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Maximizing the reactivity of phenolic and aminic radical-trapping antioxidants: Just add nitrogen!
No full textConspectus Hydrocarbon autoxidation, the archetype free radical chain reaction, challenges the longevity of both living organisms and petroleum-derived products. The most important strategy in sloing this process is via the intervention of radical-trapping antioxidants (RTAs), hich are abundant in nature and included as additives to almost every petroleum-derived product as ell as several other commercial products. Accordingly, a longstanding objective of many academic and industrial scientists has been the design and development of novel RTAs that can outperform natural and industrial standards, such as α-tocopherol, the most biologically active form of vitamin E, and dialkylated diphenylamines, respectively.Some time ago e recognized that attempts to maximize the reactivity of phenolic RTAs had largely failed because substitution of the phenolic ring ith electron-donating groups to eaken the O-H bond and accelerate the rate of H atom transfer to radicals leads to compounds that are unstable in air. e surmised that incorporating nitrogen into the phenolic ring ould render them more stable to one-electron oxidation, enabling their substitution ith strong electron-donating groups. Guided by computational chemistry, e demonstrated that replacing the phenyl ring in very electron-rich phenols ith either 3-pyridyl or 5-pyrimidyl rings leads to phenolic-like RTAs ith good air stability and great reactivity. In fact, rate constants determined for the reactions of some compounds ith peroxyl radicals ere almost 2 orders of magnitude greater than those for α-tocopherol and implied that the reactions proceeded ithout an enthalpic barrier. Folloing extensive thermochemical and kinetic characterization, e took our studies of these compounds to more physiologically relevant media, such as lipid bilayers and human lo density lipoproteins, here the heterocyclic analogues of vitamin E shone, displaying unparalleled abilities to inhibit lipid peroxidation and prompting their current investigation in animal models of degenerative disease. Moreover, e carried out studies of these compounds in several industrially relevant contexts and in particular demonstrated that they could be used synergistically ith less reactive, less expensive, phenolic RTAs.More recently, our attention has turned to the application of these ideas to maximizing the reactivity of diarylamine RTAs that are common in additives to petroleum-derived products, such as lubricating oils, transmission and hydraulic fluids, and rubber. In doing so, e have developed the most reactive diarylamines ever reported. The 3-pyridyl- and 5-pyrimidyl-containing diarylamines are easily accessed using Pd- and/or Cu-catalyzed cross-coupling reactions, and display an ideal compromise beteen reactivity and stability. The most reactive compounds are characterized by rate constants for reactions ith peroxyl radicals that are independent of temperature, implying that-as for the most reactive heterocyclic phenols-these reactions proceed ithout an enthalpic barrier. Unprecedented reactivity as also observed hen hydrocarbon autoxidations ere carried out at elevated temperatures, real-orld conditions here diarylamines are uniquely effective because of a catalytic RTA activity that makes use of the hydrocarbon substrate as a sacrificial reductant. Our studies to date suggest that heterocyclic diarylamines have real potential to increase the longevity of petroleum-derived products in a variety of applications here diphenylamines are currently used
Substituted Diarylamines and Use of Same as Antioxidants
No full textA compound of Formula I, Formula IA, Formula IB, or Formula II, or an acid or base addition salt thereof, and use of these compounds as antioxidants. In one embodiment, a compound of Formula II, wherein each of X, Y, and Z are independently a carbon or nitrogen atom; R1 and R2 are each independently a hydrogen or an electron donating group, but are not both hydrogen, and wherein R1, and R2 are each bonded to a carbon atom in their own respective aryl ring
Antioxidants and methods to maximize performance
No full textA method of preventing or reducing the level of degradation of an organic substrate is described, wherein a composition is formed that includes the organic substrate together with an effective amount of a sacrificial base and a diarylamine antioxidant
Unprecedented Inhibition of Hydrocarbon Autoxidation by Diarylamine Radical-Trapping Antioxidants
No full textThe
reactivities of novel heterocyclic diarylamine radical-trapping
antioxidants (RTAs) are profiled in a heavy hydrocarbon at 160 °C,
conditions representative of those at which diphenylamine RTAs are
used industrially. While carboxylic acids produced during the autoxidation
are shown to deactivate these more basic RTAs, the addition of a sacrificial
base leads to efficacies that are unprecedented in the decades of
academic and industrial research in this area
From Membranes to Motor Oil: Exploring the Opportunities and Limitations of Phenoxazine and Phenothiazine Antioxidants by the Application of Fundamental Physical Organic Chemistry
No full textAutoxidation is a radical mediated chain-process that involves initiation, propagation, branching and termination reactions and is responsible for the spontaneous peroxidation of hydrocarbons, formally appearing as RH + O₂ → ROOH. Autoxidation is a consequentially damaging process in many domains, ranging from materials to automotive transportation to biology and medicine. One of the key intermediates in the propagation of autoxidation is the peroxyl radical (ROO•) which can be targeted by radical-trapping antioxidants (RTAs) that promote chain-termination, mitigating the damage of autoxidation. Chapter 1 lays out the fundamental chemistry of both autoxidation and RTAs as well as a history of the rational design of phenol and diarylamine-type RTAs.
