Oxidation of Ketones to Carboxylic Acids

Oxidations of ketones give carboxylic acids with the same or smaller number of carbon atoms. 

The Willgerodt reaction, which involves heating ketones with ammonium polysulfide, is the most important route to carboxylic acids without degradation of the carbon chain. It applies especially to methyl and alkyl 

The Kindler modification dodges heating in closed vessels under pressure by using, instead of aqueous ammonium polysulfide, a mixture of sulfur and morpholine. After being refluxed for 6-12 h, the ketone is converted into the thiomorpholide of the carboxylic acid. Subsequent alkaline hydrolysis yields the carboxylic acid as the final product [501, 503, 504, 1170]. 

The uniqueness of the Willgerodt reaction lies in the ultimate formation of acids from ketones regardless of the position of the carbonyl group in the chain. 

The Willgerodt reaction of isobutyl methyl ketone with ammonium polysulfide at 200 °C gives an 88% yield of isocapronamide after 4 h of heating [1169. Yields of other aliphatic ketones are not nearly as high [1161, 1169 (equation 415). 

---

Aqueous potassium permanganate is hardly ever used to tixidize secondary alcohols to ketones, because further oxidation of ketones to carboxylic acids occurs even under mild conditions (15-30 °C) [2247]. On the other hand, oxidations of alcohols to ketones are successfully accomplished... 

Oxidation of ketones to carboxylic acids. This transition metal cluster compound catalyzes the oxidation of CO to COj by molecular oxygen. When acetone is used as solvent, acetic acid is identified as another product of oxidation. When cyclohexanone is used as solvent, adipic acid is formed in high yield. 

The direct oxidation of ketones to carboxylic acids usually implies a carbon-carbon bond cleavage [249]. Product mixtures are often obtained. However, for the preparation of dicarboxylic acids from cyclic ketones this reaction has proven to be synthetically very useful. 

A new reagent, AMiydroxyphthalimide combined with Co(acac)n (n = 2,3), transforms alkylbenzenes to ketones, whereas methylbenzenes give the corresponding carboxylic acids.1121 Phthalimide N-oxyl was found to be the key intermediate. Novel oxoperoxo Mo(VI) complexes mediate the cost-effective and environmentally benign oxidation of methylbenzenes to carboxylic acids.1384 Similar green oxidation of p-xylene to terephthalic acid was reported by using a Ru-substituted heteropolyanion.1385... 

A common step in the metabolism of alcohols is carried out by alcohol dehydrogenase enzymes that produce aldehydes from primary alcohols that have the -OH group on an end carbon and produce ketones from secondary alcohols that have the -OH group on a middle carbon, as shown by the examples in Reactions 7.3.6 and 7.3.7. As indicated by the double arrows in these reactions, the reactions are reversible and the aldehydes and ketones can be converted back to alcohols. The oxidation of aldehydes to carboxylic acids occurs readily (Reaction 7.3.8). This is an important detoxication process because aldehydes are lipid soluble and relatively toxic, whereas carboxylic acids are more water soluble and undergo phase n reactions leading to their elimination. 

Oxidations with peroxybenzoic acid are carried out in solutions in dichloromethane, chloroform, benzene, ether, or ethyl acetate at or below room temperature and include epoxidation of double bonds [295, 296, 297, 298, 299, 300, 301], oxidation of benzaldehydes to carboxylic acids or phenols [302], the Baeyer-Villiger reaction of ketones [303, 304, 305, 306, 307], and oxidation of sulfides to sulfoxides [308, 309]. Peroxybenzoic acid is also used for the anti hydroxylation of double bonds [310], the oxidation of pyrrolidines to pyrrolidones [377] and of pyrroles to succinimides [377], and the preparation of azoxy compounds from azo compounds [372]. 

Oxidation of alcohols to carboxylic acids (or ketones) with nickel peroxide (see 1st edition). 

Oxidation. Oxidation of aldehydes to carboxylic acids by t-BuOOH (70%) with CuCl as catalyst occurs at room temperature. Using anhydrous t-BuOOH in decane, primary alcohols are also converted to the same products and secondary alcohols to ketones. More unusual is the oxidation of aldehydes in the presence of an alcohol to provide esters by t-BuOOH with both Cu(C104)2 and lnBr3 as catalyst. ... 

