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(η(3)-1-PhC(3)H(4))(η(5)-C(5)H(5)) as precatalyst, which gave higher yields than the conventional Pd source, Pd(2)(dba)(3).     

How lipid unsaturation, peroxyl radical partitioning, and chromanol lipophilic tail affect the antioxidant activity of α-tocopherol: direct visualization via high-throughput fluorescence studies conducted with fluorogenic α-tocopherol analogues

The preparation of two highly sensitive fluorogenic α-tocopherol (TOH) analogues which undergo >30-fold fluorescence intensity enhancement upon reaction with peroxyl radicals is reported. The probes consist of a chromanol moiety coupled to the meso position of a BODIPY fluorophore, where the use of a methylene linker (BODIPY-2,2,5,7,8-pentamethyl-6-hydroxy-chroman adduct, H(2)B-PMHC) vs an ester linker (meso-methanoyl BODIPY-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, H(2)B-TOH) enables tuning their reactivity toward H-atom abstraction by peroxyl radicals. The development of a high-throughput fluorescence assay for monitoring kinetics of peroxyl radical reactions in liposomes is subsequently described where the evolution of the fluorescence intensity over time provides a rapid, facile method to conduct competitive kinetic studies in the presence of TOH and its analogues. A quantitative treatment is formulated for the temporal evolution of the intensity in terms of relative rate constants of H-atom abstraction (k(inh)) from the various tocopherol analogues. Combined, the new probes, the fluorescence assay, and the data analysis provide a new method to obtain, in a rapid, parallel format, relative antioxidant activities in phospholipid membranes. The method is exemplified with four chromanol-based antioxidant compounds differing in their aliphatic tails (TOH, PMHC, H(2)B-PMHC, and H(2)B-TOH). Studies were conducted in six different liposome solutions prepared from poly- and mono-unsaturated and saturated (fluid vs gel phase) lipids in the presence of either hydrophilic or lipophilic peroxyl radicals. A number of key insights into the chemistry of the TOH antioxidants in lipid membranes are provided: (1) The relative antioxidant activities of chromanols in homogeneous solution, arising from their inherent chemical reactivity, readily translate to the microheterogeneous environment at the water/lipid interface; thus similar values for k(inh)(H(2)B-PMHC)/k(inh)(H(2)B-TOH) in the range of 2-3 are recorded both in homogeneous solution and in liposome suspensions with hydrophilic or lipophilic peroxyl radicals. (2) The relative antioxidant activity between tocopherol analogues with the same inherent chemical reactivity but bearing short (PMHC) or long (TOH) aliphatic tails, k(inh)(PMHC)/k(inh)(TOH), is ~8 in the presence of hydrophilic peroxyl radicals, regardless of the nature of the lipid membrane into which they are embedded. (3) Antioxidants embedded in saturated lipids do not efficiently scavenge hydrophilic peroxyl radicals; under these conditions wastage reactions among peroxyl radicals become important, and this translates into larger times for antioxidant consumption. (4) Lipophilic peroxyl radicals show reduced discrimination between antioxidants bearing long and short aliphatic tails, with k(inh)(PMHC)/k(inh)(TOH) in the range of 3-4 for most lipid membranes. (5) Lipophilic peroxyl radicals are scavenged with the same efficiency by all four antioxidants studied, regardless of the nature of their aliphatic tail or the lipid membrane into which they are embedded. These data underpin the key role the lipid environment plays in modulating the rate of reaction of antioxidants characterized by similar inherent chemical reactivity (arising from a conserved chromanol moiety) but differing in their membrane mobility (structural differences in the lipophilic tail). Altogether, a novel, facile method of study, new insights, and a quantitative understanding on the critical role of lipid diversity in modulating antioxidant activity in the lipid milieu are reported.     

The effect of ring nitrogen atoms on the homolytic reactivity of phenolic compounds: understanding the radical-scavenging ability of 5-pyrimidinols

