Phenol copper-catalyzed oxidation

Oxidation of phenols. Copper catalyzed oxidation of phenols, notably of pyrocatechol, has been extensively studied as a biomimetic model, muconic acid being formed. 

The main product of the Elbs reaction is the 1,4-dihydroxybenzene (hydro-quinone). If the para position is already occupied by a substituent, the reaction occurs at an ortho position, leading to a catechol derivative although the yields are not as good as for a hydroquinone. Better yields of catechols 7 can be obtained by a copper-catalyzed oxidation of phenols with molecular oxygen ... 

Copper-catalyzed oxidations of phenols by dioxygen have attracted considerable interest owing to their relevance to enzymic tyrosinases (which transform phenols into o-quinones equation 24) and laccases (which dimerize or polymerize diphenols),67 and owing to their importance for the synthesis of specialty polymers [poly(phenylene oxides)]599 and fine chemicals (p-benzoquinones, muconic acid). A wide variety of oxidative transformations of phenols can be accomplished in the presence of copper complexes, depending on the reaction conditions, the phenol substituents and the copper catalyst.56... 

In products with complex combinations of various types of flavonoids and other phenolic compounds, effort has been made to ascribe the antioxidant activity of the product to different classes of polyphenols. Frankel et al. (1995) studied 20 selected California wines and related the antioxidant activity to the polyphenolic components of the wines, rather than to resveratrol. Antioxidant activity was measured by the ability of the wines to inhibit copper-catalyzed oxidation of human LDL. The correlation coefficient between antioxidant activity and total phenolic components of the wines was r = 0.94. Individual phenolic compounds (gallic acid, catechin, myricetin, quercetin, caffeic acid, rutin, epicatechin, cyanidin, malvidin-3-glucoside) contributed to the antioxidant activity. The correlation coefficient for the compounds ranged from r = 0.92 to r = 0.38 in descending order. 

The antioxidant activities of red and white commercial grape juices have been studied using in vitro inhibition of the copper-catalyzed oxidation of human LDL (Frankel et al., 1998). The correlation between total phenols, expressed as GAE, and relative percent of inhibition of LDL oxidation was r = 0.99. In red Concord grape juices, the antioxidant activity was related to the anthocyanin levels. In the white grape juice, the antioxidant activity was associated with the levels of hydrox-ycinnamates (caffeic acid) and flavanols (catechin). When compared at the same level of total phenolics (10 pM GAE), the antioxidant activities of the grape juices were comparable to the antioxidant activities of red wine (Frankel et al., 1995). Laplaud et al. (1997) found protective action of copper-mediated LDL oxidation in aqueous V. myrtillus extracts. On a molar base, the extracts were more efficient than ascorbic acid and BHT in inhibiting LDL oxidation. 

A number of aglycone flavonoids are potent inhibitors of in vitro oxidative modification of LDL [44]. Phenolic compounds isolated from red wine inhibit the copper-catalyzed oxidation of LDL in vitro (10 mmol/L), significantly more than a-tocopherol [45], possibly by regenerating a-tocopherol [44], Alternatively, chelation of divalent metal ions by flavonoids may reduce formation of free radicals induced by Fenton reactions [42]. Hydroxylation of the flavone nucleus appears to be advantageous because flavone itself is a poor inhibitor of LDL oxidation, whereas polyhydroxylated flavonoids such as quercetin, morin, hypoleatin, fisetin, gossypetin, and galangin are potent inhibitors of LDL oxidation [44],... 

Figure 8 A copper-catalyzed oxidation of 2,4-/>w(t-butyl)phenol, relevant to the mechanism of TPQ...

Figure 7.1 (a) Resonance structures for the phenoxyl radical (b) phenol carbon atoms that undergo C-C or C-0 coupling reactions and (c) reaction scheme for the copper-catalyzed oxidative coupling of DMP (R = CH3). 

The presence of the above-mentioned metal ions increases the decomposition rate of hydroperoxides and the overall oxidation rate in the autoxidation of a hydrocarbon to such an extent that even in the presence of antioxidants, the induction period of oxygen uptake is drastically shortened. In such a case, sterically hindered phenols or aromatic amines even at rather high concentrations, do not retard the oxidation rate satisfactorily. A much more efficient inhibition is then achieved hy using metal deactivators, together with antioxidants. Metal deactivators are also known as copper inhihitors, because, in practice, the copper-catalyzed oxidation of polyolefins is by far of greatest importance. This is due to the fact that polyolefins are the preferred insulation material for communication wire and power cables, which generally contain copper conductors. 

