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Melanins are stable and non‐toxic biomaterials with a great potential as chemopreventive agents for diseases connected with oxidative stress, but the mechanism of their antioxidant action is unclear. Herein, we show that polydopamine (PDA), a well‐known synthetic melanin, becomes an excellent trap for alkylperoxyl radicals (ROO., typically formed during autoxidation of lipid substrates) in the presence of hydroperoxyl radicals (HOO.). The key reaction explaining this peculiar antioxidant activity is the reduction of the ortho‐quinone moieties present in PDA by the reaction with HOO.. This reaction occurs via a H‐atom transfer mechanism, as demonstrated by the large kinetic solvent effect of the reaction of a model quinone (3,5‐di‐tert‐butyl‐1,2‐benzoquinone) with HOO. (k=1.5×107 and 1.1×105 M−1 s−1 in PhCl and MeCN). The chemistry disclosed herein is an important step to rationalize the redox‐mediated bioactivity of melanins and of quinones., Polydopamine, a melanin analogue, is an excellent trap for alkylperoxyl radicals (ROO., typically formed during autoxidation of lipid substrates) only in the presence of hydroperoxyl radicals (HOO.). Activation of the ortho‐quinone moieties by HOO., and formation of exposed semiquinones are proposed as the reason of the peculiar antioxidant activity.

Antioxidant interactions of γ-terpinene with α-tocopherol mimic 2,2,5,7,8-pentamethyl-6-chromanol (PMHC) and caffeic acid phenethyl ester (CAPE), used as models, respectively, of mono- and poly-phenols were demonstrated by differential oximetry during the inhibited autoxidation of model substrates: stripped sunflower oil, squalene, and styrene. With all substrates, γ-terpinene acts synergistically regenerating the chain-breaking antioxidants PMHC and CAPE from their radicals, via the formation of hydroperoxyl radicals. The inhibition duration for mixtures PMHC/γ-terpinene and CAPE/γ-terpinene increased with γ-terpinene concentration, while rate constants for radical-trapping were unchanged by γ-terpinene, being 3.1 × 106 and 4.8 × 105 M−1s−1 for PMHC and CAPE in chlorobenzene (30 °C). Using 3,5-di-tert-butylcatechol and 3,5-di-tert-butyl-1,2-bezoquinone we demonstrate that γ-terpinene can reduce quinones to catechols enabling their antioxidant activity. The different synergy mechanism of γ-terpinene with mono- and poly-phenolic antioxidants is discussed and its relevance is proven in homogenous lipids using natural α-tocopherol and hydroxytyrosol as antioxidants, calling for further studies in heterogenous food products.

Increasing consumer awareness for all natural products has quickly led to growing research on new resources of potent and profitable natural antioxidants. In this context, for the first time, the Kolkhoung hull oil (KHO) (Pistacia khinjuk)-unsaponifiable matters (USM) (UHO) (100, 200, and 400 mg kg−1) were incorporated into refined soybean oil (RSO) and the oxidative stability of prepared oils was measured during 32 hours of frying. Then, the obtained results (oxidative stability) were compared to the samples containing tert-butyl hydroquinone (TBHQ) (100 mg kg−1) as a common synthetic antioxidant. According to the results of oxidative stability assays of acid values, conjugated diene values and carbonyl values, and total polar compounds, the incorporation of UHO, particularly at a concentration of 200 mg kg−1, was more efficient in improving the oxidative stability compared to TBHQ. The tocol content of KHO (2043.4 mg kg−1) was higher than the reported amounts of other conventional edible oils. Furthermore, by incorporation of UHO into RSO, as compared with TBHQ, a better protection of naturally occurring antioxidants (tocopherols and sterols) was found after adding UHO to RSO. This fact was mainly attributed to the UHO's tocotrienol fraction. Hence, the USM of KHO can be used as a potent antioxidant to improve the oxidative stability of frying oils.

Measurement of antioxidant properties in plant-derived compounds requires appropriate methods that address the mechanism of antioxidant activity and focus on the kinetics of the reactions involving the antioxidants. Methods based on inhibited autoxidations are the most suited for chain-breaking antioxidants and for termination-enhancing antioxidants, while different specific studies are needed for preventive antioxidants. A selection of chemical testing methods is critically reviewed, highlighting their advantages and limitations and discussing their usefulness to investigate both pure molecules and raw extracts. The influence of the reaction medium on antioxidants' performance is also addressed.

