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 nona...

Extremely Fast Hydrogen Atom Transfer between Nitroxides and HOO· Radicals and Implication for Catalytic Coantioxidant Systems

Nitroxides are putative intermediates in the accepted reaction mechanisms of the diarylamine and hindered amine antioxidants that are universally added to preserve synthetic and natural hydrocarbon-based materials. New methodology which enables monitoring of hydrocarbon autoxidations at low rates of radical generation has revealed that diarylnitroxides and hindered nitroxides are far better inhibitors of unsaturated hydrocarbon autoxidation than their precursor amines, implying intervention of a different mechanism. Experimental and computational investigations suggest that the nitroxides catalyze the cross-dismutation of hydroperoxyl and alkylperoxyl radicals to yield O2 and a hydroperoxide, thereby halting the autoxidation chain reaction. The hydroperoxyl radicals – key players in hydrocarbon combustion, but essentially unknown in autoxidation – are proposed to derive from a tunneling-enhanced intramolecular (1,4-) hydrogen-atom transfer/elimination sequence from oxygenated radical addition intermediates. These insights suggest that nitroxides are preferred additives for the protection of hydrocarbon-based materials from autoxidation since they exhibit catalytic activity under conditions where their precursor amines are less effective and/or inefficiently converted to nitroxides in situ.

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Inhibition of hydrocarbon autoxidation by nitroxide-catalyzed cross-dismutation of hydroperoxyl and alkylperoxyl radicals

Nitroxides were recently shown to catalyze the cross-dismutation of alkylperoxyl and hydroperoxyl radicals, making them uniquely effective radical-trapping antioxidants (RTAs) in unsaturated hydrocarbons where both species are formed. Given the abundance of unsaturated lipids in biological membranes, the continuous generation of hydroperoxyl (superoxide) as a byproduct of aerobic respiration, and the demonstrated cytoprotective properties of some nitroxides, we probed if cross-dismutation operates in phospholipid bilayers and cell culture. Interestingly, only nitroxides that were efficiently converted to amines in situ were effective, with their activity paralleling the stability of the incipient aminyl radicals. The ether-linked diarylamine phenoxazine, one of the most potent RTAs known, was particularly effective as a cross-dismutation catalyst. In contrast, phenolic RTAs such as α-tocopherol (α-TOH), the most potent form of vitamin E, were found to be inefficient due to the preference for the combination of hydroperoxyl and phenoxyl radicals over H-atom transfer between them. Experiments carried out in mouse embryonic fibroblasts corroborated these findings. Cells cotreated with phenoxazine (or its nitroxide) and a superoxide source were better protected from ferroptosis than those treated with phenoxazine (or its nitroxide) alone. No such synergy was observed for cells treated with α-TOH. Live cell imaging established that cytoprotection was associated with suppression of (phospho)lipid peroxidation. These results highlight the remarkable capacity for select amines to act as effective phase-transfer catalysts for a reducing equivalent (an H atom), such that a water-soluble "reactive oxygen species" can be used to quench a lipid-soluble one.

Potent Ferroptosis Inhibitors Can Catalyze the Cross-Dismutation of Phospholipid-Derived Peroxyl Radicals and Hydroperoxyl Radicals.

The process of lipid peroxidation (LPO) plays an extremely important role in the human body due to the fact that its uncontrolled development can lead to oxidative stress and a number of serious diseases. The traditional approach to the analysis of the mechanism and kinetics of LPO is based on the well-known ideas that emerged from the study of radical-chain oxidation of hydrocarbons in a homogeneous medium. However, the distinctive feature of LPO is that this process is heterogeneous and the processes of diffusion of active intermediates between the aqueous and hydrocarbon phases should play a significant role in it. In the present work, an attempt has been made to theoretically estimate the contribution of these processes to the oxidation kinetics of model substances used in practice in the study of LPO. In the course of the calculations, a quantum chemical and kinetic analysis of the role of hydroperoxyl radical in the radical-chain mechanism of oxidation of methyl linoleate in micelles was carried out. The molecular dynamics method shows the important role of changing the dynamic rigidity of a hydrocarbon fragment of a chain during the formation of a peroxyl radical and hydroperoxyl group during the oxidation of a substrate in a heterogeneous medium. Quantum chemical calculations of the thermodynamics of reactions involving $${{{\text{HO}}_{2}}^{ \cdot }}$$
 radicals and the effects of their solvation made it possible to estimate the kinetic constants of the reaction rates. Using kinetic modeling, their relative contribution to the oxidation kinetics was revealed. In this case, it is possible to explain a number of anomalies associated with the oxidation of polyunsaturated fatty acids and their esters in micelles compared with their oxidation in a homogeneous hydrocarbon medium.

