TEMPO based molecules are either permeable through ion exchange membranes or not chemically stable enough for long‐term energy storage. Herein, a new TEMPO derivative functionalized with a dual‐ammonium dicationic group, N1, N1, N1, N3, N3, 2, 2, 6, 6‐nonamethyl‐N3‐(piperidinyloxy)propane‐1,3‐bis(ammonium) dichloride (N2‐TEMPO) as a stable, low permeable catholyte for AORFBs is reported. Ultraviolet–visible (UV–vis) and proton nuclear magnetic resonance (1H‐NMR) spectroscopic studies reveal its exceptional stability and ultra‐low permeability (1.49 × 10−12 cm2 s−1). Coupled with 1,1′‐bis[3‐(trimethylammonio)propyl]‐4,4′‐bipyridinium tetrachloride ((NPr)2V) as an anolyte, a 1.35 V N2‐TEMPO/(NPr)2V AORFB with 0.5 m electrolytes (9.05 Wh L−1) delivers a high power density of 114 mW cm−2 and 100% capacity retention for 400 cycles at 60 mA cm−2. At 1.0 m electrolyte concentrations, the N2‐TEMPO/(NPr)2V AORFB achieves an energy density of 18.1 Wh L−1 and capacity retention of 90% for 400 cycles at 60 mA cm−2.

Testing of Chemically Activated Cellulose Fibers as Adsorbents for Treatment of Arsenic Contaminated Water.

Exposure to different arsenic concentrations (higher than 10 μg/L), either due to the direct consumption of contaminated drinking water or indirectly by using contaminated food is harmful for human health. Therefore, it is important to remove arsenic from aqueous solutions. Among many arsenic removal technologies, adsorption offers a promising solution with a good efficiency, however the material used as adsorbent play a very vital role. The present investigation evaluated the behavior of two cellulose-based adsorbent materials, i.e., viscose fibers (V) and its TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) derivative, obtained by using the well-established TEMPO-mediated protocol (VF). Due to the known arsenic affinity for Fe ions the two materials were later doped with it. This was done after a preliminary functionalization with di-2-ethylhexyl phosphoric acid (DEHPA), to obtain two materials: V-DEHPA-Fe and VF-DEHPA-Fe. Arsenic adsorption is known to be pH dependent (between 6 and 8); therefore, the optimal pH range for As(V) adsorption has been established. In order to evaluate the adsorption mechanism for both the synthesized materials, the influence of contact time, temperature and initial concentration was evaluated. Langmuir, Freundlich and Sips equilibrium isotherm models were used in order to determine the ability of the model to describe As(V) adsorption process. The maximum adsorption capacity of the material V-DEHPA-Fe was 247.5 µg As(V)/g with an As(V) initial concentration of 5 mg/L and for the material VF-DEHPA-Fe it was 171.2 µg As(V)/g with initial concentration of 5 mg/L.

Highly Stable 1,2-Dicarbonyl Radical Cations Derived from N-Heterocyclic Carbenes.

Stable organic radicals have been of great academic interest not only in the context of fundamental understanding of reactive intermediates but also because of their numerous applications as functional materials. Apart from the early examples of triphenylmethyl and TEMPO derivatives, reports on air- and water-stable organic radicals are scarce, and their development remains a challenge. Herein, we present the design and synthesis of a novel organic radical based on a 1,2-dicarbonyl scaffold supported by N-heterocyclic carbenes (NHCs). The presented radical cations exhibit remarkable stability toward various harsh conditions, such as the presence of reactive chemicals (reductants, oxidants, strong acids, and bases) or high temperatures, by far exceeding the stability of triphenylmethyl and TEMPO radicals. In addition, physiological conditions including aqueous buffer and blood serum are tolerated. The steric and electronic stabilization provided by the two NHC moieties enabled the successful design of the highly stable radical.

Electrochemical characterization and thermodynamic analysis of TEMPO derivatives in ionic liquids.

In this study we investigate the reversibility of the reduction process of three TEMPO derivatives - TEMPOL, 4-cyano-TEMPO, and 4-oxo-TEMPO. The [C2mim][BF4] and [C4mpyr][OTf] ionic liquids (ILs) were used to perform cyclic voltammetry (CV) to analyse the redox potentials of the TEMPO derivatives. The former was previously shown to quench the aminoxy anion of TEMPO through a proton transfer reaction with the cation, whereas the latter supported the irreversibility of the TEMPO reduction process. In CV results on TEMPO derivatives, it was shown that [C4mpyr][OTf] could allow for a high degree of reversibility in the reduction of 4-cyano-TEMPO and a moderate degree of reversibility in the reduction of TEMPOL. In comparison, reduction of 4-cyano-TEMPO was predominantly irreversible in [C2mim][BF4], whilst TEMPOL showed complete irreversibility. 4-Oxo-TEMPO did not show any notable reduction reversibility in either IL tested. Reduction potentials showed little variation between the derivatives and 0.2 V variation between the ILs, with the most negative reduction potential being observed at -1.43 V vs. Fc/Fc+ for TEMPOL in [C4mpyr][OTf]. To explain the varying degrees of reversibility of the reduction process, four types of side reactions involving proton transfer to the aminoxy anion were studied using highly correlated quantum chemical methods. Proton transfer from the IL cation was shown to have the ability to quench all three aminoxy anions depending on the IL used. On average, TEMPOL was shown to be the most susceptible to proton transfer from the IL cation, having an average Gibbs free energy (GFE) of 10.5 kJ mol-1 more negative than that of 4-cyano-TEMPO, which was shown to have the highest GFE of proton transfer. Side reactions between water and aminoxy anions were also seen to have the potential to contribute to degradation of the aminoxy anions tested, with 4-oxo-TEMPO being shown to be the most reactive to degradation with water with a GFE of -12.6 kJ mol-1. 4-Oxo-TEMPO was found to be highly susceptible to self-quenching by its aminoxy anion and radical form with highly negative proton transfer GFEs of -47.9 kJ mol-1 and -57.7 kJ mol-1, respectively. Overall, 4-cyano-TEMPO is recommended as being the most stable of the aminoxy anions tested with TEMPOL, thus providing a viable alternative to improve solubility should the IL be tuned to maximize its stability.