The inclusion of polyphenols into nanoporous materials may significantly improve their application as radical trapping agents for therapeutic purposes. In the present work, nanosponges based on hypercross- linked cyclodextrins and calixarenes (NS1–NS3) were used as carriers of three natural phenolic antioxidants: quercetin (Que), curcumin (Cur) and phenethyl caffeate (Phec). Good w/w loadings, namely 7.3% for the Que–NS1 composite, 17.3% for Cur–NS2 and 12.9% for Phec–NS3, were achieved. The release kinetics and the inhibition rate constants (kinh) of the reaction with alkylperoxyl radicals (ROO.) in 0.1 M phosphate buffer solutions at pH 7.4 were studied and indicated better antioxidant activity as compared to the phenols alone. The three phenols suffered a dramatic reduction of kinh upon increasing their concentration, as a result of their degradation. The inclusion into the nanosponges protected the antioxidants and provided a controlled release in an aqueous medium. Hence, different applications can be envisaged, in food and pharmaceutical technology fields.

The measure of O2 consumption during the inhibited autoxidation of an easily oxidizable substrate is one of the most reliable and predictive methods to assess antioxidant activity, especially for structure-activity relationship studies, for food and industrial applications. The differential oxygen uptake apparatus described herein represents a powerful and cost-effective way to obtain antioxidant activity from inhibited autoxidation studies. These experiments provide the rate constant and the stoichiometry of the reaction between antioxidants and peroxyl radicals (ROO∙), which are involved in the propagation of radical damage. We show the operation principles and the utility of this instrumentation in the bioorganic laboratory, with regard to the recent advances in this field, ranging from the study of natural antioxidants in biomimetic system, to the use of substrates generating hydroperoxyl radicals, and to the evaluation of novel nanoantioxidants.

none 4 si Hydroperoxyl (HOO.) and alkylperoxyl (ROO.) radicals show a different behavior in H-atom-transfer processes. Both radicals react with an analogue of α-tocopherol (TOH), but HOO., unlike ROO., is able to regenerate TOH by a fast H-atom transfer: TO.+HOO.→TOH+O2. The kinetic solvent effect on the H-atom transfer from TOH to HOO.is much stronger than that observed for ROO.because noncovalent interactions with polar solvents (Solv⋅⋅⋅HOO.) destabilize the transition state. Cedrowski, Jakub; Litwinienko, Grzegorz; Baschieri, Andrea; Amorati, Riccardo Cedrowski, Jakub; Litwinienko, Grzegorz; Baschieri, Andrea; Amorati, Riccardo

none 5 no The reactions of alkylperoxyl radicals with phenols have remained difficult to investigate in water. We describe herein a simple and reliable method based on the inhibited autoxidation of water/THF mixtures, which we calibrated against pulse radiolysis. With this method we measured the rate constants kinh for the reactions of 2-tetrahydrofuranylperoxyl radicals with reference compounds: urate, ascorbate, ferrocenes, 2,2,5,7,8-pentamethyl-6-chromanol, Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid, 2,6-di-tert-butyl-4-methoxyphenol, 4-methoxyphenol, catechol and 3,5-di-tert-butylcatechol. The role of pH was investigated: the value of kinh for Trolox and 4-methoxyphenol increased 11- and 50-fold from pH 2.1 to 12, respectively, which indicate the occurrence of a SPLET-like mechanism. H(D) kinetic isotope effects combined with pH and solvent effects suggest that different types of proton-coupled electron transfer (PCET) mechanisms are involved in water: less electron-rich phenols react at low pH by concerted electron-proton transfer (EPT) to the peroxyl radical, whereas more electron-rich phenols and phenoxide anions react by multi-site EPT in which water acts as proton relay. Radical kinetics: A simple and reliable method to measure the kinetics of peroxyl radical reactions in water is described (see figure). The proton-coupled electron transfer from a variety of compounds was investigated. Electron-poorer phenols react by concerted electron-proton transfer (EPT or CPET), whereas electron-richer phenols and phenoxide anions react by multi-site EPT (separated CPET) in which water acts as proton relay, similarly to the chemistry of radical enzymes. Amorati, Riccardo; Baschieri, Andrea; Morroni, Gloria; Gambino, Rossana; Valgimigli, Luca Amorati, Riccardo; Baschieri, Andrea; Morroni, Gloria; Gambino, Rossana; Valgimigli, Luca

