Side chain oxidation carboxylic acids

Disposition in the Body. Readily absorbed after oral administration. Metabolised by side-chain oxidation, glucuronic acid conjugation, and W-dealkylation. Up to about 90% of a dose is excreted in the urine, the major urinary metabolite, probenecid acyl glucuronide, accounting for up to 50% of a dose up to 25% of a dose is excreted as hydroxylated and carboxylic acid... 

Hydroxylation of terminal methyl groups of the alkenyl side-chain to give c/s and trans (major) alcohols Oxidation of hydroxymethyl product of the alkenyl side-chain to carboxylic acids Reduction of alkenyl side-chain and oxidation of terminal methyl group... 

Oxidation of alkyl side chains. Strong oxidising agents (e.g. KMn04) can convert alkyl side chains to carboxylic acids. 

Oxidative degradation of side chains to carboxylic acids... 

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... 

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. 

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. 

Hydrazide groups can react with carbonyl groups to form stable hydrazone linkages. Derivatives of proteins formed from the reaction of their carboxylate side chains with adipic acid dihydrazide (Chapter 4, Section 8.1) and the water-soluble carbodiimide EDC (Chapter 3, Section 1.1) create activated proteins that can covalently bind to formyl residues. Hydrazide-modified enzymes prepared in this manner can bind specifically to aldehyde groups formed by mild periodate oxidation of carbohydrates (Chapter 1, Section 4.4). These reagents can be used in assay systems to detect or measure glycoproteins in cells, tissue sections, or blots (Gershoni et al., 1985). 

Side-chain oxidations of alkyl aromatic compounds to aromatic carboxylic acids by electrogenerated and regenerated chromic acid have been studied extensively in the case of saccharin formation from o-toluene sulfonamide This... 

In addition to the synthesis of saccharin, also a number of other side-chain oxidations have been studied leading to aromatic carboxylic acids by indirect electrochemical oxidation using chromic acid as oxidizing agent. They include the oxidation of p-nitrotoluene 2,4-dinitrotoluene toluene, p-xylene, and p-tolualdehyde... 

Amino acids are chemically reactive at their a-amino groups and their side chains. The carboxyl groups are relatively unreactive unless activated. A very useful reaction is the oxidative deamination of amino acids with ninhydrin. The reaction produces a blue pigment, which can be used for the detection of amino acids both qualitatively and quantitatively. The series of reactions producing the blue complex is given in Equation (4.2). 

We have already encountered three methods for preparing carboxylic acids (1) oxidation of alcohols and aldehydes, (2) oxidative cleavage of alkenes and alkynes, and (3) severe side-chain oxidation of alkylbenzenes. 

Alkaline hydrogen peroxide does not attack alkyl side chains directly, but it can be very useful for the conversion of the aromatic aldehyde to the carboxylic acid in the side chain oxidation sequence. The chemistry is covered in Section 6.1. Peracids usually do not attack alkyl side chains, but can oxidize benzylic alcohols and aldehydes to the carboxylic acids and benzylic ketones to phenyl ester. These reactions are covered in sections on alcohol (5), aldehyde (6.1) and ketone (6.2) oxidation. 

The para acids are usually made by halogenating a hydrocarbon and then oxidizing the side chain to carboxyl. 

Nickel peroxide, an undefined black oxide of nickel, is prepared from nickel sulfate hexahydrate by oxidation in alkaline medium with an ozone-oxygen mixture [929] or with sodium hypochlorite [930, 931, 932, 933]. Its main applications are the oxidation of aromatic side chains to carboxyls [933], of allylic and benzylic alcohols to aldehydes in organic solvents [929, 932] or to acids in aqueous alkaline solutions [929, 930, 932], and of aldehydes to acids [934, the conversion of aldehyde or ketone hydrazones into diazo compounds [935] the dehydrogenative coupling of ketones in the a positions with respect to carbonyl groups [931] and the dehydrogenation of primary amines to nitriles or azo compounds [936]. 

At least two other routes of degradation in soil are apparent from the nature of the deg rad ate s formed. An initial propyl side chain oxidation of PBO leads to the formation of prop-1-one PBO. This then either undergoes carboxylic acid substitution at the 6-propyl position and hydroxylation to give 5 2-(2-bu toxy ethoxy) -e t hoxy- hy droxy me thy I ]- 6-c arboxy-1,3 -benzodiox ole, or 1 oss of the butoxy ethoxy ethoxy methyl side chain to form the corresponding prop-1-one benzaldehyde (Fig. 7.9). 

Benzo[c] cinnoline aldehydes are as yet unknown. The 2- and 3-acetyl derivatives have been prepared, but the majority of known compounds relevant to this section are mono- and dicarboxylic acid derivatives. These include the 2-, - - 3-, ° and 4. - o2.J55,i57 monoacids and esters, the lactone of 10-hydroxybenzo[c]cinnoline-l-carboxylic acid, some halogeno- and methyl-substituted 2- and 4. carboxylic acids, and the 2,9-, 3,8-, - - and 4,7- dicarboxylic acids and derivatives. These compounds have been obtained by ring synthesis, or, in the case of 2-methylbenzo[c]dnnoline-9-carboxylic acid, by side-chain oxidation, " rather than by the introduction of substituents into benzo[c] cinnoline. Benzo[c]cinnoline-l-carbonitrile has been prepared, albeit in low... 

Apart from some nitration studies (Section IV,B), the only reaction of these derivatives to be described has been the side-chain oxidation of 2,9-dimethylbenzo [c] cinnoline to 2-methylbenzo [c] cinnoline-9-carboxylic acid using chromic acid.154... 

The regularities attaching to the various oxidation reactions, and their mechanisms, have not yet been fully clarified. In general, the formation of a second carboxyl group on side-chain oxidation of dialkyl aromatic compounds is favored by alkalinity and disfavored by acidity of the medium. Beyond this, the following paragraphs give some indications of the influence of substituents. 

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