Quinone methide dimers lacking labile hydrogen atoms are surprisingly excellent radical-trapping antioxidants

Raycroft, Mark A. R.; Chauvin, Jean‐Philippe R.; Galliher, Matthew S.; Romero, Kevin; Stephenson, Corey R. J.; Pratt, Derek A.

doi:10.1039/d0sc02020f

Cited by 13 publications

(14 citation statements)

References 46 publications

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“…The iron‐catalyzed oxidative coupling of the p ‐cresol derivatives 9 a (BHT) and 9 b with 5 a under the standard reaction conditions provided the N ‐benzylphenothiazines 10 a and 10 b (Scheme 5). The formation of compounds 10 proceeds via addition of the phenothiazine radical to the corresponding p ‐quinone methides generated by initial oxidation of the p ‐cresols 9 [42] . Moreover, the synthesis of 10 indicates that the present methodology can be applied for iron‐catalyzed C(sp 3 )−H/N−H coupling reactions.…”

Section: Resultsmentioning

confidence: 86%

“…The formation of compounds 10 proceeds via addition of the phenothiazine radical to the corresponding p-quinone methides generated by initial oxidation of the p-cresols 9. [42] Moreover, the synthesis of Chemistry-A European Journal 10 indicates that the present methodology can be applied for iron-catalyzed C(sp 3 )À H/NÀ H coupling reactions.…”

Section: Chemistry-a European Journalmentioning

confidence: 88%

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Iron‐Catalyzed Oxidative C−O and C−N Coupling Reactions Using Air as Sole Oxidant**

Purtsas

Rosenkranz

Dmitrieva

et al. 2022

Chemistry A European J

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We describe the oxygenation of tertiary arylamines, and the amination of tertiary arylamines and phenols. The key step of these coupling reactions is an iron-catalyzed oxidative CÀ O or CÀ N bond formation which generally provides the corresponding products in high yields and with excellent regioselectivity. The transformations are accomplished using hexadecafluorophthalocyanineÀ iron(II) (FePcF 16 ) as catalyst in the presence of an acid or a base additive and require only ambient air as sole oxidant.

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Section: Resultsmentioning

confidence: 86%

Section: Chemistry-a European Journalmentioning

confidence: 88%

Iron‐Catalyzed Oxidative C−O and C−N Coupling Reactions Using Air as Sole Oxidant**

Purtsas

Rosenkranz

Dmitrieva

et al. 2022

Chemistry A European J

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“…However, this quinone methide 8–8 dimer might be more active than the parent RSV, as has been reported by Pratt, Stephenson, and co-workers for the tert -butylated analogue, QMD; see Scheme 3 . 20 , 61 …”

Section: Resultsmentioning

confidence: 99%

Unexpected Role of pH and Microenvironment on the Antioxidant and Synergistic Activity of Resveratrol in Model Micellar and Liposomal Systems

Konopko

Litwinienko

2021

J. Org. Chem.

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Experimental and theoretical studies indicate that resveratrol (RSV, dietary polyphenol that effectively reduces cellular oxidative stress) is a good scavenger of hydroxyl, alkoxyl, and peroxyl radicals in homogeneous systems. However, the role of RSV as a chain-breaking antioxidant is still questioned. Here, we describe pH dependent effectiveness of RSV as an inhibitor of peroxidation of methyl linoleate in Triton X-100 micelles and in 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) liposomes, with the best effectiveness at pH 6 (stoichiometric factors, n , are 4.9 and 5.6, and the rate constants for reaction with peroxyl radicals, k inh , are 1200 and 3300 M –1 s –1 in micellar and liposomal systems, respectively). We propose the mechanism in which RSV-derived radicals are coupled to dimers with recovered ability to trap lipidperoxyl radicals. The formation of such dimers is facilitated due to increased local concentration of RSV at the lipid–water interface. Good synergy of RSV with α-tocopherol analogue in micelles and liposomes is in contrast to the previously reported lack of synergy in non-polar solvents; however, the increased persistency of tocopheroxyl radicals in dispersed lipid/water systems and proximal localization of both antioxidants greatly facilitate the possible recovery of α-TOH by RSV.

