The Reactivity of Air-Stable Pyridine- and Pyrimidine-Containing Diarylamine Antioxidants

Abstract

We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn et al. J. Am. Chem. Soc.2012, 134, 8306-8309), wherein we demonstrated that the incorporation of ring nitrogens into diphenylamines affords compounds that display a compromise between H-atom transfer reactivity to peroxyl radicals and stability to one-electron oxidation. Herein, we report the results of thermochemical and kinetic experiments on an expanded set of diarylamines (see the accompanying paper, DOI: 10.1021/jo301013c ), which provide a more complete picture of the structure-reactivity relationships of these compounds as antioxidants. Nitrogen incoporation into a series of alkyl-, alkoxyl-, and dialkylamino-substituted diphenylamines raises their oxidation potentials systematically with the number of nitrogen atoms, resulting in overall increases of 0.3-0.5 V on going from the diphenylamines to the dipyrimidylamines. At the same time, the effect of nitrogen incorporation on their reactivity toward peroxyl radicals was comparatively small (a decrease of only 6-fold at most), which is also reflected in their N-H bond dissociation enthalpies. Rate constants for reactions of dialkylamino-substituted diarylamines with peroxyl radicals were found to be >10(7) M(-1) s(-1), which correspond to the pre-exponential factors that we obtained for a representative trio of compounds (log A ∼ 7), indicating that the activation energies (E(a)) are negligible for these reactions. Comparison of our thermokinetic data for reactions of the diarylamines with peroxyl radicals with literature data for reactions of phenols with peroxyl radicals clearly reveals that diarylamines have higher inherent reactivities, which can be explained by a proton-coupled electron-transfer mechanism for these reactions, which is supported by theoretical calculations. A similar comparison of the reactivities of diarylamines and phenols with alkyl radicals, which must take place by a H-atom transfer mechanism, clearly reveals the importance of the polar effect in the reactions of the more acidic phenols, which makes phenols comparatively more reactive.

Maximizing the Reactivity of Phenolic and Aminic Radical-Trapping Antioxidants: Just Add Nitrogen!

“…With a large library of symmetric and unsymmetric substituted diarylamines in hand, Hanthorn was able to determine the kinetics of their reactions with peroxyl radicals using a radical clock methodology he developed in parallel, 31 as well as the redox potentials of the compounds, some of which are shown in Table 5 along with N−H BDEs determined by the eminently reliable REqEPR method. 28,29 The experimental data were again fully consistent with our theoretical predictions. For example, upon replacement of the two phenyl rings in the industrial standard dialkyldiphenyl- (16), the oxidation potential increased by 100 mV, but the reactivity dropped only 2-fold.…”

“…The high reactivities of these compounds, and the similarity in their reactivities, could clearly be attributed to their weak N−H BDEs, which were almost indistinguishable regardless of the extent of nitrogen incorporation in the ring (for comparison, the N−H BDE in the bis(N,N-dialkylamino)-substituted diphenylamine was 78.4 kcal/mol). 28,29 The temperature dependence of k inh was determined for three representative diarylamines, including 4,4′-dioctyldiphenylamine 2, and pre-exponential factors of log A ≈ 7 were found, implying that the reactions of 18−20 with peroxyl radicals proceed with E a ≈ 0 and rates that are independent of temperature.…”

“…0.1−0.3 kcal/mol per N atom in diarylamines vs 1.1−1.5 kcal/ mol per N atom in phenols). 29 We ascribed this difference to the fact that a diarylaminyl radical is inherently less electronpoor than a phenoxyl radical and is therefore destabilized to a lesser extent upon introduction of the more electronegative N atom(s) in the aromatic rings in place of carbon(s). Another intriguing finding was that diarylamines are inherently more reactive than phenolsthat is, diarylamines with a given N−H BDE react more quickly with peroxyl radicals than phenols with the same (O−H) BDE.…”

Computational strategies for predicting free radical scavengers' protection against oxidative stress: Where are we and what might follow?

“…[259] -Vitamin E, ubiquinol, eupatilin, diarylamines, sulfenic acids, and halooximes of lawsone; scavenging different oxidants. [260][261][262][263][264][265][266] Involving multiple steps Sequential Proton Loss Electron Transfer (SPLET):…”

Methods for determining the efficacy of radical-trapping antioxidants

“…∆H ‡ and ∆S ‡ ), which provide mechanistic information. 52,59,61 It is important to point out that each of the peroxyl radical clock methods were calibrated using the k inh value of α-TOH, i.e. the rate constant for Overall, the methyl linoleate, allylbenzene and the β-naphthylperbut-3-enoate derived radical clocks developed since 2001 provide simple but reliable methods to measure the absolute k inh for phenolic, aminic and organosulfur antioxidants in a number of different organic solutions.…”