Six substituted 5-pyrimidinols were synthesized, and the thermochemistry and kinetics of their reactions with free radicals were studied and compared to those of equivalently substituted phenols. To assess their potential as hydrogen-atom donors to free radicals, we measured their O-H bond dissociation enthalpies (BDEs) using the radical equilibration electron paramagnetic resonance technique. This revealed that the O-H BDEs in 5-pyrimidinols are, on average, about 2.5 kcal mol(-1) higher than those in equivalently substituted phenols. The results are in good agreement with theoretical predictions, and confirm that substituent effects on the O-H BDE of 5-pyrimidinol are essentially the same as those on the Obond;H BDE in phenol. The kinetics of the reactions of these compounds with peroxyl radicals has been studied by their inhibition of the AIBN-initiated autoxidation of styrene, and with alkyl and alkoxyl radicals by competition kinetics. Despite their larger O-H BDEs, 5-pyrimidinols appear to transfer their phenolic hydrogen-atom to peroxyl radicals as quickly as equivalently substituted phenols, while their reactivity toward alkyl radicals far exceeds that of the corresponding phenols. We suggest that this rate enhancement, which is large in the case of alkyl radical reactions, small in the case of peroxyl radical reactions, and nonexistent in the case of alkoxyl radical reactions, is due to polar effects in the transition states of these atom-transfer reactions. This hypothesis is supported by additional experimental and theoretical results. Despite this higher reactivity of 5-pyrimidinols towards radicals compared to phenols, electrochemical measurements indicate that they are more stable to one-electron oxidation than equivalently substituted phenols. For example, the 5-pyrimidinol analogues of 2,4,6-trimethylphenol and butylated hydroxytoluene (BHT) were found to have oxidation potentials approximately 400 mV higher than their phenolic counterparts, but reacted roughly one order of magnitude faster with alkyl radicals and at about the same rate with peroxyl radicals. The 5-pyrimidinol structure should, therefore, serve as a useful template for the rational design of novel air-stable radical scavengers and chain-breaking antioxidants that are more effective than phenols.     

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.     

Peroxyesters as precursors to peroxyl radical clocks

The reactions of peroxyl radicals are at the center of the oxidative degradation of essentially all petroleum-derived hydrocarbons and biological lipids and consequently, the inhibition of these processes by radical-trapping antioxidants. Recently described peroxyl radical clocks offer a simple, convenient, and inexpensive method of determining rate constants for H-atom transfer reactions to peroxyl radicals, greatly enabling the kinetic and mechanistic characterization of compounds with antioxidant properties. We follow up our preliminary communication on the development of a methodology utilizing tert-butyl styrylperacetate as a precursor to a versatile peroxyl radical clock with the present paper, wherein we describe a novel naphthyl analogue, which provides for much improved product resolution for analysis, and provide the complete details associated with its development and application. Using this new precursor, and with consideration of the expanded set of reaction products, inhibition rate constants were measured for a variety of representative phenolic and diarylamine radical-trapping antioxidants. We also provide details for the use of this methodology for the determination of mechanistic information, such as kinetic solvent effects, Arrhenius parameters, and kinetic isotope effects.     

Reactivity of natural phenols in radical reactions

Activation enthalpies and energies and the rate constants of reactions with peroxyl, alkyl, and thiyl radicals (76 reactions) were calculated for a group of natural antioxidants (19 monohydroxy and polyhydroxy phenols). The calculation was performed with the use of the model of a radical abstraction reaction as the intersection of two parabolic potential curves. The results of the calculation were compared with experimental data: the average discrepancy in the activation energies of the reactions RO ₂ ^? + ArOH was 0.8 kJ/mol. Interatomic distances in the reaction centers of the transition states of the test reactions were calculated. Factors affecting the reactivity of these compounds are discussed.     

Electronic and hydrogen bonding effects on the chain-breaking activity of sulfur-containing phenolic antioxidants

A kinetic and thermodynamic investigation of phenols para-substituted with thiyl (SR), sulfinyl (SOR), and sulfonyl (SO(2)R) groups and ortho-substituted with thiyl groups is reported. The effect of the sulfur substituents on the O-H bond dissociation enthalpy values, BDE(O-H), was measured by means of the EPR radical equilibration technique and the reactivity toward peroxyl radicals, k(inh), of these phenolic antioxidants was determined by inhibited autoxidation studies. An inverse correlation between these two parameters was found. A p-SMe substituent decreased the BDE(O-H) value to a lesser extent than a p-OMe group (-3.6 vs -4.4 kcal/mol), whereas the effect of the same groups in an ortho position showed an opposite trend (-0.85 vs -0.2 kcal/mol). The latter result is explained in terms of the different strength of the intramolecular hydrogen bond between the OH proton and the sulfur or oxygen substituents in ortho derivatives. ESI-MS analysis of the products formed by reacting the sulfides with peroxyl radicals from the azoinitiator AIBN revealed the formation of a complex mixture of products, which may play an important role in determining the overall antioxidant activity of the parent compounds.     

