Maximizing the reactivity of phenolic and aminic radical-trapping antioxidants: Just add nitrogen!

Conspectus 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.