Quantum chemical evaluation of the role of $${{{\text{HO}}_{2}}^{ \cdot }}$$ HO 2 · radicals in the kinetics of the methyl linoleate oxidation in micelles

Kinetics of oxidation of benzyl alcohols with molecular oxygen catalyzed by N‐hydroxyphthalimide: Role of hydroperoxyl radicals

Kinetics and Mechanism of Radical‐Chain Oxidation of 1,2‐Substituted Ethylene and 1,4‐Substituted Butadiene‐1,3

The effect of solvation on the rate constants of hydroperoxyl radical addition to the double bonds of 1,1-substituted ethylene vinyl compounds was studied in the medium of different polarity solvents. The values of rate constants of this process were determined in a series of experiments on the co-oxidation of diphenylethylene (was used as the source of hydroperoxyl radicals) with the studied vinyl compounds at 323 K using the method of microvolumetry in combination with ESR spectroscopy and computer kinetic modeling. The observed linear relationship between the values of rate constant logarithms and the dielectric permittivity of reaction medium in coordinates of the Kirkwood–Onsager equation allows for the conclusion that the effect of nonspecific solvation due to the electrostatic forces does take place in the studied systems.

The effect of solvation on the reactivity of 1,1-substituted ethylenes in hydroperoxyl radical addition reactions

The kinetics of oxidation (323 K) of bicycloolefins from the norbornene series: norbornene, vinylnorbornene, ethylidenenorbornene, and norbornadiene, inhibited by phenols (PhOH), aromatic amines (AmH), transition metal compounds (Men), or stable nitroxyl radicals of the piperidine series (>NO·), in chlorobenzene solutions have been studied. It has been found that the phenols are single-action inhibitors, whereas the amines, the transition metals, and the nitroxyl radicals repeatedly terminate oxidation chains. The results are explained in terms of phenomenology of the bicycloolefin oxidation process associated with the fact that peroxide radicals attack different reaction centers (π- and α-CH bonds), thereby resulting in the formation of different types of chain carrier radicals: low-molecular-weight hydroperoxide and polyperoxide radicals.

The mechanism of inhibited oxidation of norbornene series bicycloolefins

The Role of Solvation in the Kinetics and the Mechanism of Hydroperoxide Radicals Addition to π‐Bonds of 1,2‐Diphenylethylene and 1,4‐Diphenylbutadiene‐1,3

The mechanism of 1,2-substituted ethylene and 1,4-substituted butadiene oxidation with cyclic multiple chain termination by nitroxide radicals has been confirmed using a large set of nitroxides of piperidine, pyrroline, pyrrolidine and imidazoline series. This mechanism includes hydroperoxyl radicals as chain propagating agents and is realized both in non-polar and in polar media. The solvent effect on the rate constant of nitroxide and hydroperoxide radicals interaction is explained by the specific solvation of $${\text{HO}}_{{2}}^{{{ \bullet }}}$$
 radicals. An additional effect in high dielectric constant media can be provided by the nonspecific solvation of nitroxide radicals. In low polar solvents the reactivity of > NO• is almost completely determined by > NO–H bond energy of hydroxylamine.

Roman Pliss

Papers

Kinetics and Mechanism of Radical‐Chain Oxidation of 1,2‐Substituted Ethylene and 1,4‐Substituted Butadiene‐1,3

The effect of solvation on the reactivity of 1,1-substituted ethylenes in hydroperoxyl radical addition reactions

The mechanism of inhibited oxidation of norbornene series bicycloolefins

The Role of Solvation in the Kinetics and the Mechanism of Hydroperoxide Radicals Addition to π‐Bonds of 1,2‐Diphenylethylene and 1,4‐Diphenylbutadiene‐1,3

The influence of medium polarity on the kinetics and mechanism of interaction of aliphatic nitroxides with hydroperoxyl radicals