Do garlic-derived allyl sulfides scavenge peroxyl radicals?

The chain-breaking antioxidant activities of two garlic-derived allyl sulfides, i.e. diallyl disulfide (1), the main component of steam-distilled garlic oil, and allyl methyl sulfide (3) were evaluated by studying the thermally initiated autoxidation of cumene or styrene in their presence. Although the rate of cumene oxidation was reduced by addition of both 1 and 3, the dependence on the concentration of the two sulfides could not be explained on the basis of the classic antioxidant mechanism as with phenolic antioxidants. The rate of oxidation of styrene, on the other hand, did not show significant changes upon addition of either 1 or 3. This unusual behaviour was explained in terms of the co-oxidant effect, consisting in the decrease of the autoxidation rate of a substrate forming tertiary peroxyl radicals (i.e. cumene) upon addition of little amounts of a second oxidizable substrate giving rise instead to secondary peroxyl radicals. The relevant rate constants for the reaction of ROO(.) with 1 and 3 were measured as 1.6 and 1.0 M(-1) s(-1), respectively, fully consistent with the H-atom abstraction from substituted sulfides. It is therefore concluded that sulfides 1 and 3 do not scavenge peroxyl radicals and therefore cannot be considered chain-breaking antioxidants.     

The unusual reaction of semiquinone radicals with molecular oxygen

Hydroquinones (benzene-1,4-diols) are naturally occurring chain-breaking antioxidants, whose reactions with peroxyl radicals yield 1,4-semiquinone radicals. Unlike the 1,2-semiquinone radicals derived from catechols (benzene-1,2-diols), the 1,4-semiquinone radicals do not always trap another peroxyl radical, and instead the stoichiometric factor of hydroquinones varies widely between 0 and 2 as a function of ring-substitution and reaction conditions. This variable antioxidant behavior has been attributed to the competing reaction of the 1,4-semiquinone radical with molecular oxygen. Herein we report the results of experiments and theoretical calculations focused on understanding this key reaction. Our experiments, which include detailed kinetic and mechanistic investigations by laser flash photolysis and inhibited autoxidation studies, and our theoretical calculations, which include detailed studies of the reactions of both 1,4-semiquinones and 1,2-semiquinones with O2, provide many important insights. They show that the reaction of O2 with 2,5-di-tert-butyl-1,4-semiquinone radical (used as model compound) has a rate constant of 2.4 +/- 0.9 x 10(5) M-1 s-1 in acetonitrile and as high as 2.0 +/- 0.9 x 10(6) M-1 s-1 in chlorobenzene, i.e., similar to that previously reported in water at pH approximately 7. These results, considered alongside our theoretical calculations, suggest that the reaction occurs by an unusual hydrogen atom abstraction mechanism, taking place in a two-step process consisting first of addition of O2 to the semiquinone radical and second an intramolecular H-atom transfer concerted with elimination of hydroperoxyl to yield the quinone. This reaction appears to be much more facile for 1,4-semiquinones than for their 1,2-isomers.     

Naphthalene diols: a new class of antioxidants intramolecular hydrogen bonding in catechols,naphthalene diols,and their aryloxyl radicals

1,8-Naphthalenediol, 5, and its 4-methoxy derivative, 6, were found to be potent H-atom transfer (HAT) compounds on the basis of their rate constants for H-atom transfer to the 2,2-di(4-t-octylphenyl)-1-picrylhydrazyl radical (DOPPH*), k(ArOH/DOPPH)*, or as antioxidants during inhibited styrene autoxidation, k(ArOH/ROO)*, initiated with AIBN. The rate constants showed that 5 and 6 are more active HAT compounds than the ortho-diols, catechol, 1, 2,3-naphthalenediol, 2, and 3,5-di-tert-butylcatechol, 3. Compound 6 has almost twice the antioxidant activity, k(ArOH/ROO)* = 6.0 x 10(6) M(-)(1) s(-1), of that of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol, 4. Calculations of the O-H bond dissociation enthalpies compared to those of phenols, (deltaBDEs), of 1-6 predict a HAT order of reactivity of 2 < 1 < 3 approximately 4 < 5 < 6 in general agreement with kinetic results. Calculations on the diols show that intramolecular H-bonding stabilizes the radicals formed on H-atom transfer more than it does the parent diols, and this effect contributes to the increased HAT activity of 5 and 6 compared to the activities of the catechols. For example, the increased stabilization due to the intramolecular H-bond of 5 radical over 5 parent of 8.6 kcal/mol was about double that of 2 radical over 2 parent of 4.6 kcal/mol. Linear free energy plots of log k(ArOH/DOPPH)* and log k(ArOH/ROO)* versus deltaBDEs for compounds 1-6 along with available literature values for nonsterically hindered monophenols placed the compounds on common scales. The derived Evans-Polanyi constants from the plots for the two reactions, alpha(DOPPH)* = 0.48 > alpha(ROO)* = 0.32, gave the expected order, since the ROO* reaction is more exothermic than the DOPPH* reaction. Compound 6 is sufficiently reactive to react directly with oxygen, and it lies off the log k(ArOH/ROO)* versus deltaBDE plot.     

