- Solvolysis of 3,5-di-tert-butyl-4-hydroxybenzyl acetate in alcohol solutions
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Solvolysis of 3,5-di-tert-butyl-4-hydroxybenzyl acetate in alcohol solutions involves intermediate formation of 2,6-di-tert-butyl-4-methylene-1-benzoquinone that further takes up a molecule of the alcohol.
- Bukharov,Syakaev,Pod''yachev,Nugumanova,Mukmeneva
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- Synthesis of phosphorylated derivatives of isatin with sterically hindered phenol fragments
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The synthesis of N-[dimethoxyphosphoryl-(3,5-di-tert-butyl-4-hydroxyphenyl)]methylisatins has been performed by the addition of isatin and 5-butylisatin to the double bond of dimethyl-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)methylphosphonate. Subsequent functionalization of the compounds synthesized with thiosemicarbazide hydrochloride, 3-(3?,5?-di-tert-butyl-4?-hydroxyphenyl)propionic acid hydrazide, and isonicotinic acid. Hydrazide gave isatin derivatives containing several pharmacophore fragments. Each of them has the ability to the increase the antioxidant and biological activities of these compounds.
- Bukharov, Sergey V.,Burilov, Alexander R.,Oludina, Yulia N.,Tagasheva, Roza G.,Syakaev, Viktor V.,Musin, Rashid Z.,Nugumanova, Gulnara N.
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- Iron-Catalyzed Alkene Trifluoromethylation in Tandem with Phenol Dearomatizing Spirocyclization: Regioselective Construction of Trifluoromethylated Spirocarbocycles
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In the presence of Fe(III) complex and Bipy ligand, CF3-containing spirocarbocycles were conveniently obtained in 20–99% yields with high regioselectivity through Iron-catalyzed trifluoromethylation of unactivated alkenes coupled with phenol de
- Han, Guifang,Hou, Jingli,Li, Chengwen,Liu, Yangping,Song, Yuguang,Wang, Xue,Xu, Zelin,Yao, Ru,Zhang, Liming,Zhao, Yilin
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supporting information
(2021/11/30)
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- Phenol Oxidation by a Nickel(III)–Fluoride Complex: Exploring the Influence of the Proton Accepting Ligand in PCET Oxidation
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In order to gain insight into the influence of the H+-accepting terminal ligand in high-valent oxidant mediated proton coupled electron transfer (PCET) reactions, the reactivity of a high valent nickel–fluoride complex [NiIII(F)(L)] (2, L=N,N’-(2,6-dimethylphenyl)-2,6-pyridinecarboxamidate) with substituted phenols was explored. Analysis of kinetic data from these reactions (Evans–Polanyi, Hammett, and Marcus plots, and KIE measurements) and the formed products show that 2 reacted with electron rich phenols through a hydrogen atom transfer (HAT, or concerted PCET) mechanism and with electron poor phenols through a stepwise proton transfer/electron transfer (PT/ET) reaction mechanism. The analogous complexes [NiIII(Z)(L)] (Z=Cl, OCO2H, O2CCH3, ONO2) reacted with all phenols through a HAT mechanism. We explore the reason for a change in mechanism with the highly basic fluoride ligand in 2. Complex 2 was also found to react one to two orders of magnitude faster than the corresponding analogous [NiIII(Z)(L)] complexes. This was ascribed to a high bond dissociation free energy value associated with H?F (135 kcal mol?1), which is postulated to be the product formed from PCET oxidation by 2 and is believed to be the driving force for the reaction. Our findings show that high-valent metal–fluoride complexes represent a class of highly reactive PCET oxidants.
- Mondal, Prasenjit,McDonald, Aidan R.
