Oxidation of the phenolic hydroxyl group

Oxidation of phenols is one of the most important aspects of these compounds to the biologist. Oxidation of phenolic compounds can result in the browning of tissues. Well-known examples are the browning of lfuits after they have been cut. Oxidation can also result in the formation of metabolites that are toxic to animals and plants, and that can account for spoilage of foods in processing. On the other hand, toxic compounds formed from the oxidation of phenolics can inhibit pathogenic microorganisms. Certain phenols are used as retardants or antioxidants to prevent the oxidation of fatty acids. 

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Chemical Properties. Lignin is subject to oxidation, reduction, discoloration, hydrolysis, and other chemical and enzymatic reactions. Many ate briefly described elsewhere (51). Key to these reactions is the ability of the phenolic hydroxyl groups of lignin to participate in the formation of reactive intermediates, eg, phenoxy radical (4), quinonemethide (5), and phenoxy anion (6) ... 

Properties. Vanillin is a colorless crystalline solid mp 82-83 °C) with a typical vanilla odor. Because it possesses aldehyde and hydroxyl substituents, it undergoes many reactions. Additional reactions are possible due to the reactivity of the aromatic nucleus. Vanillyl alcohol and 2-methoxy-4-methylphenol are obtained by catalytic hydrogenation vanillic acid derivatives are formed after oxidation and protection of the phenolic hydroxyl group. Since vanillin is a phenol aldehyde, it is stable to autoxidation and does not undergo the Cannizzarro reaction. Numerous derivatives can be prepared by etherification or esterification of the hydroxyl group and by aldol condensation at the aldehyde group. Several of these derivatives are intermediates, for example, in the synthesis of pharmaceuticals. 

Tratnyek and Hoigne (1994) investigated 25 substituted phenoxide anions for QSARs that can be used to predict rate constants for the reaction of additional phenolic compounds oxidized by chlorine dioxide (OCIO). Correlating oxidation rates of phenols in aqueous solution is complicated by the dissociation of the phenolic hydroxyl group. The undissociated phenol and the phenoxide anion react as independent species and exhibit very different properties. The correlation analysis should be performed on the two sets of rate constants separately. 

The oxidation of substituted phenols illustrates the importance of including speciation. Dissociation of the phenolic hydroxyl group results in an equilibrium mixture of the parent compound and its dissociated form, the phenoxide (or phenolate) anion. The undissociated phenol and the phenoxide anion react as independent species with very different rate constants, designated kArOU and kAr0. For the oxidation of 4-nitrophenol (pKa = 7.2) by C102, 1(1,0,11 = 1.4 x 10 1 M 1 s, andkArCr = 4.0 x 103 M 1 s 1 (42). Estimates of the pH-corrected second-order rate constant, kM, can be made using... 

The dienone (210) has also been prepared (152, 153) by oxidation of the amide (211) with potassium ferricyanide, when 212 was obtained in 67% yield. After protection of the phenolic hydroxyl group, reduction with LAH... 

The alkaloids are chiral as a result of restricted rotation of the biaryl system as well as of the possession of asymmetric carbon atoms the methyl at C-3 is on the a-face in all alkaloids and that at C-1 on the B-face in most, but not all cases. The structure of ancistrocladine has been determined by oxidation to the acid (13) the methyl ester of which is prepared by two routes, and by Hofmann degradation of its 0,n-dimethyl-derivative successively to the methine base (14) and the nitrogen-free products (15) and (16), the second of which on ozonolysis gives an aldehyde which yields the lactone (17) on oxidation. The position of the phenolic hydroxyl group in the alkaloid has been confirmed by Claisen rearrangement of the allyl ether (T.R. Govindachari and P.C. Parthasarathy, Tetrahedron, 1971, 1013). 

Conversion to benzoate ester 96, obtained by conversion of 94 into the corresponding acid chloride 95 followed by addition of alcohol 91, then set the stage for macrolide formation. This cyclization was effected by deprotonation and intramolecular alkylation at the benzylic position in 41% yield. Desulfurization and concomitant reduction of the olefin then provided 0-methyl lasiodiplodin (97) in 68% yield. Although Tsuji was readily able to construct the six-membered ring at the proper oxidation level, the symmetry implicit in this strategy precluded the required differentiation of the phenolic hydroxyl groups. 

This analytical method, first developed by Freudenberg and coworkers in 1936 [reviewed in ref 38], was then comprehensively developed and improved by Miksche and coworkers [39]. This oxidative degradation conducted at alkaline pH involves an initial peralkylation of the phenolic hydroxyl groups (with diethylsulfate or dim-ethylsulfate), followed by two sequential oxidation steps with permanganate and... 

The spectrophotometric evidence reviewed above for the binding of a proportion of the phenolic hydroxyl groups of the tyrosine residues of native proteins is supported by work on the action of tyrosinase on proteins. Sizer (1946) found that this enzyme oxidizes the tyrosine residues in native trypsin, pepsin, chymotrypsin, casein, peptone, insulin, and hemoglobin. Native ovalbumin, human and bovine serum albumin, tobacco mosaic virus (nucleoprotein), human y- and bovine /3-globulins, and bovine fibrinogen are not susceptible to tyrosinase, but become so after tryptic digestion. It was shown (Sizer, 1947) that for the proteins which are oxidized by tyrosinase in the native state, the observed reaction does indeed occur with the intact proteins and does not require preliminary degradation to tyrosine peptides or free tyrosine. The kinetics of the oxidation of tyrosine by tyrosinase have been studied spectropho-tometrically (Mason, 1948 etc.). 

Dezocine has a half-life of 2.6 to 2.8 hours in healthy patients and 4.2 hours in patients with liver cirrhosis. The onset of action of dezocine is faster (30 minutes) than equivalent analgesic doses of morphine, and its duration of action is longer (4-6 hours). Dezocine is extensively metabolized by glucuronidation of the phenolic hydroxyl group and by N-oxidation. Metabolites are inactive and excreted mostly via the renal tract. 

Bennett (1949) observed that the nitrogen content of commmercial lignin was increased substantially by treatment with concentrated ammonium hydroxide, but methylation essentially prevented fixation of the nitrogen. His work seems to support the conclusions of Mattson and Koutler-Andersson that simultaneous oxidation and ammonia fixation take place by way of the phenolic hydroxyl groups. 

Protection of the phenolic hydroxyl group during the oxidation can also be effected by carbethoxylation. 

This prediction was borne out by later structural studies (96). Methyla-tion of laudanidine (LII) with diazomethane gave Zepo-laudanosine (XIII) this relationship accounted for the ring system and all functional groups but left the position of the phenolic hydroxyl group in doubt. This question was settled by ethylation to Zepo-ethyllaudanidine and oxidation to the same 3-ethoxy-4-methoxybenzoic acid obtained from the racemic mixture. 

The positions of the phenolic hydroxyl groups were ascertained by exhaustive methylation of cocHaurine diethyl ether followed by oxidation whereby 3-ethoxy-4-methoxy-6-ethylbenzoic acid (from the isoquinoline portion), and p-ethoxybenzoic acid (from the hydroxybenzyl moiety) were obtained. 

On mild oxidation with ferric chloride the pentaphenolic quaternary base (CXLVII R = H) afforded a tetrahydroxyaporphine (CXLI) identical with the product obtained from V-methyllaudanosoline under similar conditions (202). An interesting aspect of this reaction is the elimination of the phenolic hydroxyl group at carbon 8, a fact that poses the problem whether or not the mechanism involved is the same as the one proposed for identical oxidations of other phenolic quaternary benzylisoquinolines where only hydrogen atoms are eliminated. 

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