Antioxidant action of organic sulfites—II. Esters of sulfurous acid as primary antioxidants

The effect of esters of sulfurous acid as primary antioxidants was examined. Different aliphatic, aromatic, open-chain and cyclic sulfites were synthesized. The reactions of organic sulfites with RO₂ and RO radicals, the chain carriers of the autoxidation of hydrocarbons and polymers, were simulated by means of the thermal decomposition of azobisisobutyronitrile (AIBN) in the presence of oxygen and of di-tert-butylperoxalate (DTBPO). The reactivity of organic sulfites with 2-cyanoisopropylperoxyl radicals is low. Only aromatic sulfites are able to trap peroxyl radicals; however, they are not very effective primary antioxidants. The reactions of the organic sulfites with tert-butoxyl radicals generally lead to an increase in the rate of decomposition of DTBPO, as determined from rate constants measured at 50 °C. A decomposition of DTBPO induced by liberated tert-butyl radicals in the presence of alkyl sulfites is very probable. Alkyl sulfites and aromatic sulfites with aliphatic groups act mainly as hydrogen donors in reactions with alkoxyl and peroxyl radicals.     

Thiophenols,Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics

The activity of 12 thiophenols as primary antioxidants in aqueous solution has been studied using density functional theory. Twelve different substituted thiophenols were tested as peroxyl radicals scavengers. Single electron transfer (SET) and formal hydrogen transfer (FHT) were investigated. The SET mechanism was found to be the main mechanism, with rate constants that are close to the diffusion limit, which means that these thiophenolic compounds have the capacity to scavenge peroxyl radicals before they can damage biomolecules. All 12 thiophenolic compounds react faster with methylperoxyl than with hydroperoxyl radicals. In addition, it was found that pH plays an important role in the reactivity of these compounds. © 2019 Wiley Periodicals, Inc.     

Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants.

A procedure based on density functional theory is used for the calculation of the gas-phase bond dissociation enthalpy (BDE) and ionization potential for molecules belonging to the class of phenolic antioxidants. We show that use of locally dense basis sets (LDBS) vs full basis sets gives very similar results for monosubstituted phenols, and that the LDBS procedure gives good agreement with the change in experimental BDE values for highly substituted phenols in benzene solvent. Procedures for estimating the O--H BDE based on group additivity rules are given and tested. Several interesting classes of phenolic antioxidants are studied with these methods, including commercial antioxidants used as food additives, compounds related to Vitamin E, flavonoids in tea, aminophenols, stilbenes related to resveratrol, and sterically hindered phenols. On the basis of these results we are able to interpret relative rates for the reaction of antioxidants with free radicals, including a comparison of both H-atom-transfer and single-electron-transfer mechanisms, and conclude that in most cases H-atom transfer will be dominant.     

Multi‐faceted Reactivity of Alkyltellurophenols Towards Peroxyl Radicals: Catalytic Antioxidant Versus Thiol‐Depletion Effect

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO^. radicals with rate constants as high as 10⁷ M ^?1 s^?1 at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO^. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro‐oxidative (thiol depletion) when thiol concentrations are low.     