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supporting information
p. 10083 - 10089
(2020/07/13)
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- High-Valent d7 NiIII versus d8 CuIII Oxidants in PCET
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Oxygenases have been postulated to utilize d4 FeIV and d8 CuIII oxidants in proton-coupled electron transfer (PCET) hydrocarbon oxidation. In order to explore the influence the metal ion and d-electron count can hold over the PCET reactivity, two metastable high-valent metal-oxygen adducts, [NiIII(OAc)(L)] (1b) and [CuIII(OAc)(L)] (2b), L = N,N′-(2,6-diisopropylphenyl)-2,6-pyridinedicarboxamidate, were prepared from their low-valent precursors [NiII(OAc)(L)]- (1a) and [CuII(OAc)(L)]- (2a). The complexes 1a/b-2a/b were characterized using nuclear magnetic resonance, Fourier transform infrared, electron paramagnetic resonance, X-ray diffraction, and absorption spectroscopies and mass spectrometry. Both complexes were capable of activating substrates through a concerted PCET mechanism (hydrogen atom transfer, HAT, or concerted proton and electron transfer, CPET). The reactivity of 1b and 2b toward a series of para-substituted 2,6-di-tert-butylphenols (p-X-2,6-DTBP; X = OCH3, C(CH3)3, CH3, H, Br, CN, NO2) was studied, showing similar rates of reaction for both complexes. In the oxidation of xanthene, the d8 CuIII oxidant displayed a small increase in the rate constant compared to that of the d7 NiIII oxidant. The d8 CuIII oxidant was capable of oxidizing a large family of hydrocarbon substrates with bond dissociation enthalpy (BDEC-H) values up to 90 kcal/mol. It was previously observed that exchanging the ancillary anionic donor ligand in such complexes resulted in a 20-fold enhancement in the rate constant, an observation that is further enforced by comparison of 1b and 2b to the literature precedents. In contrast, we observed only minor differences in the rate constants upon comparing 1b to 2b. It was thus concluded that in this case the metal ion has a minor impact, while the ancillary donor ligand yields more kinetic control over HAT/CPET oxidation.
- Unjaroen, Duenpen,Gericke, Robert,Lovisari, Marta,Nelis, Daniel,Mondal, Prasenjit,Pirovano, Paolo,Twamley, Brendan,Farquhar, Erik R.,Mcdonald, Aidan R.
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supporting information
p. 16838 - 16848
(2019/12/24)
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- Chemistry of the 8-Nitroguanine DNA Lesion: Reactivity, Labelling and Repair
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The 8-nitroguanine lesion in DNA is increasingly associated with inflammation-related carcinogenesis, whereas the same modification on guanosine 3′,5′-cyclic monophosphate generates a second messenger in NO-mediated signal transduction. Very little is known about the chemistry of 8-nitroguanine nucleotides, despite the fact that their biological effects are closely linked to their chemical properties. To this end, a selection of chemical reactions have been performed on 8-nitroguanine nucleosides and oligodeoxynucleotides. Reactions with alkylating reagents reveal how the 8-nitro substituent affects the reactivity of the purine ring, by significantly decreasing the reactivity of the N2 position, whilst the relative reactivity at N1 appears to be enhanced. Interestingly, the displacement of the nitro group with thiols results in an efficient and specific method of labelling this lesion and is demonstrated in oligodeoxynucleotides. Additionally, the repair of this lesion is also shown to be a chemically feasible reaction through a reductive denitration with a hydride source.
- Alexander, Katie J.,McConville, Matthew,Williams, Kathryn R.,Luzyanin, Konstantin V.,O'Neil, Ian A.,Cosstick, Richard
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supporting information
p. 3013 - 3020
(2018/02/09)
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- Electron transfer between protonated and unprotonated phenoxyl radicals
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(Chemical Equation Presented) The reaction of phenoxyl radicals with acids is investigated. 2,4,6-Tri-tert-butylphenoxyl radical (13), a persistent radical, deteriorates in MeOH/PhH in the presence of an acid yielding 4-methoxycyclohexa-2,5-dienone 18a and the parent phenol (14). The reaction is facilitated by a strong acid. Treatment of 2,6-di-tert-butyl-4-methylphenoxyl radical (2), a short-lived radical, generated by dissociation of its dimer, with an acid in MeOH provides 4-methoxycyclohexa-2,5-dienone 4 and the products from disproportionation of 2 including the parent phenol (3). A strong acid in a high concentration favors the formation of 4 while the yield of 3 is always kept high. Oxidation of the parent phenol (33) with PbO2 to generate transient 2,6-di-tert-butylphenoxyl radical (35) in AcOH/H2O containing an added acid provides eventually p-benzoquinone 39 and 4,4′-diphenoquinone 42, the product from dimerization of 35. A strong acid in a high concentration favors the formation of 39. These results suggest that a phenoxyl radical is protonated by an acid and electron transfer takes place from another phenoxyl radical to the protonated phenoxyl radical, thus generating the phenoxyl cation, which can add an oxygen nucleophile, and the phenol (eq 5). The electron transfer is a fast reaction.
- Omura, Kanji
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p. 858 - 867
(2008/09/19)
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- Practical process for the air oxidation of cresols: Part A. Mechanistic investigations
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The catalytic air oxidation of p-cresol and 2,6-di-tert-butyl-4- methylphenol to the corresponding benzaldehydes was investigated to determine the mechanism at work in these oxidation reactions. A number of intermediates and byproducts, mainly in the form of dimers, were observed during the course of the reactions, and their structures were elucidated by spectroscopic and chromatographic methods. The existence of these compounds in the reaction mixtures, and their proposed methods of formation, provided further insight into the mechanism involved in these oxidations.