Antioxidant activity of native vitamin C (ascorbic acid, AH2) is hampered by instability in solution. Selective loading of AH2 into the inner lumen of natural halloysite nanotubes (HNT) yields a composite nanoantioxidant (HNT/AH2), which was characterized and investigated for its reactivity with the persistent 1,1-diphenyl-2-picrylhydrazyl (DPPH&bull, ) radical and with transient peroxyl radicals in the inhibited autoxidation of organic substrates, both in organic solution (acetonitrile) and in buffered (pH 7.4) water in comparison with native AH2. HNT/AH2 showed excellent antioxidant performance being more effective than native ascorbic acid by 131% in acetonitrile and 290% (three-fold) in aqueous solution, under identical settings. Reaction with peroxyl radicals has a rate constant of 1.4 &times, 106 M&minus, 1 s&minus, 1 and 5.1 &times, 104 M&minus, 1, respectively, in buffered water (pH 7.4) and acetonitrile, at 30 &deg, C. Results offer physical understanding of the factors governing HNT/AH2 reactivity. Improved performance of HNT/AH2 is unprecedented among forms of stabilized ascorbic acid and its relevance is discussed on kinetic grounds.

Sulfur chemistry plays a central role in cellular redox homeostasis and cysteine-derived antioxidants like glutathione are the most abundant in biological systems. Inspired by Nature, the insertion of divalent sulfur as a substituent in phenolic antioxidants, e.g in thiatocopherol, seeking for improved antioxidant performance, has been an important strategy for long time. Replacement of sulfur with heavier chalcogens like Selenium and Tellurium has brought to even more performing antioxidants, able to quench peroxyl radical in a catalytic fashion and to express unusually high reactivity. On the other hand, natural bioactive compounds like plant-derived thiosulfinates (R-S(O)S-R) own their exceptional antioxidant properties to the ability of releasing sulfenic acids, whose antioxidant behavior has only recently been clarified. The chemistry and redox properties of unstable sulfenic acids (R-SOH), and analogous selenenic acids (R-SeOH) have also recently been elucidated, to better understand the properties of chalcogen-based natural antioxidants, and to develop novel bio-inspired compounds. This fascinating chemistry will be reviewed and the most significant achievement will be presented.

We report a novel coantioxidant system based on TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical) that, in biologically relevant model systems, rapidly converts chain-carrying alkylperoxyl radicals to HOO·. Extremely efficient quenching of HOO· by TEMPO blocks the oxidative chain. Rate constants in chlorobenzene were measured to be 1.1 × 109 M-1 s-1 for the reductive reaction TEMPO + HOO· → TEMPOH + O2 and 5.0 × 107 M-1 s-1 for the oxidative reaction TEMPOH + HOO· → TEMPO + H2O2. These rate constants are significantly higher than that associated with the reaction of HOO· with α-tocopherol, Nature's best lipid soluble antioxidant (k = 1.6 × 106 M-1 s-1). These data show that in the presence of ROO·-to-HOO· chain-transfer agents, which are common in lipophilic environments, the TEMPO/TEMPOH couple protects organic molecules from oxidation by establishing an efficient reductive catalytic cycle. This catalytic cycle provides a new understanding of the efficacy of the antioxidant capability of TEMPO in nonaqueous systems and its potential to act as a chemoprotective against radical damage.

Metal nanoparticles are reported to be toxic due to the generation of free radicals at their surface. Relatively inert thiol-capped gold nanoparticles (AuNPs) have been reported to induce radical formation in the presence of hydroperoxides, which would conflict with their potential use as inert scaffolds for the design of novel nano-antioxidants. With the aim of clarifying this aspect, we investigated the pro-oxidant activity of dodecanethiol-capped AuNPs (∼5 nm diameter), prepared through the Brust–Schiffrin synthesis, by oxygen-uptake kinetic studies. The pro-oxidant activity was found to be proportional to the impurities of the transfer agent tetraoctylammonium bromide (TOAB) left from the synthesis and decreased on repeated washing of the nanoparticles. Under identical settings similar batches of AuNP (∼9 nm diameter) prepared through the Ulman method without onium salts showed no pro-oxidant behavior. The alternative onium phase-transfer agents Oct4NBF4 (Oct=octyl), Hex4NBF4 (Hex=hexyl), and Hex4NPF6 were comparatively investigated and showed lower pro-oxidant activity depending on the counterion (Br−>PF6−>BF4−).