Multi-Functional TEMPO Derivatives for High-Performance Lithium Oxygen Batteries

Lithium oxygen batteries (LOBs) have been spotlighted as the next generation of rechargeable batteries due to their high theoretical capacity. One of the key issues of LOBs is how effectively lithium peroxide as the discharge product is removed. (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) was reported as a charge redox mediator to remove lithium peroxide during charge. TEMPO is oxidized to TEMPO+ at 3.70V vs. Li/Li+ and then withdraw electron from lithium peroxide. In this presentation, we present the effects of functional groups attached to 4'-C of TEMPO on LOB performances. Several TEMPO derivatives improved cycling stability significantly. In addition to redox mediation role on charging, a group of TEMPO derivatives promoted disproportionation reaction of superoxide radical during discharging to change the morphology of lithium peroxide. Another group of TEMPO derivatives improved the cycling stability by forming a protective interface film on lithium metal cathode.

Enhanced Intersystem Crossing and Transient Electron Spin Polarization in a Photoexcited Pentacene-Trityl Radical.

Identifying and characterizing systems that generate well-defined states with large electron spin polarization is of high interest for applications in molecular spintronics, high-energy physics, and magnetic resonance spectroscopy. The generation of electron spin polarization on free-radical substituents tethered to pentacene derivatives has recently gained a great deal of interest for its applications in molecular electronics. After photoexcitation of the chromophore, pentacene-radical derivatives can rapidly form spin-polarized triplet excited states through enhanced intersystem crossing. Under the right conditions, the triplet spin polarization, arising from mS-selective intersystem crossing rates, can be transferred to the tethered stable radical. The efficiency of this spin polarization transfer depends on many factors: local magnetic and electric fields, excited-state energetics, molecular geometry, and spin-spin coupling. Here, we present transient electron paramagnetic resonance (EPR) measurements on three pentacene derivatives tethered to Finland trityl, BDPA, or TEMPO radicals to explore the influence of the nature of the radical on the spin polarization transfer. We observe efficient polarization transfer between the pentacene excited triplet and the trityl radical but do not observe the same for the BDPA and TEMPO derivatives. The polarization transfer behavior in the pentacene-trityl system is also investigated in different glassy matrices and is found to depend markedly on the solvent used. The EPR results are rationalized with the help of femtosecond and nanosecond transient absorption measurements, yielding complementary information on the excited-state dynamics of the three pentacene derivatives. Notably, we observe a 2 orders of magnitude difference in the time scale of triplet formation between the pentacene-trityl system and the pentacene systems tethered with the BDPA and TEMPO radicals.

Post-polymerization modification of polymeric active esters towards TEMPO containing polymers: A systematic study

Organic radical batteries (ORB) are a novel promising class for energy storage, particularly featuring a fast charging capability and extraordinary cycle life. The representative polymer, i.e. poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl methacrylate) (PTMA), is usually synthesized by a post-polymerization oxidation method. As an alternate strategy for developing TEMPO-containing polymers, we focused on the post-polymerization modification of poly(pentafluorophenyl acrylate) and poly(pentafluorophenyl methacrylate) with three different TEMPO nucleophiles by transesterification or amidation reactions. Optimizing the conditions of the post-polymerization functionalization reaction by varying different parameters, such as the type of nucleophile, catalyst and solvent, the feeding ratios of catalysts and nucleophiles, along with reaction time and temperatures, resulted in structurally distinct TEMPO containing polymers with varying backbone composition. Intriguingly, poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl acrylamide) revealed the highest degree functionalization with TEMPO (96.2%) within 3 hrs. under considerably mild conditions, while poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl methylmethacrylamide) exhibited the lowest TEMPO content owing to the steric hindrance from methyl group on both the methacrylate chain and the TEMPO derivative. All other four TEMPO containing polymers had a radical content similar to PTMA (66.6%) synthesized by the post-oxidation methodology. Noteworthy, compared to TEA (trimethylamine), DMAP (4-dimethylaminopyridine) facilitated an efficient ester bond cleavage independent of the polymer precursor, thus, side reactions such as hydrolysis were increased. Though hydrolysis side reaction occurred, the resulting carboxylic acid group was proven to accelerate ion transfer in a certain way during the redox process. Furthermore, due to the higher TEMPO content, poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl acrylamide) exhibited a 12–22 mAh/g higher specific capacity compared to the PTMA-oxidation when running at 5C for 500 cycles.

New TEMPO containing polymers for all polymeric oxidation procedure

2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) is a versatile compound which is used mainly in organic oxidation reactions and organic battery applications. Incorporating TEMPO into a polymer could provide many applications into its repertoire. In this study, new polymeric TEMPO derivatives are synthesized and characterized to be used as catalysts in the presence of another polymer which constitutes N-halamine functionality. These polymeric mixtures were superior since the mixture could easily be separated from the reaction medium by simple filtration and reused in some other oxidation reactions numerous times. In turn, an all polymeric oxidation method was developed for oxidation of primary alcohols.