Side chain oxidative

Side chain oxidation of alkylbenzenes is important in certain metabolic processes One way m which the body rids itself of foreign substances is by oxidation m the liver to compounds that are more polar and hence more easily excreted m the urine Toluene for example is oxidized to benzoic acid by this process and is eliminated rather readily... 

Pellagra is a disease caused by a deficiency of niacm (C6FI5NO2) in the diet Niacin can be synthesized in the laboratory by the side chain oxidation of 3 methylpyndine with chromic acid or potassium permanganate Suggest a reasonable structure for niacin... 

You will recognize the side chain oxidation of p xylene to terephthahc acid as a reaction type discussed previously (Section 11 13) Examples of other reactions encoun tered earlier that can be applied to the synthesis of carboxylic acids are collected m Table 19 4... 

Tocotrienols differ from tocopherols by the presence of three isolated double bonds in the branched alkyl side chain. Oxidation of tocopherol leads to ring opening and the formation of tocoquinones that show an intense red color. This species is a significant contributor to color quaUty problems in oils that have been abused. Tocopherols function as natural antioxidants (qv). An important factor in their activity is their slow reaction rate with oxygen relative to combination with other free radicals (11). 

Further side-chain oxidation of vitamin metabohtes may be necessary for phosphate transport (188,189). 24,25-Dihydtoxycholecalcifetol is... 

The hterature suggests that more than one mechanism may be operative for a given antiozonant, and that different mechanisms may be appHcable to different types of antiozonants. All of the evidence, however, indicates that the scavenger mechanism is the most important. All antiozonants react with ozone at a much higher rate than does the mbber which they protect. The extremely high reactivity with ozone of/)-phenylenediamines, compared to other amines, is best explained by their unique abiUty to react ftee-tadicaHy. The chemistry of ozone—/)-PDA reactions is known in some detail (30,31). The first step is beheved to be the formation of an ozone—/)-PDA adduct (32), or in some cases a radical ion. Pour competing fates for dissociation of the initial adduct have been described amine oxide formation, side-chain oxidation, nitroxide radical formation, and amino radical formation. 

Wipf and Miller have reported side-chain oxidation of 3-hydroxy amides with the Dess-Martin periodinane, followed by immediate cyclodehydration with triphenylphosphine-iodine, which provides a versatile extension of the Robinson-Gabriel method to substituted oxazoles. Application of this method was used to prepare the oxazole fragment 10 in 55% overall yield from 3-hydroxy amide 8. 

The mechanism of side-chain oxidation is complex and involves reaction of C-J-l bonds at the position next to the aromatic ring to form intermediate ben-zylic radicals, tert- Butyl benzene has no benzylic hydrogens, however, and is therefore inert. 

Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine /3-monooxygenase and occurs by a radical mechanism. A copper-oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. 

Similar treatment of an arenediazonium salt with CuCN yields the nitrile, ArCN, which can then be further converted into other functional groups such as carboxyl, for example, Sandmeyer reaction of o-methylbenzenediazonium bisulfate with CuCN yields o-methylbenzonitrile, which can be hydrolyzed to give o-methylbenzoic acid. This product can t be prepared from o-xvlene by the usual side-chain oxidation route because both methyl groups would be oxidized. 

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Nitration vs side-chain oxidation of toluene in dilute MA was investigated by Namba et al (Ref 69). They found that addition of sulfuric acid accelerated both reactions but nitration more than oxidation. Addition of water to the MA favors oxidation as does an increase in reaction temp... 

Figure 22. Side-chain oxidation with H2O2.

FIGURE 3.6 Degradation of toluene by side-chain oxidation. 

FIGURE 8.3 Aerobic degradation of toluene by (a) side-chain oxidation, (b) dioxygenation of the ring, and (c) monooxygenation. (From Neilson, A.H. and Allard, A.-S. The Handbook of Environmental Chemistry, Springer, 1998. With permission.)... 

FIGURE 8.35 Degradation of (a) mandelate, (b) 4-hydroxyacetophenone by side-chain oxidation pathways, (c) acetophenone by Baeyer-Villiger monooxygenation. 

FIGURE 10.3 Pathways for degradation of L-tryptophan by (a) tryptophanase, (b) deamination and oxidation, and (c) side-chain oxidation and decarboxylation to indole. 

Lonza, for example, has commercialized processes for highly chemo- and regioselective microbial ring hydroxylation and side-chain oxidation of heteroaromatics (see Fig. 2.32 for examples) (Kiener, 1995, 1999). The pharmaceutical intermediate 5-methylpyrazine-2-carboxylic acid, for example, is manufactured by microbial oxidation of 2,5-dimethylpyrazine. Many conversions of the type shown in Fig. 2.32 would not be possible by conventional chemical means. 

Scheme 12.22. Side Chain Oxidation of Aromatic Compounds... 

Ni et al. [143] investigated the profile of the major metabolites of primaquine produced by in vitro liver microsomal metabolism, with silica gel thin-layer and high performance liquid chromatography analysis. Results indicated that the liver microsomal metabolism could simultaneously produce both 5-hydroxyprimaquine (quinoline ring oxidation product) and carboxyprimaquine (side-chain oxidative deamination product). However, the quantitative comparative study of microsomal metabolism showed that the production of 5-hydroxyprimaquine was far much higher than that of carboxyprimaquine. 

When the alkyl substituent contains secondary C-H bonds, both ring and side chain oxidation at the secondary C-H bond occur. Thus, ethylbenzene gives... 

This protocol is also effective for the cyclization of an allenylaldehyde, the synthetic utility of which has been demonstrated in the synthesis of (+)-testudinariol A (Scheme 16.89) [97]. Cyclization of an allenylaldehyde provides a ris-cyclopentanol bearing a 2-propenyl group at the C2 position. The reaction mechanism may be accounted for by coordination of Ni(0) with both the aldehyde and the proximal alle-nyl double bond in an eclipsed fashion with a pseudo-equatorial orientation of the side chain, oxidative cyclization to a metallacycle, followed by Me2Zn transmetalla-tion and reductive elimination. 

Thus, although organophosphorus compounds like fenitrothion may be metabolized in aquatic organisms through oxidative desulfuration, side chain oxidation, hydrolytic cleavage of P-O-arryl linkage, as well as O-demethylation, the turn-over rate apparently is much lower than in mammals. 

Scheme 1 EGA catalysis in side-chain oxidation of methyl arenes.

Scheme 38 Side-chain oxidation of aromatic compounds mediated by Fe(ll).

Scheme41 p-Aminobenzoate synthesis applying mediated side-chain oxidation.

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