- Barton, Benita,Logie, Catherine G.,Schoonees, Barbara M.,Zeelie, Bernard
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- Lung toxicity and tumor promotion by hydroxylated derivatives of 2,6-di-tert-butyl-4-methylphenol (BHT) and 2-tert-butyl-4-methyl-6-iso-propylphenol: correlation with quinone methide reactivity.
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Acute pulmonary toxicity and tumor promotion by the food additive 2,6-di-tert-butyl-4-methylphenol (BHT) in mice are well documented. These effects have been attributed to either of two quinone methides, 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM) formed through direct oxidation of BHT by pulmonary cytochrome P450 or a quinone methide formed by hydroxylation of a tert-butyl group of BHT (to form BHTOH) followed by oxidation of this metabolite to BHTOH-QM. BHTOH-QM is a more reactive electrophile compared to BHT-QM due to intramolecular interactions of the side-chain hydroxyl with the carbonyl oxygen. To further examine this bioactivation pathway, an analogue of BHTOH was prepared, 2-tert-butyl-6-(1'-hydroxy-1'-methyl)ethyl-4-methylphenol (BPPOH), that is structurally very similar to BHTOH but forms a quinone methide (BPPOH-QM) capable of more efficient intramolecular hydrogen bonding and, therefore, higher electrophilicity than BHTOH-QM. BPPOH-QM was synthesized and its reactivity with water, methanol, and glutathione determined to be >10-fold higher than that of BHTOH-QM. The conversions of BPPOH and BHTOH to quinone methides in lung microsomes from male BALB/cByJ mice were quantitatively similar, but in vivo the former was pneumotoxic at one-half of the dose required for the latter and one-eighth of the dose required for BHT, as determined by increased lung weight:body weight ratios following a single i.p. injection. Similar differences were found in the doses of BHT, BHTOH, or BPPOH required for tumor promotion after a single initiating dose of 3-methylcholanthrene followed by three weekly injections of the phenol. The downregulaton of calpain II, previously shown to accompany lung tumor promotion by BHT and BHTOH, also occurred with BPPOH. The correlation between biologic activities of these phenols and the reactivities of their corresponding quinone methides provides additional support for the role of BHTOH-QM as the principal metabolite responsible for the effects of BHT on mouse lung.
- Kupfer, Rene,Dwyer-Nield, Lori D,Malkinson, Alvin M,Thompson, John A
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p. 1106 - 1112
(2007/10/03)
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- A novel approach towards intermolecular stabilization of para-quinone methides. First complexation of the elusive, simplest quinone methide, 4-methylene-2,5-cyclohexadien-1-one
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A novel approach towards the intermolecular stabilization of "simple" (i.e. methylene-unsubstituted) p-quinone methides (QMs) by their coordination to a transition-metal center is described. 4-Bromomethyl phenols, protected by a silyl group, were employed as the QM precursors and cis-chelating diphosphine Pd0 complexes were chosen as the metal precursors, since they have strong back-bonding interactions with the electron-poor QM moiety. Removal of the silyl protecting-group from the corresponding [LPd(benzyl)Br] complex (L=bisphosphine) with fluoride results in the spontaneous rearrangement of the unobserved zwitterionic PdII complex into the QM-Pd0 complex. The feasibility of this approach was demonstrated in the synthesis of the structurally characterized Pd0 complex of BHT-QM (4), a biologically relevant metabolite of 2,6-di-tert-butyl-p-cresol, and the synthesis of the complex of 4-methylene-2,5-cyclohexadien-1-one (11), the simplest, and so far unobserved QM molecule. These complexes exhibit a remarkable thermal stability and do not react with alcohol or water. In both cases, the use of an appropriate incoming ligand allowed the release of the coordinated QM into the reaction media in which it was effectively trapped by added nucleophiles.
- Rabin, Oded,Vigalok, Arkadi,Milstein, David
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p. 454 - 462
(2007/10/03)
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- Substrate specificity of the kinetic resolution of sulfides by enantioselective sulfoxide formation
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The kinetic resolution of tazofelone (1) has been reported. The resolution of this sulfide was accomplished via enantioselective sulfoxide formation with tert-Bu hydroperoxide in the presence of a chiral tartrate/titanium complex. The resolution was performed on analogues of compound 1 in order to explore the substrate specificity of the kinetic resolution, These experiments have shown that the success of the enantioselective oxidation of this sulfide by tert-Bu hydroperoxide is greatly influenced by the nature of the neighboring amide functionality.
