Temperature-Dependent Effects of Alkyl Substitution on Diarylamine Antioxidant Reactivity

Abstract

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.

Radical-Trapping Antioxidant Activity of Copper and Nickel Bis(Thiosemicarbazone) Complexes Underlies Their Potency as Inhibitors of Ferroptotic Cell Death

“…Thus, the availability of an aminic N–H in CuATSM serves to drive the initial addition forward by providing an irreversible path, leading to a larger observed k inh . Indeed, the abstraction of the aminic N–H after the initial peroxyl radical addition is predicted to strengthen the C–O bond in the adduct by 17.5 kcal/mol (from 17.0 to 34.5 kcal/mol; the difference increases to 18.5 kcal/mol in the gas phase)with the latter now on par with the C–O bonds in peroxyl adducts of phenolic/aminic RTAs resulting from the combination of peroxyl radicals with phenoxyl/aminyl radicals formed from initial HAT reactions …”

“…Indeed, the abstraction of the aminic N−H after the initial peroxyl radical addition is predicted to strengthen the C−O bond in the adduct by 17.5 kcal/mol (from 17.0 to 34.5 kcal/ mol; the difference increases to 18.5 kcal/mol in the gas phase)with the latter now on par with the C−O bonds in peroxyl adducts of phenolic/aminic RTAs resulting from the combination of peroxyl radicals with phenoxyl/aminyl radicals formed from initial HAT reactions. 48 CuATSP was chosen for study since it was anticipated that CuATSP would be more reactive to initial HAT given the increased stabilization of the incipient aminyl radical by the phenyl ring relative to the hyperconjugative stabilization provided by the methyl group in the aminyl radical derived from CuATSM. Although the N−H BDE of CuATSP is predicted to be 2.2 kcal/mol lower than in CuATSM (Figure 5; the difference increases to 3.0 kcal/mol in the gas phase), the reactivities of CuATSP and CuATSM were practically indistinguishable.…”

The NLRP1 and CARD8 inflammasomes detect reductive stress

“…JSH-23, SKI II, WZ3146, AZD3463, and Fer-1 all have aromatic secondary amines that can potentially scavenge free radicals ( Figure S6A , colored red) 38 – 40 but are otherwise not structurally related. We noticed that several additional hits from the primary screen similarly had such secondary aromatic amines (WZ4002, WZ8040, WHI-P154, and RAF265), but some other hits did not (MC1568, bazedoxifene) ( Figures 1D , blue arrows, and S6A ).…”

Enhancement of Diarylamine Antioxidant Activity by Molybdenum Dithiocarbamates

“…The inhibition rate constant ( k inh ) of the added antioxidant can be derived from the initial rate of PBD-BODIPY consumption, and the radical-trapping stoichiometry ( n ) can be derived from the duration of the inhibited period (when well-defined), as shown in Figure B. We initially carried out experiments using 1-hexadecene as the autoxidizable substrate as the reactivity of PBD-BODIPY has been characterized under these conditions ( k PBD‑BODIPY = 1.8 × 10 4 M –1 s –1 ). − Representative data are shown in Figure C.…”