Synthesis and antioxidant activity of [60]fullerene-BHT conjugates

Fullerene derivatives incorporating one or two 3,5-di-tert-butyl-4-hydroxyphenyl groups were synthesized by 1,3-dipolar cycloaddition of azomethine ylides to C(60). The O-H bond dissociation enthalpies (BDEs) of these compounds were estimated by studying, by means of EPR spectroscopy, the equilibration of each of these phenols and 2,6-di-tert-butyl-4-methylphenol (BHT) with the corresponding phenoxyl radicals. The antioxidant activity of the investigated phenols was also determined by measuring the rate constants for their reaction with peroxyl radicals in controlled autoxidation experiments and compared to that recorded under identical experimental settings for [60]fullerene itself and unlinked BHT. The results indicate that linking of the BHT structure to C(60) does not substantially alter the thermochemistry and kinetics of its reaction with peroxyl radicals, but such adducts may behave as interesting bimodal radical scavengers. The inherent rate constant for trapping of peroxyl radicals by C(60) per se (k(inh)=3.1+/-1.1 x 10(2) m(-1) s(-1)) indicates that, contrary to previous reports, [60]fullerene is an extremely weak chain-breaking antioxidant.     

Loading of free radicals on the functional graphene combined with liquid chromatography–tandem mass spectrometry screening method for the detection of radical-scavenging natural antioxidants

A novel free radical reaction combined with liquid chromatography electrospray ionization tandem mass spectrometry (FRR-LC–PDA-ESI/APCI-MS/MS) screening method was developed for the detection and identification of radical-scavenging natural antioxidants. Functionalized graphene was prepared by chemical method for loading free radicals (superoxide radical, peroxyl radical and PAHs free radical). Separation was performed with and without a preliminary exposure of the sample to specific free radicals on the functionalized graphene, which can facilitate reaction kinetics (charge transfers) between free radicals and potential antioxidants. The difference in chromatographic peak areas is used to identify potential antioxidants. The structure of the antioxidants in one sample (Swertia chirayita) is identified using MS/MS and comparison with standards. Thirteen compounds were found to possess potential antioxidant activity, and their free radical-scavenging capacities were investigated. The thirteen compounds were identified as 1,3,5-trihydroxyxanthone-8-O-β-d-glucopyranoside (PD1), norswertianin (PD2), 1,3,5,8-tetrahydroxyxanthone (PD3), 3, 3′, 4′, 5, 8-penta hydroxyflavone-6-β-d-glucopyranosiduronic acid-6′-pentopyranose-7-O-glucopyranoside (PD4), 1,5,8-trihydroxy-3-methoxyxanthone (PD5), swertiamarin (PS1), 2-C-β-d-glucopyranosyl-1,3,7-trihydroxylxanthone (PS2), 1,3,7-trihydroxylxanthone-8-O-β-d-glucopyranoside (PL1), 1,3,8-trihydroxyl xanthone-5-O-β-d-glucopyranoside (PL2), 1,3,7-trihydroxy-8-methoxyxanthone (PL3), 1,2,3-trihydroxy-7,8-dimethoxyxanthone (PL4), 1,8-dihydroxy-2,6-dimethoxy xanthone (PL5) and 1,3,5,8-tetramethoxydecussatin (PL6). The reactivity and SC₅₀ values of those compounds were investigated, respectively. PD4 showed the strongest capability for scavenging PAHs free radical; PL4 showed prominent scavenging capacities in the lipid peroxidation processes; it was found that all components in S. chirayita exhibited weak reactivity in the superoxide radical scavenging capacity. The use of the free radical reaction screening method based on LC–PDA-ESI/APCI-MS/MS would provide a new approach for rapid detection and identification of radical-scavenging natural antioxidants from complex matrices.     

Phenols and aromatic amines as thermal stabilizers in polyolefin processing

Scavenging of C‐ and O‐centered free radicals is mandatory in processing stabilization of polypropylene. Phenolic antioxidants act principally as O‐radical scavengers only. Aromatic amines, N,N'‐disubstituted 1,4‐phenylenediamines (PD) and 4,4'disubstituted diphenylamines (DPA), scavenge both C‐ and O‐centered radicals and have consequently a broader activity spectrum. PD cannot be used, however, in polypropylene because of formation of strongly discoloring and staining sacrificial transformation products. Such products formed from DPA have even more discoloring properties. A good processing stability and acceptable extent of discoloration can be achieved by blends of phenols with 4,4'‐di‐tert.octyl DPA. The effect is considered as a beneficial cooperation between the two chain‐breaking antioxidants involving interactions with amine‐based transformation products.     