Lipid-peroxidation (i.e. autoxidation) is a key feature of ferroptosis which is a form of cell death that has been associated with many serious conditions such as ALS, Alzheimer's, Huntington's and Parkinson's disease, and lipid-soluble RTAs such as Vitamin E have been shown to acutely suppress ferroptosis. An aspect of RTA chemistry that has not been well studied/understood hitherto is their kinetic behaviour in phospholipid membranes, and we hypothesized that this would be a very relevant consideration for designing compounds that target lipid-peroxidation and ferroptosis. In Chapter 2 we systematically examine the kinetic behaviour for a series of hindered and unhindered phenolic RTAs in various mediums, particularly in phosphatidylcholine (PC) liposomes. The key chemical interaction in the PC membrane that fundamentally changed the observed kinetics of the phenolic RTAs is a very strong hydrogen-bonding interaction with the phosphate-diester headgroup that suppresses the phenols' ability to trap ROO•, an effect that was previously overlooked.
In Chapter 3 we further expanded/validated the model by studying over 40 phenoxazine (PNX) and phenothiazine-based (PTZ) RTAs, which showed the quantitative/predictive capabilities of the H-bonding effect. By introducing a water-soluble co-antioxidant, Vitamin C (ascorbate), we were able to study many features of the PNX/PTZ radical intermediates with respect to their reactivity and dynamics. The PNX/PTZ were far more persistent than the Vitamin E analogue 2,2,5,7,8-pentamethyl-6-chromanol (PMC), meaning that they catalytically trapped lipid-peroxyls far more efficiently (i.e., higher turnover number). Additionally, there is strong evidence suggesting that the PNX/ascorbate synergism is a diffusion-controlled process. The study was further expanded to biological models. Ferroptosis in vitro was inhibited by every single one of these compounds, and there was a general positive correlation between RTA kinetics (kᵢₙₕ) and ferroptosis rescue potency (EC₅₀) as well as a positive correlation between lipophilicity (logP) and ferroptosis rescue potency. A lead PNX compound, 3-trifluoromethyl-8-tert-butylphenoxazine, was identified in this study on the basis of superior potency and metabolic stability. When used to treat mice with GPx4 deletion in kidneys, an in vivo model of ferroptosis, it was found to extend the life of the mice in a statistically significant fashion compared to the vehicle control.
In Chapter 4 there is further elaboration on the dynamics of PNX/ascorbate synergy and a demonstration of the early works toward developing a drug-like-PNX ferroptosis inhibitor, based on the conclusions from the work in Chapter 3.
In Chapters 5 and 6 the research is focused on the development novel RTAs for the application of inhibiting autoxidation in lubricants in high temperature environments. Heavy machinery and most transportation technologies require lubrication to aid safe and efficient movement, and these lubricants/greases are highly susceptible to autoxidation. Large quantities of RTA additives are expended to extend the service life of these materials and there is a constant appetite for innovation to find new and improved RTAs for improved economics and competitiveness. In Chapter 5 the behaviour of PNX and PTZ in a simulated high temperature lubricant autoxidations are analyzed, revealing that PNX is highly susceptible to direct O₂-mediated oxidation due to its rapid electron-transfer kinetics, while PTZ is far more resilient despite both compounds having nearly identical oxidation potentials. In Chapter 6, in this same context, previously unreported substituent effects are analyzed which significantly enhance the period of inhibition (tᵢₙₕ) for PTZ compounds. Particular alkyl substituents on the PTZ can increase the number of chains-trapped at high temperatures by fortuitous substituent oxidation that promotes termination, substantially improving their atom-economy. These findings prompt a broader critique of putative catalytic RTA mechanisms which have been taken for granted for nearly three decades
Towards Fluorinated Substrate Analogs and N-Acylated 2-Aminopyrimidine Inhibitors of Lipoxygenases
No full textCyclooxygenase (COX) and lipoxygenase (LOX) catalyze the rate-determining step in the production of arachidonic acid- derived signaling molecules (eicosanoids) within the body. COX has been extensively investigated, which has enabled the design of non-steroidal inflammatory drugs (NSAIDs) such as aspirin, acetaminophen (ApAP) and ibuprofen. However, there are still fundamental questions surrounding the LOX family of enzymes, which has limited the development of isoform specific inhibitors. The structural basis and regio- and stereoselectivity of the LOX isoforms are not known. Herein, we describe two strategies to develop isoform-specific inhibitors of lipoxygenase.