Hydroquinone production is feasible via the copper-catalyzed oxidation of phenol with dioxygen to p-benzoquinone, with subsequent reduction [105,106], which can be effected using the same CuCl/acetonitrile catalyst under hydrogen. 

Another proposed mechanism of the polymerization is a two-electron transfer mechanism, which involvs phenolate-bridged dinuclear copper(II) complex as starting species. The complex generated phenoxonium cations and phenolate anion through a double one-electron transfer from a phenolate to both copper centres (step v) and form the quinone-ketal intermediate via nucleophilic attack (step vi). This reaction pathway is supported by theoretical calculations of atomic charges of monomeric and dimeric species of 2,6-DMP where phenoxonium cations are proposed as key intermediates. Ab Initio calculations on 2,6-DMP and 4-(2,6-Dimethylphenoxy)-2,6-dimethylphenol provided evidence of the phenoxonium cation in the copper-catalyzed oxidative coupling reaction which proposed that the selective C-O coupling was achieved via the nucleophilic attack of a phenolate on the para-carbon of a phenoxonium cation (25). Based on the experimental evidence currently reported, both... 

The copper catalyzed oxidation of benzoic acid to phenol proceeds through benzoyl salicylic acid (I), which undergoes hydrolysis and decarboxylation ... 

SCHEME 7. 26 Copper-catalyzed oxidative cross-dehydrogenative-coupling of 3-ketoesters or 2-carbonyl-substituted phenols with ethers. 

Red wine contains quercetin, rutin, catechin, and epicatechin, among other flavonoids (Frankel and others 1993). Quercetin and other phenolic compounds isolated from wines were found to be more effective than a-tocopherol in inhibiting copper-catalyzed LDL oxidation. It has been determined that quercetin has also several anti-inflammatory effects it inhibits inflammatory cytokine production (Boots and others 2008), inducible NO synthase expression and activation of inflammatory transcription factors (Hamalainen and others 2007), and activity of cyclooxygenase and lipooxygenase (Issa 2006), among others. 

Tyrosinase is a monooxygenase which catalyzes the incorporation of one oxygen atom from dioxygen into phenols and further oxidizes the catechols formed to o-quinones (oxidase action). A comparison of spectral (EPR, electronic absorption, CD, and resonance Raman) properties of oxy-tyrosinase and its derivatives with those of oxy-Hc establishes a close similarity of the active site structures in these proteins (26-29). Thus, it seems likely that there is a close relationship between the binding of dioxygen and the ability to "activate" it for reaction and incoiporation into organic substrates. Other important copper monooxygenases which are however of lesser relevance to the model studies discussed below include dopamine p-hydroxylase (16,30) and a recently described copper-dependent phenylalanine hydroxylase (31). 

The multi-copper oxidases include laccase, ceruloplasmin, and ascorbate oxidase. Laccase can be found in tree sap and in fungi ascorbate oxidase, in cucumber and related plants and ceruloplasmin, in vertebrate blood serum. Laccases catalyze oxidation of phenolic compounds to radicals with a concomitant 4e reduction of O2 to water, and it is thought that this process may be important in the breakdown of lignin. Ceruloplasmin, whose real biological function is either quite varied or unknown, also catalyzes oxidation of a variety of substrates, again via a 4e reduction of O2 to water. Ferroxidase activity has been demonstrated for it, as has SOD activity. Ascorbate oxidase catalyzes the oxidation of ascorbate, again via a 4e reduction of O2 to water. Excellent reviews of these three systems can be found in Volume 111 of Copper Proteins and Copper Enzymes (Lontie, 1984). 

In fact, the role of copper and oxygen in the Wacker Process is certainly more complicated than indicated in equations (151) and (152) and in Scheme 10, and could be similar to that previously discussed for the rhodium/copper-catalyzed ketonization of terminal alkenes. Hosokawa and coworkers have recently studied the Wacker-type asymmetric intramolecular oxidative cyclization of irons-2-(2-butenyl)phenol (132) by 02 in the presence of (+)-(3,2,10-i -pinene)palladium(II) acetate (133) and Cu(OAc)2 (equation 156).413 It has been shown that the chiral pinanyl ligand is retained by palladium throughout the reaction, and therefore it is suggested that the active catalyst consists of copper and palladium linked by an acetate bridge. The role of copper would be to act as an oxygen carrier capable of rapidly reoxidizing palladium hydride into a hydroperoxide species (equation 157).413 Such a process is also likely to occur in the palladium-catalyzed acetoxylation of alkenes (see Section 61.3.4.3). 