Modern methods for oxidation of aldehydes to carboxylic acids and ketones have been reviewed ... 

It should come as no surprise that biological systems do not use agents such as potassium dichromate or the oxides of other transition metals for the oxidation of alcohols to aldehydes and ketones or for the oxidation of aldehydes to carboxylic acids. What biological systems use instead is NAD+ (AD = a combination of adenine and ribose).The function of the Ad portion of the molecule is to position NAD" on the surface of the enzyme in the proper orientation relative to the molecule it is to oxidize. 

Silver nitrate catalyzes the oxidation of sulfides to sulfoxides by r-BuOOH and the oxidation of aldehydes to carboxylic acids by H202 in aq acetonitrile. Under visible light irradiation the selective oxidation of alcohols to aldehydes or ketones can be performed in water using dye-sensitized ZnO in combination with AgN03/TEMP0. 5 ... 

Perhaps the most important reaction of alcohols is their oxidation to carbonyl compounds. Primary alcohols yield either aldehydes or carboxylic acids, secondary alcohols yield ketones, but tertiary alcohols are not normally oxidized. Pyridinium chlorochromate (PCC) in dichloromethane is often used for oxidizing primary alcohols to aldehydes and secondary alcohols to ketones. A solution of Cr03 in aqueous acid is frequently used for oxidizing primary alcohols to carboxylic acids and secondary alcohols to ketones. 

For the dehydrogenation of CH—XH structures, for example, of alcohols to ketones, of aldehydes to carboxylic acids, or of amines to nitriles, there is a wealth of anodic reactions available, such as the nickel hydroxide electrode [126], indirect electrolysis [127, 128] (Chapter 15) with I , NO, thioanisole [129, 130], or RUO2/CP [131]. Likewise, selective chemical oxidations (Cr(VI), Mn02, MnOJ, DMSO/AC2O, Ag20/Celite , and 02/Pt) [94] are available for that purpose. The advantages of the electrochemical conversion are a lower price, an easier scale-up, and reduced problems of pollution. 

This is one of the most important applications for RuO. Oxidative cleavage of alkenes and alkynes by a variety of reagents has been reviewed [30, 35, 50, 60, 68-71]. The gentler cleavage reactions of alkenes to aldehydes or ketones are considered first (Table 3.3), then the commoner cases of cleavage to carboxylic acids (Table 3.6). 

Taylor and Flood could show that polystyrene-bound phenylselenic acid in the presence of TBHP can catalyze the oxidation of benzylic alcohols to ketones or aldehydes in a biphasic system (polymer-TBHP/alcohol in CCI4) in good yields (69-100%) (Scheme 117) °. No overoxidation of aldehydes to carboxylic acids was observed and unactivated allylic alcohols or aliphatic alcohols were unreactive under these conditions. In 1999, Berkessel and Sklorz presented a manganese-catalyzed method for the oxidation of primary and secondary alcohols to the corresponding carboxylic acids and ketones (Scheme 118). The authors employed the Mn-tmtacn complex (Mn/168a) in the presence of sodium ascorbate as very efficient cocatalyst and 30% H2O2 as oxidant to oxidize 1-butanol to butyric acid and 2-pentanol to 2-pentanone in yields of 90% and 97%, respectively. This catalytic system shows very good catalytic activity, as can be seen from the fact that for the oxidation of 2-pentanol as little as 0.03% of the catalyst is necessary to obtain the ketone in excellent yield. 

Ruthenium-oxo species (Ru04)2 and (Ru04) oxidize primary alcohols to carboxylic acids and secondary alcohols to ketones. New species (Ru02Cl3)(PPh4) and Ru02(bipy)Cl2 cleanly oxidize a wide range of alcohols to aldehydes and ketones without attack of double bonds.638... 

This oxidant is a bright-orange solid that is soluble in organic solvents, and very convenient to store and manipulate, because of its lack of hydro-philicity. Pyridinium dichromate (PDC), which is normally used in dichlor-omethane at room temperature, is a very efficient oxidant able to transform alcohols in aldehydes and ketones in high yield. The absence of water in the reaction media prevents the over-oxidation of aldehydes into carboxylic acids. 

---