Efforts were focused on the synthesis of unnatural lipid derivatives, in which the methylene hydrogen atoms on the substrate were replaced with a moiety lacking a labile hydrogen atom, such as fluorine. This would allow the LOX enzyme to remain in an active form, while preventing enzyme turnover. This preliminary work will enable the assessment of their activity as inhibitors and attempts at their co-crystallization might provide the first insight into the binding mode of these fatty acid substrates.
The preparation of a small library of acylated 2-aminopyrimidines and their efficacy as inhibitors of soybean lipoxygenase-1 was explored. Preliminary studies suggest the mode of action occurs through a bi-dentate coordination of the ferric iron atom. Modifications of the acylated 2-aminopyrimidines to make it more substrate-like and to increase its lipophilicity, yielded inhibitors with low micromolar IC50 values. With further optimization, acyl 2-aminopyrimidines could serve as a useful platform for the discovery of safe and efficient isoform specific inhibitors
Towards Fluorinated Substrate Analogs and N-Acylated 2-Aminopyrimidine Inhibitors of Lipoxygenases
No full textCyclooxygenase (COX) and lipoxygenase (LOX) catalyze the rate-determining step in the production of arachidonic acid- derived signaling molecules (eicosanoids) within the body. COX has been extensively investigated, which has enabled the design of non-steroidal inflammatory drugs (NSAIDs) such as aspirin, acetaminophen (ApAP) and ibuprofen. However, there are still fundamental questions surrounding the LOX family of enzymes, which has limited the development of isoform specific inhibitors. The structural basis and regio- and stereoselectivity of the LOX isoforms are not known. Herein, we describe two strategies to develop isoform-specific inhibitors of lipoxygenase.
Efforts were focused on the synthesis of unnatural lipid derivatives, in which the methylene hydrogen atoms on the substrate were replaced with a moiety lacking a labile hydrogen atom, such as fluorine. This would allow the LOX enzyme to remain in an active form, while preventing enzyme turnover. This preliminary work will enable the assessment of their activity as inhibitors and attempts at their co-crystallization might provide the first insight into the binding mode of these fatty acid substrates.
The preparation of a small library of acylated 2-aminopyrimidines and their efficacy as inhibitors of soybean lipoxygenase-1 was explored. Preliminary studies suggest the mode of action occurs through a bi-dentate coordination of the ferric iron atom. Modifications of the acylated 2-aminopyrimidines to make it more substrate-like and to increase its lipophilicity, yielded inhibitors with low micromolar IC50 values. With further optimization, acyl 2-aminopyrimidines could serve as a useful platform for the discovery of safe and efficient isoform specific inhibitors
On the Origin of Formamides in Diarylamine-Inhibited Autoxidations & The Development of Latent Radical Trapping Antioxidants for High-Temperature Applications
No full textAutoxidation is a free radical chain reaction by which hydrocarbons undergo oxidative degradation. This process involves insertion of molecular oxygen into hydrocarbon-based materials such as oils, lubricants, polymers, etc. thereby altering their properties. Unlike living organisms, petroleum-derived products do not have inherent mechanisms to combat autoxidation. Therefore, they must be formulated with radical-trapping antioxidants (RTAs) which trap chain-propagating peroxyl radicals, terminating the radical chain. Although this technology has existed for decades, improvements are sought to keep up with ever more stringent environmental regulations, which requires internal combustion engines to operate at higher temperatures than previously, putting the lubricants under far greater oxidative stress. To improve RTAs, the process by which they are consumed and/or deactivated must be further understood.
Previous studies in our group revealed that N-formyl alkylated diphenylamines (ADPAs) are predominant products formed during ADPA-inhibited autoxidations of hydrocarbons at elevated temperatures. From previously known autoxidation products (acids, aldehydes, ketones, peracids, and alcohols), we hypothesized that N-formyl ADPAs arise from reactions of ADPAs with formate esters formed from Baeyer-Villiger oxidations of aldehydes. Herein we demonstrate that N-formyl ADPAs can be formed by this pathway. This was followed by a computational study to provide additional insight on the competition between formate ester and carboxylic acid formation, as the latter is almost exclusively observed in B-V oxidations of aldehydes. Surprisingly, the selectivity arising from these competing pathways has never been systematically evaluated as a function of temperature.
Additionally, to improve the stability - and therefore efficacy - of highly reactive diarylamine RTAs such as phenothiazine (PTZ) and phenoxazine (PNX), we have investigated the potential of N-acyl PTX and N-acyl PNZ derivatives as latent RTAs. Thus, we prepared various N-acyl derivatives that could serve as precursors to the reactive free amine by either intermolecular or intramolecular acyl substitution in situ. Additionally, we investigated the impact of para-substitution (relative to the amine) to investigate how electronics influence both the rate of release and the efficacy of the RTAs, which were determined in n-hexadecane autoxidations at 165 °C. Combining the performance metrics with kinetics of release will pave the way forward in RTA design
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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