- Phillips, Michael L.,Panetta, Jill A.
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p. 2109 - 2114
(2007/10/03)
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- Alkylation of 2'-deoxynucleosides and DNA by quinone methides derived from 2,6-Di-tert-butyl-4-methylphenol
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4-Alkylphenols, such as the antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT), exhibit toxicities that appear to be mediated by their oxidative metabolism to electrophilic quinone methides. Reactions of these Michael acceptors with simple nucleophiles and proteins have been reported, but little information is available on quinone methide binding to the competing nucleophilic sites in DNA. In the present investigation, 2'-deoxynucleoside adducts generated in vitro with two BHT-derived quinone methides, 2,6-di- tert-butyl-4-methylenecyclohexa-2,5-dienone and 6-tert-butyl-2-(2'-hydroxy- 1',1'-dimethylethyl)-4-methylenecyclohexa-2,5-dienone (BHTOH-QM) were isolated and identified. Both quinone methides produced adducts at the 1- and N2-positions of deoxyguanosine (dG) and the N6-position of deoxyadenosine (dA). In addition, a labile adduct formed at the 7-position of dG, which degraded to the corresponding 7-alkylguanine derivative. Additional work was conducted with BHTOH-QM, the more reactive of the two quinone methides. This species also formed stable adducts at the N4-position of deoxycytosine (dC) and the 3-position of thymidine and formed a labile adduct at the 3-position of dC that underwent hydrolytic cleavage to regenerate dC. In mixtures of deoxynucleosides treated with [14C]BHTOH-QM, alkylation occurred primarily at the N2- and 7-positions of dG and the N6-position of dA and occurred secondarily at the 1-position of dG. Treatment of calf thymus DNA with this quinone methide yielded N6-dA and N2-dG adducts with the former predominating. The unstable 7-dG adduct was detected by analysis of the 7- alkylguanine product from depurination. These results demonstrate that quinone methides are most likely to damage DNA through alkylation of the exocyclic amino groups of purine residues and possibly also by attack at the 7-position of dG followed by depurination.
- Lewis, Mark A.,Yoerg, Darla Graff,Bolton, Judy L.,Thompson, John A.
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p. 1368 - 1374
(2007/10/03)
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- Antioxidant Synergism Between Butylated Hydroxyanisole and Butylated Hydroxytoluene
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Decay of the 2,6-di-tert-butyl-4-methylphenoxy radical in the presence of butylated hydroxyanisole (BHA) was investigated in 1,2-dimethoxyethane with or without triethylamine.BHT-radical was conveniently generated by dissociation of its unstable dimer in solution.The products were BHT, 3,3'-di-tert-butyl-5,5'-dimethoxy-2,2'-dihydroxybiphenyl (BHA-dimer), 2,6-di-tert-butyl-p-quinone methide (QM), 1,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)ethane, and 3,3',5,5'-tetra-tert-butyl-4,4'-stilbenequinone.The reaction without added triethylamine gave larger quantities of the last two products and BHA (recovery), whereas the reaction with it provided larger quantities of the first two products.The marked difference in the product distribution can be accounted for by a series of reactions including reversible dehydrogenation of BHA with BHT-radical, which generates 2-tert-butyl-4-methoxyphenoxy radical (BHA-radical) and BHT, reversible dimerization of BHA-radical, which affords an intermediary bis(cyclohexadienone), and spontaneous and base-catalysed prototropic rearrangement of the intermediate into BHA-dimer.Products of coupling between BHT-radical and BHA-radical were not obtained.BHA was found to undergo facile acid-catalyzed addition to QM, providing two isomeric bis(hydroxyphenyl)methanes.The results help to elucidate the mechanism of antioxidant synergism between BHA and BHT and may suggest that the synergism can be affected by base or acid. - Key words: Antioxidant synergism; butylated hydroxyanisole; butylated hydroxytoluene; effect of acid; effect of base; fate of phenoxy radicals involved.
