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Plasmalogens have been reported to possess antioxidant activity; a paradoxical finding given that plasmalogens often comprise highly oxidizable polyunsaturated fatty acids esterified to the central position of the glycerol backbone. However a reasonable mechanism accounting for plasmenyl lipid activity has yet to be advanced, despite the fact that other monounsaturated lipids including cholesterol and oleate have been extensively studied. Plasmenylcholine was synthesized de novo to resolve its antioxidant activity as well as to carry out mechanistic studies to understand its basis. Autoxidation of a vinyl ether model substrate yielded a kp of 6 M-1 s-1, which affirmed it was as slower than cholesterol. However, corresponding experiments with a deuterated substrate yielded a value of 89 M-1 s-1, questioning the reliability of these studies. Our studies of plasmenyl lipid peroxidation inspired us to look into the mechanism of autoxidation of the monounsaturated lipid, oleate (using LC-MS/MS with APCI+), which was reported to proceed exclusively via H-atom transfer (HAT). Herein we have shown for the first time that oleate epoxides are formed in the autoxidation of the monounsaturated lipid.

Hydrocarbon autoxidation, a free radical chain reaction, is one of the most important chemical processes, and is ubiquitous in biological systems and industry. While it is vital to maintaining cellular homeostasis and plays central roles in the immune and inflammatory responses, it is also believed to play a role in the onset and development of diseases and degenerative disorders when not kept in check. In vivo, this process is generally initiated by the reduction of O2 to superoxide (O2•-), which can then afford various reactive oxygen species (ROS), such as HOO•, H2O2, HO•, and 1O2. Recently, it was suggested that antibodies, as part of the immune system, produce another ROS: ozone. The evidence for endogenous ozone formation was based largely on the isolation of the known cholesterol ozonolysis products in extracts of arterial plaque and brain tissue. Identification was accomplished by derivatization and subsequent HPLC-MS analysis. Herein, an alternative, more likely explanation for the appearance of these two compounds and their derivatized forms is given, via acid-catalyzed Hock cleavage of cholesterol 5-hydroperoxide. Radical-trapping chain-breaking antioxidants inhibit hydrocarbon autoxidation; in Nature and as additives in industrial materials, formulations, etc. Nature typically employs phenols in this context, and it is well documented that their potency is based largely on the lability of their phenolic O-H bond. While their reactivity can be improved by making the phenol more electron-rich by introducing electron-donating groups on the aromatic ring, this increases their air (oxygen) sensitivity, leading them to decompose in air and generate ROS themselves! To prevent this, nitrogen(s) can be introduced in the aromatic ring to make 3-pyridinols and 5-pyrimidinols; the most effective air-stable radical-trapping antioxidants reported to date. Unfortunately, introduction of nitrogen in the phenolic ring leads to a concomitant increase in the acidity of the O-H bond, leading to stronger interactions with H-bond accepting solvents. This interaction reduces the efficacy of these compounds as antioxidants in polar and heterogeneous media. Herein we describe our efforts to minimize the effect of this interaction, thereby maintaining the strong antioxidant activities of 3-pyridinols and 5-pyrimidinols, by introducing two tert-butyl moieties flanking the reactive hydroxyl group. / Thesis (Master, Chemistry) -- Queen's University, 2008-11-21 14:30:19.24

Cholesterol is one of the most abundant lipids in the body, and like all unsaturated lipids, it can be oxidized by a variety of reactive oxygen species (ROS). Lipid peroxidation is one of the main pathways by which ROS induce oxidative damage, and has been linked to neurodegenerative and cardiovascular diseases. In 2003, Wentworth et al. detected both 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A) and its intramolecular aldolization product 3β-hydroxy-5β-hydroxy-B-norcholestane-6β-carboxaldehyde (secosterol-B) in human atherosclerotic plaques – compounds which, at the time, were only known to be formed by cholesterol ozonolysis. However, our group has shown that cholesterol 5α-hydroperoxide, which is the product of the reaction of cholesterol with singlet oxygen, can undergo acid-catalyzed Hock fragmentation to generate secosterol-A and -B as well. Nevertheless, cholesterol 5α-hydroperoxide readily rearranges to a more thermodynamically stable cholesterol 7-hydroperoxide. Herein we show that cholesterol 7-hydroperoxide, the main product of cholesterol autoxidation, can also undergo acid-catalyzed Hock fragmentation that gives rise to electrophilic species with similar chromatographic characteristics to those that were allegedly identified as secosterol-A and -B. We also proposed to prepare authentic products of the Hock fragmentation of cholesterol 7-hydroperoxide by subjecting Δ⁶’⁷-cholesterol to ozonolysis. Herein, we explore the limitations and complications of Δ⁶’⁷-cholesterol ozonolysis as well as cholesterol 7-OOH Hock fragmentation which both resulted in unexpected (unprecedented) products.