Recently, a copper-catalyzed synthesis of trimethyl- 1,4-benzoquinone, a key intermediate in the industrial synthesis of vitamin E, has been reported (Eq. 11) [49]. In the proposed mechanism, a tetranuclear cluster [Cu4(a -O)Cl10], isolated from the reaction mixture, deprotonates phenol and oxidizes it to a copper-bound phenolate radical, which reacts with dioxygen. 

Many amine-copper complexes, as well as a few amine complexes of other metals, and certain metal oxides have since been shown to induce similar reactions (17, 18, 22, 23, 30). This chapter is concerned largely with the mechanism of oxidative polymerization of phenols to linear polyarylene ethers most of the work reported has dealt with the copper-amine catalyzed oxidation of 2,6-xylenol, which is the basis for the commercial production of the polymer marketed under the trade name PPO, but the principal features of the reaction are common to the oxidative polymerization of other 2,6-disubstituted phenols. 

The experiments discussed above deal with the copper-amine catalyzed oxidation of 2,6-xylenol, but oxidation of xylenol by metal oxides takes place by the same mechanism (22). The oxidative coupling of other 2,6-disubstituted phenols has the same characteristics as the oxida-... 

Copper compounds are catalysts for the Michael addition reaction (249), olefin dimerizations (245, 248), the polymerization of propylene sulfide (142), and the preparation of straight-chain poly phenol ethers by oxidation of 2,6-dimethylphenol in the presence of ethyl- or phenyl-copper (209a). Pentafluorophenylcopper tetramer is an intriguing catalyst for the rearrangement of highly strained polycyclic molecules (116). The copper compound promotes the cleavage of different bonds in 1,2,2-tri-methylbicyclo[1.1.0]butane compared to ruthenium or rhodium complexes. Methylcopper also catalyzes the decomposition of tetramethyllead in alcohol solution (78, 81). 

Like BINOL, salicylaldehyde imines have become very important in asymmetric catalysis and a variety of polydentate ligands prepared from chiral monoamines and diamines are employed in oxidation reactions, carbenoid reactions and Lewis acid catalyzed reactions. As in the previous section, this section emphasizes the effect of the phenol moiety on the asymmetric catalysis. An imine derived from a chiral 1-phenethylamine and salicylaldehyde was employed in the copper catalyzed asymmetric cyclopropanation by Nozaki, Noyori and coworkers in 1966, which is the first example of the asymmetric catalysis in a homogeneous system . Salicylaldehyde imines with ethylenediamine (salen) have been studied extensively by Jacobsen and Katsuki and their coworkers since 1990 in asymmetric catalysis. Jacobsen and coworkers employed the ligands prepared from chiral 1,2-diamines and Katsuki and coworkers sophisticated ligands possess chirality not only at the diamine moiety but also at the 3,3 -positions. 

The main function of metal deactivators (MD) is to retard efficiently metal-catalyzed oxidation of polymers. Polymer contact with metals occur widely, for example, when certain fillers, reinforcements, and pigments are added to polymers, and, more importantly when polymers, such as polyolefins and PVC, are used as insulation materials for copper wires and power cables (copper is a pro-oxidant since it accelerates the decomposition of hydroperoxides to free radicals, which initiate polymer oxidation). The deactivators are normally poly functional chelating compounds with ligands containing atoms like N, O, S, and P (e.g., see Table 1, AOs 33 and 34) that can chelate with metals and decrease their catalytic activity. Depending on their chemical structures, many metal deactivators also function by other antioxidant mechanisms, e.g., AO 33 contains the hindered phenol moiety and would also function as CB-D antioxidants. 

Tyrosinases (synonyms phenol oxidases, poly-phenolases or polyphenol oxidases) are copper-containing monooxygenases, which catalyze two consecutive reactions with molecular oxygen as cosubstrate, namely the ortho-hydroxylation of phenols and the oxidation of the resulting catechols to ortho-quinones (Fig. 16.3-4). 

Some enzymes capable of oxidizing C-H bonds contain copper ions [52]. For example, tyrosinase [53a] contains a coupled, binuclear copper active site which reversibly binds dioxygen as a peroxide that bridges between the two copper ions. This enzyme catalyzes the orthohydroxylation of phenols with further oxidation of catechol to an ortho-quimne [53b-d], The mechanism proposed for phenolase activity of tyrosinase is shown in Scheme XI. 13 [521]. 

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