A dimer of quercetin prepared through a Mannich reaction protects pyridinium bisretinoid A2E from photooxidation at 430 nm in aqueous medium at pH 7.4. In the presence of light and O2, A2E is quickly attacked by 1O2 produced in situ (by excited A2E) to give nonaoxirane and other oxygenated compounds which can be involved in diseases of the macula. Peroxyl radicals might have only a marginal role on the photooxidation of A2E. The dimer is actually a potent quencher of 1O2 with a rate constant kQ of 8.5 × 108 M−1 s−1 in methanol at room temperature. On the other hand, its antioxidant abilities against ROO· radicals are quite limited since kROO· = 7.3 × 105 M−1 s−1 (in buffer solution at pH 7.4), the value being essentially identical to that of quercetin. The quenching of 1O2 by the dimer is therefore the main reason for the A2E protection and prevention of age-related macular degeneration.

Multidefence antioxidants represent a valuable solution for the protection against oxidative stress. From the planned synthesis of a catechol-tocopherol hybrid, we isolated a catechol-hydroquinone hybrid through a BBr3-mediated benzochromene-fluoren-1-ol transposition. The compound prepared showed a remarkable chain-breaking antioxidant in the catechol portion, while the very sensitive hydroquinone moiety revealed to be an efficient generator of hydroperoxyl radicals.

Nanomaterials represent one of the most promising frontiers in the research for improved antioxidants. Some nanomaterials, including organic (i.e. melanin, lignin) metal oxides (i.e. cerium oxide) or metal (i.e. gold, platinum) based nanoparticles, exhibit intrinsic redox activity that is often associated with radical trapping and/or with superoxide dismutase-like and catalase-like activities. Redox inactive nanomaterials can be transformed into antioxidants by grafting low molecular weight antioxidants on them. Herein, we propose a classification of nanoantioxidants based on their mechanism of action, and we review the chemical methods used to measure antioxidant activity by providing a rationale of the chemistry behind them.

none 5 no Chemical modification of magnolol, an uncommon dimeric neolignan contained in Magnolia genus trees, provides a unique array of polyphenols having interesting biological activity potentially related to radical scavenging. The chain-breaking antioxidant activity of four new hydroxylated and methoxylated magnolol derivatives was explored by experimental and computational methods. The measurement of the rate constant of the reaction with ROO radicals (kinh) in an apolar solvent showed that the introduction of hydroxyl groups ortho to the phenolic OH in magnolol increased the kinhvalue, being 2.4 × 105M-1s-1and 3.3 × 105M-1s-1for the mono and the dihydroxy derivatives respectively (kinhof magnolol is 6.1 × 104M-1s-1). The di-methoxylated derivative is less reactive than magnolol (kinh= 1.1 × 104M-1s-1), while the insertion of both hydroxyl and methoxyl groups showed no effect (6.0 × 104M-1s-1). Infrared spectroscopy and theoretical calculations allowed a rationalization of these results and pointed out the crucial role of intramolecular H-bonds. We also show that a correct estimation of the rate constant of the reaction with ROO radicals, by using BDE(OH) calculations, requires that the geometry of the radical is as close as possible to that of the parent phenol. Baschieri, Andrea; Pulvirenti, Luana; Muccilli, Vera; Amorati, Riccardo; Tringali, Corrado Baschieri, Andrea; Pulvirenti, Luana; Muccilli, Vera; Amorati, Riccardo; Tringali, Corrado

Limonene, linalool and citral are common non-phenolic terpenoid components of essential oils, with attributed controversial antioxidant properties. The kinetics of their antioxidant activity was investigated using the inhibited autoxidation of a standard model substrate. Results indicate that antioxidant behavior of limonene, linalool and citral occurs by co-oxidation with the substrate, due to very fast self-termination and cross-termination of the oxidative chain. Rate constants kp and 2kt, (M−1s−1) at 30°C were 4.5 and 3.5×106 for limonene, 2.2 and 9.0×105 for linalool and 39 and 1.0×108 for citral. Behavior is bimodal antioxidant/pro-oxidant depending on the concentration. Calculations at the M05/6-311+g(2df,2p) level indicate that citral reacts selectively at the aldehyde C–H having activation enthalpy and energy respectively lower by 1.3 and 1.8kcal/mol compared to the most activated allyl position. Their termination-enhancing antioxidant chemistry might be relevant in food preservation and could be exploited under appropriate settings.