Nitroxides are intermediates in the accepted reaction mechanisms of the antioxidant activity of diarylamines and hindered alkyl amines. The parent amines are used as additives to preserve synthetic and natural hydrocarbon-based materials from oxidative degradation. 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 previously overlooked mechanism. Experimental and computational investigations suggest that the nitroxides catalyze the cross-dismutation of alkylperoxyl and hydroperoxyl radicals to yield a hydroperoxide and O2, 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 unsaturated hydrocarbonbased 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. Polyunsaturated fatty acids (PUFAs) are highly autoxidizable lipids that are integral structural components of biological membranes as well as substrates for enzymes the produce inflammatory mediators implicated in a host of degenerative diseases. In particular, the interactions between these substrates and their respective native enzymes are hotly pursued since elucidation of the underlying mechanisms could lead to the discovery of better small molecule inhibitors for the ailments to which they contribute. In the past decade, an additional mode of cellular degeneration has been unveiled in the process of ferroptosis whose hallmark includes a sharp increase in the cellular pool of PUFA derived hydroperoxides. As a result, there is further incentive to uncover all mechanisms by which these inflammatory precursors are developed. Herein, progress toward the synthesis of fluorinated PUFAs is presented. These are proposed to be useful to probe the interactions of PUFAs with lipoxygenase enzymes, which metabolize polyunsaturated fatty acids to their hydroperoxide derivatives.

The reactive nitric oxide species (RNOS) nitroxyl (HNO) has exhibited both beneficial and deleterious biological effects. In particular, HNO autoxidation can lead to harmful modifications of biomolecules, yet the products of HNO/O₂ remain undetermined. A conceivable product is peroxynitrous acid (ONOOH), however a comparison of the chemistry of HNO/O₂ to synthetic peroxynitrite (ONOO⁻) determined that these RNOS have distinct reactive profiles. This study compares the reactivity of HNO and NO⁻ in the presence of O₂ to synthetic ONOO⁻ and the autoxidation of HNO at high pH (NO⁻/O₂) in an effort to shed light on the products of HNO autoxidation. All species exhibited the capacity for two-electron oxidation, but differences between ONOO⁻ and NO⁻/O₂ and HNO/O₂ were observed in terms of one-electron oxidation, hydroxylation, nitration and buffer effects. NO⁻/O₂ exhibited a reactive profile similar to ONOO⁻, suggesting that protonation of ONOO⁻leads to a unique species from the autoxidation of HNO.

The thermal oxidative stability of middle distillate fuels is a topic of considerable concern. There are several examples of ambient temperature oxidation of fuel, leading to particulate matter and filtration issues. It is shown that particulate matter values vary globally based on region and fuel type, suggesting the problem is more than mere inorganic matter. The variability of filtration times is not dependent on absolute particulate matter present; it is suggested to be dependent upon the nature or morphology of deposit. <br>For a more thorough understanding of the chemistry responsible for deposit formation, flask oxidation was employed to test the Soluble Macromolecular Oxidatively Reactive Species (SMORS) mechanism. Spectral data suggest the presence of alcoholic and carbonylic functionality, which is in agreement with how the SMORS mechanism defines deposit formation. It has also been determined that the introduction of compounds conceivably indigenous to jet fuels has a negative impact on deposit formation. In addition, it has been shown the elemental composition of thermally induced deposit entails significant heteroatom content. <Br>According to the SMORS mechanism, one of the primary reasons for deposit formation is the presence of radical initiators. The paraffinic blending of fuels shows promise in oxidatively stabilizing jet fuels. Research suggests blending reduces oxidation by diluting both the radical initiators and soluble deposit precursors. It is possible the use of this method could improve filter life and decrease operational costs. <br>A better understanding of the chemistry of deposit formation can lead to improved deposit inhibitors. Additives that have shown promise in bomb tubing studies were tested using flask oxidation. Additionally, extracted fuel polars reintroduced into the fuel at 0.3% v/v were tested for antioxidative activity. It was concluded the introduction of ppm levels of polar compounds extracted from fuel back into a fuel is very successful in limiting oxidative product formation. <br>One strategy for inhibiting deposit formation is the use of compounds that can act as oxygen/hydroperoxide scavengers. A linear free energy Hammett plot was developed for the reaction between molecular oxygen and triarylphosphines. Results indicate a very small positive charge buildup, suggesting a nonsynchronous concerted reaction. / Bayer School of Natural and Environmental Sciences / Chemistry and Biochemistry / PhD / Dissertation

University, Diss--Hohenheim, 2000.

