Hydroxylations of aromatic rings

The uncatalysed p-coumaric acid oxidation led to the formation of intermediates (not shown here) almost similar to those of the catalysed reaction, without formation of dihydroxylated aromatic compounds, such as 3,4- dihydroxybenzaldehyde. This result shows that the catalyst may promote the hydroxylation of aromatic ring by enhancing the formation of hydroxyl radicals in the reaction mixture. 

An intramolecular hydrogen migration observed in the hydroxylation of aromatic rings in certain enzyme-catalyzed reactions as well as some chemical reactions. The rearrangement was first observed at the National Institutes of Health (hence the name NIH ) in studies of the synthesis of L-tyrosine from L-phenylalanine via phenylalanine hydroxylase. Observation of this shift requires appropriate deuteration of the aromatic reactant. 

Hydroxylation of aromatic rings is a very common and an important step in the biosynthesis of natural products.181,182 Arene oxides were suggested as intermediates in the biosynthesis of natural products as early as in 1967.183 However, not all hydroxylations proceed through arene oxides. A number of instances have been documented,184 as in the case of cinnamic and benzoic acids, where ortho and para hydroxylations take place by the involvement of an NIH shift (arene oxides). 

The active oxygen species of cytochromes P-450 is reactive enough to transfer its oxygen atom to most organic compounds. However, the most frequently encountered reactions are (1) the hydroxylation of C—H bonds, (2) the epoxidation of double bonds, (3) the hydroxylation of aromatic rings, and (4) the transfer of an oxygen atom to compounds containing an N, S, or P heteroatom. 

Cytochromes P-450 also catalyze the hydroxylation of aromatic rings. In most cases, these reactions involve the intermediate formation of arene oxides derived from the epoxidation of a double bond of the aromatic compound and an isomerization of these very reactive epoxides into the corresponding phenols. 

Hydroxylations of aromatic rings are also achieved via transient esters that are easily hydrolyzed in situ to the corresponding phenols. In this way, anisole and diphenyl ether are oxidized by peroxytrifluoroacetic acid to predominantly ortho-hydroxy compounds in low yields (equation 147) [1118]. 

Hydroxylation of aromatic rings in the presence of oxygen Oxidation of alkenyl stannates —copper mediated homocoupling [56] ... 

NIH shift The INTRAMOLECULAR hydrogen MIGRATION that can be observed in enzymatic and chemical hydroxylations of aromatic rings. It is evidenced by appropriate deuterium labeling, for example ... 

S. Banfi, M. Cavazzini, G. Pozzi, S. V. Barkanova, O. L. Kaliya, Kinetic studies on the interactions of manganese-porph)Tins with peracetic acid. Part 1. Epoxidation of alkenes and hydroxylation of aromatic rings, J. Chem. Soc. Perkin Trans. 2(4) (2000) 871. 

Hydroxylation of aromatic rings probably occurs by a similar mechanism i.e. the electron-rich aromatic ring nucleophilically attacks the flavin peroxide (electrophihc attack by the peroxide on the aromatic ring at activated positions) (XXXXV). 

Hydroxylation of aromatic rings. Aromatic rings are frequently oxidized into phenols followed by conjugation and excretion. The mechanism of the reaction is discussed later, and we shall first consider an example of phenol formation. In the hydroxylation of chlorobenzene, all three isomers are produced, i.e. ortho-, meta- and para-dnloro-phenol, but in different amounts (Fig. 31.13). As a rule, hydroxylation occurs on the less hindered site, usually the para position. Electronic factors are also operative. This is seen in the hydroxylation of many drugs, two of which are shown in Fig. 31.14. 

Metabolism of this compound class usually starts with hydroxylation of aromatic rings or alkyl or alkoxy groups. Cleavage of the amide bond takes place at a later stage in most cases [39]. Fourteen metabolites have been detected during a study of furametpyr (7) in mammals, some of which are shown in Scheme 13.3.3 [40,... 

Considerable amount of v ork has been reported in the hydroxylation of aromatic rings. Thus, benzene on oxidation with Pseudomonas putida in presence of oxygen gives the cis-diol (Scheme 6). The cis-diol obtained could be converted by four steps into 1,2,3,4-tetrahydroxy compound, conduritol-and by five steps into the hexahydroxy compound, pinitol, an antidiabetic agent (Scheme 6)." ... 

Mixed Oxygenases. Several reactions that may be considered to be hydroxylations have been shown to require both molecular oxygen and a reduced pyridine nucleotide. Examples include hydroxylation of aromatic rings (IX) hydroxylation of steroids (X) and cleavage of an imidazole ring XI. ... 

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