none 4 si Despite its importance, little is known about the absolute performance and the mechanism for quercetin’s antioxidant activity in water solution. We have investigated this aspect by combining differential oxygen-uptake kinetic measurements and B3LYP/6311+g (d,p) calculations. At pH = 2.1 (30 °C), quercetin had modest activity (kinh = 4.0 x 103 M-1 s-1), superimposable to catechol. On raising the pH to 7.4, reactivity was boosted 40-fold, trapping two peroxyl radicals in the chromen-4-one core and two in the catechol with kinh of 1.6 x 105 and 7.0 x 104 M-1 s-1. Reaction occurs from the equilibrating mono-anions in positions 40 and 7 and involves firstly the OH in position 3, having bond dissociation enthalpies of 75.0 and 78.7 kcal/mol, respectively, for the two anions. Reaction proceeds by a combination of proton-coupled electron-transfer mechanisms: electron–proton transfer (EPT) and sequential proton loss electron transfer (SPLET). Our results help rationalize quercetin’s reactivity with peroxyl radicals and its importance under biomimetic settings, to act as a nutritional antioxidant. Amorati, Riccardo; Baschieri, Andrea; Cowden, Adam; Valgimigli, Luca Amorati, Riccardo; Baschieri, Andrea; Cowden, Adam; Valgimigli, Luca

There is a growing need for innovative food preservation systems. Reduction of food waste is recognised as a priority target by both FAO (2016) and the European Commission (2016). Antioxidants represent an important class of food preservatives because they are able to slow down the oxidation of unsaturated lipids (LH) contained in food, preventing therefore the development of rancidity (Schaich, 2005). Atmospheric oxygen (together with microorganisms) is the main oxidant species responsible for the decay of the organoleptic qualities of food. The reaction involved (called lipid autoxidation or peroxidation) is mediated by free radicals, which catalyse the formation of lipid hydroperoxides (LOOH) with a radical‐chain mechanism (Schaich, 2005). Butylated hydroxyanisole (BHA, E320), butylated hydroxytoluene (BHT, E321), propyl gallate (PG, E310) and tert‐butylhydroquinone (TBHQ, E319) are synthetic antioxidants commonly added to food to inhibit lipid peroxidation and the consequent rancidification. The impact of these petroleum‐derived antioxidants on human health is still under debate and generally natural alternatives are increasingly preferred (Williams et al ., 1999; Carocho et al ., 2014).

Phenols with intramolecular hydrogen bond between a pendant base and the phenolic OH group react differently in polar and non-polar environments with electron/proton acceptors. This was demonstrated by using time resolved chemically induced dynamic nuclear polarization (TR CIDNP) and theoretical calculations. In benzene, those phenols undergo a concerted electron–proton transfer (EPT) that yields neutral ketyl and phenoxyl radicals. In polar acetonitrile, the reaction mechanism turns into an electron transfer from the phenol to the triplet ketone, accompanied by the shift of a proton from the phenolic OH group to the nitrogen atom of the pendant base to form a distonic radical cation. This behavior is similar to that of tyrosine H-bonded to basic residues in some radical enzymes. This solvent-induced mechanism switch in proton-coupled electron transfers is important in different biological systems, in which the same metabolites and intermediates can react differently depending on the specific local environments.

Noncovalent sulfur···oxygen interactions can increase the stability of chalcogen ortho-substituted phenoxyl radicals. This effect contributes to transforming the 7-hydroxybenzo[b]thiophene moiety in a privileged structural motif to enhance the activity of phenolic antioxidants. A cascade of five consecutive electrophilic reactions occurring in one pot afforded potent and biocompatible α-tocopherol-like antioxidants.

Reactive oxygen and nitrogen species (ROS and RNS) are detrimental to human health because they initiate free radical–catalyzed oxidations of fundamental biomolecules such as DNA, proteins, lipids in low-density lipoprotein (LDL) and cell membranes, polysaccharides, etc. Molecular oxygen in its triplet ground state (the oxygen we breathe), 3O2, is the oxidant species in these processes called autoxidation or peroxidation. Cells are equipped with defensive systems able to quench most of the radicals responsible for initiating or propagating autoxidation in organic matter. Enzymes (superoxide dismutases, catalases, glutathione peroxidases, and peroxiredoxins) destroy radicals such as O2·− or non-radical species such as H2O2 and ROOH. Other small molecules, mainly phenols, present in the diet are able to react with radicals and hence may cooperate with the enzymes in keeping “oxidative stress” at bay. However, the physiological concentrations of phenols are frequently low, and this has cast doubt on their effectiveness in vivo. On the other hand, there is evidence that vitamin E is an effective peroxyl radical (ROO·) scavenger both in vitro and in vivo with rate constants of ~106 M−1 s−1. Its effectiveness in vivo against other radicals and non-radical oxidative species (HO·, R·, NO2 ·, RS·, 1O2, O3, and HOCl) is however uncertain. Vitamin C and ubiquinol-10 are able to regenerate vitamin E from its radicals.