The reaction of sulfenic acids with peroxyl radicals: insights into the radical-trapping antioxidant activity of plant-derived thiosulfinates

Sulfenic acids play a prominent role in biology as key participants in cellular signaling relating to redox homeostasis, in the formation of protein-disulfide linkages, and as the central players in the fascinating organosulfur chemistry of the Allium species (e.g., garlic). Despite their relevance, direct measurements of their reaction kinetics have proven difficult owing to their high reactivity. Herein, we describe the results of hydrocarbon autoxidations inhibited by the persistent 9-triptycenesulfenic acid, which yields a second order rate constant of 3.0×10(6) M(-1) s(-1) for its reaction with peroxyl radicals in PhCl at 30?°C. This rate constant drops 19-fold in CH(3)CN, and is subject to a significant primary deuterium kinetic isotope effect, k(H)/k(D) = 6.1, supporting a formal H-atom transfer (HAT) mechanism. Analogous autoxidations inhibited by the Allium-derived (S)-benzyl phenylmethanethiosulfinate and a corresponding deuterium-labeled derivative unequivocally demonstrate the role of sulfenic acids in the radical-trapping antioxidant activity of thiosulfinates, through the rate-determining Cope elimination of phenylmethanesulfenic acid (k(H)/k(D) ≈ 4.5) and its subsequent formal HAT reaction with peroxyl radicals (k(H)/k(D) ≈ 3.5). The rate constant that we derived from these experiments for the reaction of phenylmethanesulfenic acid with peroxyl radicals was 2.8×10(7) M(-1) s(-1); a value 10-fold larger than that we measured for the reaction of 9-triptycenesulfenic acid with peroxyl radicals. We propose that whereas phenylmethanesulfenic acid can adopt the optimal syn geometry for a 5-centre proton-coupled electron-transfer reaction with a peroxyl radical, the 9-triptycenesulfenic is too sterically hindered, and undergoes the reaction instead through the less-energetically favorable anti geometry, which is reminiscent of a conventional HAT.     

On the peroxyl scavenging activity of hydroxycinnamic acid derivatives: mechanisms, kinetics, and importance of the acid-base equilibrium

The peroxyl radical scavenging activity of four hydroxycinnamic acid derivatives (HCAD) has been studied in non-polar and aqueous solutions, using the density functional theory. The studied HCAD are: ferulic acid (4-hydroxy-3-methoxycinnamic acid), p-coumaric acid (trans-4-hydroxycinnamic acid), caffeic acid (3,4-dihydroxycinnamic acid), and dihydrocaffeic acid (3-(3,4-dihydroxyphenyl)-2-propionic acid). It was found that the polarity of the environment plays an important role in the relative efficiency of these compounds as peroxyl scavengers. It was also found that in aqueous solution the pH is a key factor for the overall reactivity of HCAD towards peroxyl radicals, for their relative antioxidant capacity, and for the relative importance of the different mechanisms of reaction. The H transfer from the phenolic OH has been identified as the main mechanism of reaction in non-polar media and in aqueous solution at acid pHs. On the other hand, the single electron transfer mechanism from the phenoxide anion is proposed to be the one contributing the most to the overall peroxyl scavenging activity of HCAD in aqueous solution at physiological pH (7.4). This process is also predicted to be a key factor in the reactivity of these compounds towards a large variety of free radicals.     

On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals

The reactions of melatonin (MLT) with hydroxyl and several peroxyl radicals have been studied using the Density Functional Theory, specifically the M05-2X functional. Five mechanisms of reaction have been considered: radical adduct formation (RAF), Hydrogen atom transfer (HAT), single electron transfer (SET), sequential electron proton transfer (SEPT) and proton coupled electron transfer (PCET). It has been found that MLT reacts with OH radicals in a diffusion-limited way, regardless of the polarity of the environment, which indicates that MLT is an excellent OH radical scavenger. The calculated values of the overall rate coefficient of MLT + ˙OH reaction in benzene and water solutions are 2.23 × 10(10) and 1.85 × 10(10) M(-1) s(-1), respectively. MLT is also predicted to be a very good ˙OOCCl(3) scavenger but rather ineffective for scavenging less reactive peroxyl radicals, such as alkenyl peroxyl radicals and ˙OOH. Therefore it is concluded that the protective effect of MLT against lipid peroxidation does not take place by directly trapping peroxyl radicals, but rather by scavenging more reactive species, such as ˙OH, which can initiate the degradation process. Branching ratios for the different channels of reaction are reported for the first time. In aqueous solutions SEPT was found to be the main mechanism for the MLT + ˙OH reaction, accounting for about 44.1% of the overall reactivity of MLT towards this radical. The good agreement between the calculated and the available experimental data, on the studied processes, supports the reliability of the results presented in this work.