- Omura, Kanji
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p. 1565 - 1570
(2007/10/03)
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- Reinvestigation on the Reaction of 2,6-Di-tert-butylbenzoquinone Methide and 2,6-Di-tert-butylphenol
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The reaction of quinone methide 1 and phenol 2 in equimolar amounts was investigated in pentane at 30 deg C.Products were isolated by means of column chromatography on SiO2.There was a marked difference in product distribution between the reactions in the presence and absence of added Et3N.Dienones 3 and 10 were obtained only from the former reaction, while formation of 1,2-bis(4-hydroxyphenyl)ethane 18 and 4,4'-dihydroxybiphenyl 20 was overwhelming in the latter reaction.Other products from both reactions were relatively small quantities of 4,4'-stilbenequinone 17, 4,4'-diphenoquinone 21, and bis(4-hydroxyphenyl)methane 24, but dienone 4 was not obtained.Compounds 20 and 24 obtained from the latter reaction were formed by isomerization of dienones 19 and 23, respectively, during chromatography.The reaction is initiated by dimerization of 1 to generate biradical 11.Subsequent processes involving hydrogenation-dehydrogenation, coupling-dissociation, and dienone-phenol rearrangement account for the formation or the lack of formation of the products.The difference in product distribution is ascribed to capability of Et3N to catalyze the isomerization.Quinone methide 1 also adds to 2 to give 23.The decay of 1 in the presence of both 2 and phenol 6 gave dienone 8 additionally.The formation of 24 and 4 was facilitated by conducting the reaction of 1 and 2 in DMSO.Dehydrogenation of 10 and 3 with PbO2 afforded spirodienones 27 and 28, respectively.Compounds 27 and 28 were unstable, and their decay in solution was investigated in the presence or absence of added 2.The results show that the decay is initiated by homolytic scission of the C-C bond connecting the dienone rings in the cyclopentane (in 27) and cyclohexane (in 28) rings.Compound 28 is novel in that it bears two kinds of such C-C bonds.Reversibility of the dimerization of 1 is suggested.
- Omura, Kanji
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p. 306 - 312
(2007/10/02)
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- Oxidation by Cobalt(III) Acetate. Part 13. Oxidation of Substituted Phenols with Cobalt(III) Acetate in Acetic Acid
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The oxidation of 2,6-di- and 2,4,6-tri-substituted phenols with cobalt(III) acetate has been investigated in acetic acid under an inert atmosphere; the former gave the corresponding diphenoquinones in excellent yields, and the latter yielded side-chain or nuclear acetoxylated products in moderate to good yields.
- Hirano, Masao,Ishii, Tadamichi,Morimoto, Takashi
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p. 1434 - 1436
(2007/10/02)
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- Electroorganic Reactions. 31. Quinonemethide Radical-Anions and Dianoins: Their Cathodic Generation and Reactivity
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The cathodic reactions of a number of relatively stable quinonemethides have been examined in detail by cyclic voltammetry, controlled potential coulometry, and rigorous product analysis following preparative-scale electrolyses.The results of cyclic voltammetric experiments differ in some respects from those of earlier polarographic work.The lifetimes of the electrogenerated radical-anions and dianions, in the absence of added electrophile, are governed by steric hindrance.Hindered intermediates are relatively long-lived yet hydrogenate in the presence of proton donor and alkylate in the presence of methyl iodide.Less hindered analogue efficiently and rapidly dimerize, at carbon, with concomitant protonation or O-methylation depending on added electrophile.The ambident cathodically generated nucleophiles alkylate at both carbon and oxygen, and the competition is crucially dependent on the cation (Bu4N+ or Li+).Fuchsone 3 gives reduction products which vary with initial concentration and on the presence, or otherwise, of oxygen.Efficient reaction between oxygen and triarylmethyl radicals generated, e.g., from 3 has been demonstrated.
- Goulart, Marilia O. F.,Utley, James H. P.
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p. 2520 - 2525
(2007/10/02)
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- Studies on the Antioxidants. XX. The Effect of Butylated Hydroxytoluene on tert-Butylhydroperoxide-Induced Oxidation of Butylated Hydroxyanisole
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Hydrogen donation from butylated hydroxyanisole (BHA) and/or butylated hydroxytoluene (BHT) to the peroxyl radical prepared by cobalt-catalyzed cleavage of tert-butylhydroperoxide was investigated, and the relation of this process to synergism in the antioxidative effect was discussed.BHA initially donated a hydrogen to the peroxyl radical to form its phenoxyl radical to form its phenoxyl radical, and this radical reacted with either the peroxyl radical or another phenoxyl radical to form its adduct.In the combination of BHA and BHT, BHA donated a hydrogen to the peroxyl radical initially, and its phenoxyl radical accepted hydrogen from BHT to regenerate BHA, with enhanced oxidation of BHT to quinone methide.This hydrogen acceptance of the phenoxyl radical of BHA from BHT may be closely correlated with the synergism in the antioxidative effect of the mixture of BHA and BHT.
- Kurechi, Tsutao,Kato, Tetsuta
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p. 1772 - 1776
(2007/10/02)
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