Preparation of Highly Reactive Pyridine- and Pyrimidine-Containing Diarylamine Antioxidants

We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn, J. J. et al. J. Am. Chem. Soc. 2012, 134, 8306−8309) wherein we demonstrated that the incorporation of ring nitrogens into diphenylamines affords compounds which display a compromise between H-atom transfer reactivity to peroxyl radicals and stability to one-electron oxidation. Herein we provide the details of the synthetic efforts associated with that report, which have been substantially expanded to produce a library of substituted heterocyclic diarylamines that we have used to provide further insight into the structure–reactivity relationships of these compounds as antioxidants (see the accompanying paper, DOI: 10.1021/jo301012x). The diarylamines were prepared in short, modular sequences from 2-aminopyridine and 2-aminopyrimidine wherein aminations of intermediate pyri­(mi)­dyl bromides and then Pd-catalyzed cross-coupling reactions of the amines and precursor bromides were the key steps to yield the diarylamines. The cross-coupling reactions were found to proceed best with Pd­(η³-1-PhC₃H₄)­(η⁵-C₅H₅) as precatalyst, which gave higher yields than the conventional Pd source, Pd₂(dba)₃

Antioxidant Activity of Magnolol and Honokiol: Kinetic and Mechanistic Investigations of Their Reaction with Peroxyl Radicals

Magnolol and honokiol, the bioactive phytochemicals contained in Magnolia officinalis, are uncommon antioxidants bearing isomeric bisphenol cores substituted with allyl functions. We have elucidated the chemistry behind their antioxidant activity by experimental and computational methods. In the inhibited autoxidation of cumene and styrene at 303 K, magnolol trapped four peroxyl radicals, with a <i>k</i>_inh of 6.1 × 10⁴ M^–1 s^–1 in chlorobenzene and 6.0 × 10³ M^–1 s^–1 in acetonitrile, and honokiol trapped two peroxyl radicals in chlorobenzene (<i>k</i>_inh = 3.8 × 10⁴ M^–1 s^–1) and four peroxyl radicals in acetonitrile (<i>k</i>_inh = 9.5 × 10³ M^–1 s^–1). Their different behavior arises from a combination of intramolecular hydrogen bonding among the reactive OH groups (in magnolol) and of the OH groups with the aromatic and allyl π-systems, as confirmed by FT-IR spectroscopy and DFT calculations. Comparison with structurally related 3,3′,5,5′-tetramethylbiphenyl-4,4′-diol, 2-allylphenol, and 2-allylanisole allowed us to exclude that the antioxidant behavior of magnolol and honokiol is due to the allyl groups. The reaction of the allyl group with a peroxyl radical (C–H hydrogen abstraction) proceeds with rate constant of 1.1 M^–1 s^–1 at 303 K. Magnolol and honokiol radicals do not react with molecular oxygen and produce no superoxide radical under the typical settings of inhibited autoxidations

Incorporation of Ring Nitrogens into Diphenylamine Antioxidants: Striking a Balance between Reactivity and Stability

The incorporation of nitrogen atoms into the aryl rings of conventional diphenylamine antioxidants enables the preparation of readily accessible, air-stable analogues, several of which have temperature-independent radical-trapping activities up to 200-fold greater than those of typical commercial diphenylamines. Amazingly, the nitrogen atoms raise the oxidation potentials of the amines without greatly changing their radical-trapping (H-atom transfer) reactivity

Unprecedented Inhibition of Hydrocarbon Autoxidation by Diarylamine Radical-Trapping Antioxidants

The 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

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

We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn et al. <i>J. Am. Chem. Soc.</i> <b>2012</b>, <i>134</i>, 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 >10⁷ M^–1 s^–1, which correspond to the pre-exponential factors that we obtained for a representative trio of compounds (log <i>A</i> ∼ 7), indicating that the activation energies (<i>E</i>_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

5‑<i>S</i>‑Lipoylhydroxytyrosol, a Multidefense Antioxidant Featuring a Solvent-Tunable Peroxyl Radical-Scavenging 3‑Thio-1,2-dihydroxybenzene Motif

