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Compounds comprising a diaryl ether skeleton exist among natural phenols. The diaryl ether skeleton is thought to be biosynthesized through the coupling of two or more phenols. It is an important structural feature in medicines and agrochemicals, and it is imperative to develop methods for constructing such skeletons in organic synthesis. However, by the synthesis method through the coupling of phenols, coupling occurs preferentially at the ortho-substituted carbon atom of phenols. In this study, various radical-generating reagents and conditions were investigated with the aim of developing a short-step construction method of the diaryl ether skeleton by the radical homo-coupling of two phenol molecules. In addition, cross-coupling reactions between radicals of 2,4,6-tri-tert-butylphenol and p-substituted phenol were conducted to synthesize eight C (ortho)–O coupling products. Based on the results, a computational chemical approach was employed to verify the cause of C (ortho)–O bond formation.

A highly efficient approach to the famous flavor and fragrance compound vanillin has been developed starting from 4-cresol with the attention focused on improving the sustainability of all the reactions. The approach involves a three-step sequence of the quasi-quantitative selective clean oxybromination of 4-cresol, the high-yield selective aerobic oxidation of 2-bromo-4-cresol, and the quantitative methoxylation of 3-bromo-4-hydroxybenzaldehyde with the recovery of pure methanol. Herein, the pivotal oxidation and methoxylation reactions are logically investigated and developed into two concise methodologies. As a green alternative, the approach holds significant value for the sustainable manufacturing of vanillin. the Partner Organisations 2014.

A hindered para-hydroxyl group-directed remote benzylic C(sp3)-H oxyfunctionalization has been developed for the straightforward transformation of 2,6-disubstituted 4-cresols, 4-alkylphenols, 4-hydroxybenzyl alcohols and 4-hydroxybenzyl alkyl ethers into various aromatic carbonyl compounds. The ligand- and additive-free Cu(OAc)2-catalyzed atmospheric oxidation mediated by ethylene glycol unlocks a facile, atom-economical, and environmentally benign C=O formation for the functionalization of primary and secondary benzyl groups. Due to the pharmaceutical importance of 4-hydroxybenzaldehydes and 4-hydroxyphenones, the methodology is expected to be of significant value for both fundamental research and practical applications.

Liquid-phase oxidation of p-cresol over insoluble cobalt oxide (Co 3O4) catalyst under elevated pressure of air gave 95% selectivity to p-hydroxybenzaldehyde, an important flavoring intermediate. The selectivity to p-hydroxybenzaldehyde could be enhanced by manipulating the concentrations of p-cresol, sodium hydroxide, and catalyst and the partial pressure of oxygen in such a way that the byproducts normally encountered in this oxidation process were eliminated or minimized significantly.

To gain insight into the chemical nature of drug-induced photoallergy, model studies have been carried out on the photochemical modification of proteins by tiaprofenic acid. Irradiation of decarboxylated tiaprofenic acid (DTPA) in the presence of p-cresol leads to C-C- and C-O-connected p-cresol 'dimers', together with DTPA hydrodimers. The p-cresol-DTPA cross-coupling product was not detected in this reaction. However, a product of this type is formed using a more hindered phenol, such as 2,6-di-tert-butylphenol. Similar results are obtained when tiaprofenic acid (TPA) or its methyl ester are used as photosensitizers. The observed formation of 'dimers' can be related to protein photo-crosslinking, through the coupling of two tyrosine units. On the other hand, phenol-(D)TPA cross-coupling may be relevant to the understanding of drug-protein photobinding.

The mechanisms of aqueous oxidation-reduction interactions between Cr(VI) and substituted phenols (RArOH) were characterized by kinetic analysis and determinations of reaction products and intermediates. A rapid, peroxidative equilibrium between HCrO4(-) and RArOH forms chromate ester intermediates, as verified by spectroscopy. The subsequent rate-limiting ester decomposition proceeds via innersphere electron transfer. The overall rate dependence on [H(+)] is well accounted for by three parallel redox pathways involving zero, one, and two protons. The two-proton pathway dominates at pH = 5. The parallel reaction rate expression was fitted to data for 4-methyl-, 4-methoxy-, 2,6-dimethoxy-, and 3,4-dimethoxyphenol for pH 1-6. Beside accurately predicting rates for the calibrated conditions, the model predicts a sharp decline in rates at pH >= 6. Rates subsequently measured at pH 7 agreed well with those calculated a priori. Such predictions suggest that the proposed mechanism is robust and accurate. Rate constants were correlated with Hammett-type substituent parameters. Reaction products indicated both one- and two-electron pathways.

The reaction of cerium(IV) ammonium nitrate with simple phenols (2-, 3- and 4-methylphenols) has been examined in the presence and absence of hydrogen peroxide.It has been observed that though the oxophilicity of cerium(IV) can be controlled by addition of hydrogen peroxide in the reaction medium, there is also a difference in the nature of products formed.The reaction can be used to obtain new terphenyls (3a, 3b and 3e), biphenyls (2a, and 2e), 2-hydroxy-1,9-dimethyl-7-nitro-dibenzyl-p-dioxin (4) and 3,7-dimethyl-1,9-dinitrodibenzofuran (5) in acceptable net yields.

The oxophilicity of cerium(IV) ammonium nitrate is moderated by the addition of hydrogen peroxide.The reaction with simple phenols becomes regioselective when carried out in a silica gel matrix.The methodology has been employed for the synthesis of new functionalized terphenyls and biphenyls.

4-Hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (HMBOA) is a compound of considerable interest because of its pharmacological, agrochemical, and antimicrobial properties. A plausible bioactive metabolite of HMBOA is 4-acetoxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (AMBOA). Electrophilic reactions of AMBOA with phenols, anilines, thiols, heteroaromatics, amino acid derivatives and nucleic acids were investigated in relation to the chemical mechanisms of the biological effects elicited by the compound. The results suggest that HMBOA acts as an alkylating agent of proteins and nucleic acids in vivo after metabolic O-acylation.

The reaction of four substituted bis(3-alkoxybenzoyl) peroxides (1b-e) in neat phenols (2a-e) affords mainly 8-alkoxy-6H-dibenzopyran-6-ones (7) and ortho-benzoyloxylation products (4) of the phenol.Diaroyl peroxides without electron-releasing meta substituents afford essentially products 4.A mechanism involving monoelectronic oxidation of the phenol by the peroxide and biaryl coupling by preferential addition of the phenol radical cation to the ortho positions to the alkoxy group of the diaroyl peroxide is suggested.

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N-p-ToluenesulfonylO-(4-tolyl)hydroxylamine (1) reacts with p-cresol in the presence of trifluoroacetic acid to yield biscresol (2) and Pummerer's ketone (3). KEYWORDS ---- phenoxenium ion; Pummerer's ketone; oxidation; oxidative coupling

The free radical oxidation of p-cresol and p-isopropylphenol using peroxy radicals produced by thermolysis of azoinitiators in oxygen at 50 degC in purified water is considered.The major primary products of oxidation of p-cresol are the peroxycyclohexadienones and the corresponding hydroperoxides; smaller amounts of two phenolic dimers are also found in each case.A variety of other products thought to result from ortho substitution also were observed but not characterized.The general features of the reactions in water are much the same as observed in organic solvents.Cupric ion causes further reaction of the peroxide products, leading to additional oxidation of phenol and possible formation of some p-quinone; Fe2+ ion in contrast is a strong inhibitor of phenol oxidation by RO2*.