Oxidation of aromatic rings

In some instances, particularly in hydroxyla-tions meta to a halide substituent, the hydrogen on the hydroxylated carbon is quantitatively lost (i.e., there is no NIH shift), and a small deuterium kinetic isotope effect is observed These hydroxylations could result from direct oxygen insertion into the C-H bond, as in a true hydrox-ylation mechanism, but they are more likely to result from oxidation of the aromatic ring without the formation of a discrete epoxide intermediate. Isotope effect studies with deuterated benzenes bearing a variety of substituents have shed some light on this process A small, normal isotope effect is observed for weta-hydroxylation when deuterium is located meta- to the halogen in chlorobenzene = 1.1-1.3), but a small, 

3-trifluorobenzene, and 1,2,4-trifluorobenzene suggests that the reaction is initiated by direct attack of the electrophilic ferryl oxygen on the aromatic rr-system rather than by an initial electron abstraction . More refined local density approximation calculations for the oxidation of benzene and OTono-fluorobenzene suggest that epoxidation is disfavored vs a direct NIH shift from a tetrahedral oxygen-addition intermediate, and that hydroxylationpara to the fluorine is favored . In addition to the electronic effect of the halide, a steric interference is observed in the ability of the 

4-iodoanisole is oxidized to 4-methoxyphenol without the incorporation of label from H2 0 or This finding argues that the phenol hydroxyl is not absolutely required for the reaction, so the addition can occur via p5o-addition without prior formation of the phenoxy radical. In accord with an jpso-mechanism, the substituent is eliminated from 4-halophenols as a halide anion, a para-CH20H group as formaldehyde, and a PhCO-substituent as benzoic acid.  

Furthermore, the methyl in 4-methylphenol is not a viable leaving group and this compound is simply oxidized to 4-hydroxy-4-methyl-2,5-cyclo-hexadiene-l-one. It is to be noted that the regiochemical results do not rule out epoxide formation, as electron donation from the phenolic hydroxyl group would regiospecifically open the epoxide to the same products, but epoxide formation appears an unlikely explanation for the collective results. 

The oxidation of phenols via HAT from the hydroxyl group (or sequential electron transfer and deprotonation) is supported by data on the oxidation of estradiol and estrone. In accord with a key role for the phenolic hydroxyl group, the predominant ortAo-hydroxylation of estradiol does not occur when the phenolic hydroxyl is replaced by a methyl ether . Early experiments established that 2-hydroxylation of estradiol occurs without a detectable NIH shift . More recent work has shown that, whereas estrone is converted to both 2- and 4-hydroxyestrone by CYP3A4, conjugation of an additional aromatic ring, as in equilenin and 2-naphthol, leads exclusively to 4-hydroxylation of estrone and 1-hydrox-ylation of 2-naphthol. In both these reactions, the site that is exclusively hydroxylated is that expected to carry the greatest share of the unpaired electron density if the initial step is 

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Phenol biosynthesis in plants proceeds from carbohydrate precursors whereas the pathway in animals involves oxidation of aromatic rings... 

The NIH shift has been found to occur during aromatic hydroxylations catalyzed by enzymes present in plants, animals, fungi and bacteria. It is thus evident that the acid catalyzed (or spontaneous) isomerization of oxepins-arene oxides is a very important type of in vivo reaction. It should be emphasized that the NIH shift may occur under either acid-catalyzed or neutral (spontaneous) conditions (76ACR378). The direct chemical oxidation of aromatic rings has also yielded both phenols (obtained via the NIH shift) and arene oxides (80JCS(P1)1693>. 

Degradative oxidation of aromatic rings into carboxylic acids4b and oxidation of aromatic compounds to quinones2a... 

Because hydroxyl radicals can cause nucleophilic oxidation of aromatic rings when dissolved 02 is present, the reaction rate is directly dependent on the oxygen partial pressure. Five FAs from different sources were used to compare the effects on the photodegradation of phenanthrene. 

R. T. Williams, ed., Biological Oxidation of Aromatic Rings, Biochem. Soc. Symp., No. 5, Cambridge University Press (19501. 

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