Autoxidation, a radical chain reaction, is largely responsible for the degradation of most man-made and biological materials. These include chemical products such as lubricants, plastics and rubber; as well as biological molecules and membranes within our bodies. The development of means to hinder this process has been a major focus of the petroleum, chemical, pharmaceutical and biotechnology industry over the past century. The two most common strategies to emerge from these efforts have been the use of compounds that either prevent the initiation of autoxidation or trap the propagating radicals, so-called radical-trapping antioxidants (RTAs). Herein, we describe our efforts towards the design and development of extremely potent heterocyclic diarylamine RTAs, and their activity in a variety of applications ranging from isotropic organic solution to mammalian cells. We have elucidated the important structural motifs and mechanistic considerations necessary for the development of next-generation arylamine RTAs. Some of the substituted heterocyclic diarylamines analogs we disclose are among the best inhibitors of high temperature autoxidations described to date. Alongside, we developed novel analytical tools to facilitate the studies and acquisition of results for characterizing RTA activity in organic solutions and lipid bilayers. These fluorescent probes are highly relevant and allow for the determination of hydroperoxide and acid concentrations rapidly, as well as screen (or counter-screen) RTAs in liposomal membranes. Our methodologies address numerous drawbacks from frequently used ‘plug-and-play’ assays and we anticipate they will fill a current unmet need in both industrial and academic laboratories worldwide. Moreover, the recent characterization of ferroptosis – a novel regulated necrotic-like cell-death pathway associated with the accumulation of lipid hydroperoxides – has paved a way forward for studying oxidation induced damage in a biological context. Utilizing our expertise in lipid peroxidation and inhibition, we elucidated the prominent role of autoxidation in the execution of ferroptotic cell death. Alongside, our analytical tools and RTAs have also enabled the identification and characterization of novel ferroptosis inhibitors. Furthermore, this has prompted the development of a correlation to predict anti-ferroptosis activity of small-molecules using simple spectrophotometric assays.

The oxidative degradation of organic materials typically operates through a radical-mediated chain mechanism known as autoxidation; a process that has severe consequences in both biological settings (i.e. accumulation of lipid peroxides) and non-living substrates (i.e. breakdown of petroleum-derived materials, such as lubricants/oils, plastics, polymers, rubbers, etc.). However, autoxidation can be retarded by radical-trapping antioxidants (RTAs); chemical species that capture chain-carrying radicals to break the chain of oxidation. A particular class of RTA, diarylamines, have proven especially effective at elevated temperatures due to a purported catalytic mechanism of inhibiting autoxidation, and thus, have found significant use as protective agents in engine lubricant oils. However, the current diarylamine technology struggles to manage the increased oxidative stress placed on it by modern internal combustion engines (ICEs), which burn fuel at higher temperatures in order to meet emission standards. Designing superior diarylamines is not straightforward, however, as the mechanisms by which they are forced from their catalytic cycle are not well understood. Herein, we report our investigations into the fate of an industrially-representative, isotopically-enriched diarylamine during hydrocarbon autoxidation at elevated temperatures using a novel 2D 1H – 15N heteronuclear multiple bond correlation (HMBC) spectroscopic technique. Synthesis of a small scope of oxidation products allowed for the identification of a previously unreported product of diarylamine autoxidation. Additionally, a consistent pattern of diarylamine speciation under varying conditions was observed spectroscopically. Use of the HMBC technique also confirmed previous reports of the regenerative ability of the diarylamine and the intermediates of its purported catalytic cycle. Quantification studies using ultra performance liquid chromatography (UPLC) during the early stages of autoxidation provided insight into the formation of initial diarylaminic intermediates. Additionally, we examined the fate of the diarylamine during autoxidations in the presence of nitrogen oxides (NOx), which are found in the blow-by gas of ICEs and have been shown to exacerbate hydrocarbon autoxidation. The performance of diarylamine was drastically reduced under such conditions, and HMBC spectroscopy illustrated its rapid conversion to a number of intermediates. The most prominent two intermediates were identified as mono- and di-nitrated analogues of the original diarylamine, and were demonstrated to possess no RTA activity; regardless of temperature or substrate. HMBC spectroscopy also illustrated the differences in product distribution under each set of conditions.