5-<i>S</i>-Lipoylhydroxytyrosol (<b>1</b>), the parent member of a novel group of bioinspired multidefense antioxidants, is shown herein to exhibit potent peroxyl radical scavenging properties that are controlled in a solvent-dependent manner by the sulfur center adjacent to the active <i>o</i>-diphenol moiety. With respect to the parent hydroxytyrosol (HTy), <b>1</b> proved to be a more potent inhibitor of model autoxidation processes in a polar solvent (acetonitrile), due to a lower susceptibility to the adverse effects of hydrogen bonding with the solvent. Determination of O–H bond dissociation enthalpies (BDE) in <i>t</i>-butanol by EPR radical equilibration technique consistently indicated a ca. 1.5 kcal/mol lower value for <b>1</b> relative to HTy. In good agreement, DFT calculations of the BDE_OH using an explicit methanol molecule to mimic solvent effects predicted a 1.2 kcal/mol lower value for <b>1</b> relative to HTy. Forcing the geometry of the -S-R group to coplanarity with the aromatic ring resulted in a dramatic decrease in the computed BDE_OH values suggesting a potentially higher activity than the reference antioxidant α-tocopherol, depending on geometrical constrains in microheterogeneous environments. These results point to sulfur substitution as an expedient tool to tailor the chain-breaking antioxidant properties of catechol derivatives in a rational and predictable fashion

Redox Chemistry of Selenenic Acids and the Insight It Brings on Transition State Geometry in the Reactions of Peroxyl Radicals

The redox chemistry of selenenic acids has been explored for the first time using a persistent selenenic acid, 9-triptyceneselenenic acid (RSeOH), and the results have been compared with those we recently obtained with its lighter chalcogen analogue, 9-triptycenesulfenic acid (RSOH). Specifically, the selenenyl radical was characterized by EPR spectroscopy and equilibrated with a phenoxyl radical of known stability in order to determine the O–H bond dissociation enthalpy of RSeOH (80.9 ± 0.8 kcal/mol): ca. 9 kcal/mol stronger than in RSOH. Kinetic measurements of the reactions of RSeOH with peroxyl radicals demonstrate that it readily undergoes H-atom transfer reactions (e.g., <i>k</i> = 1.7 × 10⁵ M^–1 s^–1 in PhCl), which are subject to kinetic solvent effects and kinetic isotope effects similar to RSOH and other good H-atom donors. Interestingly, the rate constants for these reactions are only 18- and 5-fold smaller than those measured for RSOH in PhCl and CH₃CN, respectively, despite being 9 kcal/mol less exothermic for RSeOH. IR spectroscopic studies demonstrate that RSeOH is less H-bond acidic than RSOH, accounting for these solvent effects and enabling estimates of the p<i>K</i>_as in RSeOH and RSOH of ca. 15 and 10, respectively. Calculations suggest that the TS structures for these reactions have significant charge transfer between the chalcogen atom and the internal oxygen atom of the peroxyl radical, which is nominally better for the more polarizable selenenic acid. The higher than expected reactivity of RSeOH toward peroxyl radicals is the strongest experimental evidence to date for charge transfer/secondary orbital interactions in the reactions of peroxyl radicals with good H-atom donors

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

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<b>·</b>. Extremely efficient quenching of HOO<b>·</b> 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<b>·</b> → TEMPOH + O₂ and 5.0 × 10⁷ M^–1 s^–1 for the oxidative reaction TEMPOH + HOO<b>·</b> → 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 (<i>k</i> = 1.6 × 10⁶ M^–1 s^–1). These data show that in the presence of ROO<b>·</b>-to-HOO<b>·</b> 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 nonaqueous systems and its potential to act as a chemoprotective against radical damage

Red-Hair-Inspired Chromogenic System Based on a Proton-Switched Dehydrogenative Free-Radical Coupling

In the presence of micromolar peroxides or biometals (Fe(III), Cu(II), V(V) salts), and following a strong acid input, the stable 3-phenyl-2<i>H</i>-1,4-benzothiazine is efficiently converted to a green-blue Δ^2,2′-bi(2<i>H</i>-1,4-benzothiazine) chromophore via dehydrogenative coupling of a 1,4-benzothiazinyl radical. The new system is of potential practical interest for colorimetric peroxide and redox biometal detection