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“…This is reminiscent of the known reaction of a 1,4-semiquinone radical with a peroxyl radical to yield a quinone, which has comparable thermodynamics . Addition of a peroxyl radical to the resultant quinone-imine methide is expected to follow and is reminiscent of the known addition of a peroxyl radical to quinone methides, which we recently showed can be a decent chain-breaking reaction ( k ∼ 10 4 M –1 s –1 at 37 °C) . Given the greater thermodynamic stability of the diarylaminyl radical that results from addition to the N -aryl imino-quinone methide as compared to the phenoxyl radical resulting from addition to the quinone methide, the former should be an even better reaction than the latter.…”

Section: Discussionmentioning

confidence: 99%

“…39 Addition of a peroxyl radical to the resultant quinone-imine methide is expected to follow and is reminiscent of the known addition of a peroxyl radical to quinone methides, which we recently showed can be a decent chain-breaking reaction (k ∼ 10 4 M −1 s −1 at 37 °C). 40 Given the greater thermodynamic stability of the diarylaminyl radical that results from addition to the N-aryl imino-quinone methide as compared to the phenoxyl radical resulting from addition to the quinone methide, the former should be an even better reaction than the latter. The resultant diarylaminyl radical can be further oxidized to the p-formyl derivative, which could re-engage the Korcek cycle.…”

Section: ■ Discussionmentioning

confidence: 99%

Temperature-Dependent Effects of Alkyl Substitution on Diarylamine Antioxidant Reactivity

et al. 2021

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Alkylated diphenylamines are among the most efficacious radical-trapping antioxidants (RTAs) for applications at elevated temperatures since they are able to trap multiple radical equivalents due to catalytic cycles involving persistent diphenylnitroxide and diphenylaminyl radical intermediates. We have previously shown that some heterocyclic diarylamine RTAs possess markedly greater efficacy than typical alkylated diphenylamines, and herein, report on our efforts to identify optimal alkyl substitution of the scaffold, which we had found to be the ideal compromise between reactivity and stability. Interestingly, the structure–activity relationships differ dramatically with temperature: para-alkyl substitution slightly increased reactivity and stoichiometry at 37 and 100 °C due to more favorable (stereo)electronic effects and corresponding diarylaminyl/diarylnitroxide formation, while ortho-alkyl substitution slightly decreased both reactivity and stoichiometry. No such trends were evident at 160 °C; instead, the compounds were segregated into two groups based on the presence/absence of benzylic C–H bonds. Electron spin resonance spectroscopy indicates that increased efficacy was associated with lesser diarylnitroxide formation, and deuterium-labeling suggests that this is due to abstraction of the benzylic H atom, precluding nitroxide formation. Computations predict that this reaction path is competitive with established fates of the diarylaminyl radical, thereby minimizing the formation of off-cycle products and leading to significant gains in high-temperature RTA efficacy.

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Quinone methide dimers lacking labile hydrogen atoms are surprisingly excellent radical-trapping antioxidants

Abstract: Quinone method dimers, (bio)synthetic intermediates en route to many naturally products derived from resveratrol, are potent radical-trapping antioxidants, besting the phenols from which they are derived and to which they can be converted.

Cited by 13 publications

References 46 publications

Iron‐Catalyzed Oxidative C−O and C−N Coupling Reactions Using Air as Sole Oxidant**

Iron‐Catalyzed Oxidative C−O and C−N Coupling Reactions Using Air as Sole Oxidant**

Unexpected Role of pH and Microenvironment on the Antioxidant and Synergistic Activity of Resveratrol in Model Micellar and Liposomal Systems

Temperature-Dependent Effects of Alkyl Substitution on Diarylamine Antioxidant Reactivity

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