We describe the preparation and properties of the first example of a synergic nanoantioxidant, obtained by different functionalizations of the external surface and the inner lumen of halloysite nanotubes (HNTs). Trolox, a mimic of natural α-tocopherol, was selectively grafted on the HNT external surface; while quercetin, a natural polyphenolic antioxidant, was loaded into the inner lumen to afford a bi-functional nanoantioxidant, HNT–Trolox/Que, which was investigated for its reactivity with transient peroxyl radicals and a persistent 1,1-diphenyl-2-picrylhydrazyl (DPPH˙) radical in comparison with the corresponding mono-functional analogues HNT–Trolox and HNT/Que. Both HNT–Trolox and HNT/Que showed good antioxidant performance in the inhibited autoxidation of organic substrates; however HNT–Trolox/Que protection by reaction with peroxyl radicals was 35% higher in acetonitrile and 65% in chlorobenzene, as compared to the expected performance based on the sum of contributions of NHT-Trolox and NHT/Que. Similar enhancement was observed also in the trapping of DPPH˙ radicals. Synergism between the distinct antioxidant functions was based on the rapid reaction of externally exposed Trolox (rate constant with peroxyl radicals was 1.1 × 106 M−1 s−1 and 9 × 104 M−1 s−1 respectively in chlorobenzene and acetonitrile, at 30 °C), followed by its regeneration by quercetin released from the HNT lumen. The advantages of this novel nanoantioxidant are discussed.

Thiols are well known for their role in cellular redox homeostasis, while aromatic amines and phenols are the best known classes of chain-breaking antioxidants. On the other hand, thiyl radicals are known to catalyse the double bond isomerization in PUFA. We investigated the role and interplay of 2-mercaptoethanol and diphenylamine in the parallel processes of peroxidation and cis-trans isomerization of linoleic acid (LA) during gamma radiolysis, both in solution and micelles. Both compounds, used alone were able to protect LA from oxidation; however pro-oxidant activity and enhanced isomerization was observed when they were used together, depending on the experimental settings. Instead, alpha-tocopherol protected LA from both oxidation and isomerization in the presence of thiols under any tested settings. The mechanistic scenario is discussed highlighting the role of diphenylaminyl radicals in promoting thiyl-radical-induced cis-trans isomerization in the presence of oxygen. (C) 2015 Elsevier Ltd. All rights reserved.

Persistent dialkylnitroxides (e.g., 2,2,6,6-tetramethylpiperidin-1-oxyl, TEMPO) play a central role in the activity of hindered amine light stabilizers (HALS)-additives that inhibit the (photo)oxidative degradation of consumer and industrial products. The accepted mechanism of HALS comprises a catalytic cycle involving the rapid combination of a nitroxide with an alkyl radical to yield an alkoxyamine that subsequently reacts with a peroxyl radical to eventually re-form the nitroxide. Herein, we offer evidence in favor of an alternative reaction mechanism involving the acid-catalyzed reaction of a nitroxide with a peroxyl radical to yield an oxoammonium ion followed by electron transfer from an alkyl radical to the oxoammonium ion to re-form the nitroxide. In preliminary work, we showed that TEMPO reacts with peroxyl radicals at diffusion-controlled rates in the presence of acids. Now, we show that TEMPO can be regenerated from its oxoammonium ion by reaction with alkyl radicals. We have determined that this reaction, which has been proposed to be a key step in TEMPO-catalyzed synthetic transformations, occurs with k ∼ 1-3 × 10(10) M(-1) s(-1), thereby enabling it to compete with O2 for alkyl radicals. The addition of weak acids facilitates this reaction, whereas the addition of strong acids slows it by enabling back electron transfer. The chemistry is shown to occur in hydrocarbon autoxidations at elevated temperatures without added acid due to the in situ formation of carboxylic acids, accounting for the long-known catalytic radical-trapping antioxidant activity of TEMPO that prompted the development of HALS.