Carboxylic Acids

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Chapter: Organic Chemistry : Functional Group Synthesis

Carboxylic acids have a relatively high oxidation level (+3), and thus a majority of synthetic methods to access carboxylic acids are oxidative in nature.


Carboxylic acids have a relatively high oxidation level (+3), and thus a majority of synthetic methods to access carboxylic acids are oxidative in nature. Traditional preparations include the following:

Oxidation of olefins

Oxidation of primary alcohols

Oxidation of alkylbenzenes

Hydrolysis of nitriles

While the above reactions will provide carboxylic acid products, each has problems associated with it. The cleavage of olefins to carboxylic acids [reaction (7.1)] can be carried out using potassium permanganate or by ozonolysis at low temperature followed by oxidative workup with hydrogen peroxide. Neither of these methods is very useful since only symmetric olefins provide a single carboxylic acid product. Unsymmetrical olefins give a mixture of two acids which must be separated. Furthermore the most useful synthetic processes are those which build up structures, whereas these reactions are degradative in nature.

Primary alcohols can be oxidized to carboxylic acids by a variety of reagents [reaction (7.2)]. Often potassium permanganate or sodium dichromate were given as reagents to use in this transformation. These are powerful oxidants, and many other functional groups that might be present cannot survive the reaction con-ditions. Milder oxidants are preferred and the best of these is chromic acid in acetone (Jones reagent). Jones reagent is a mixture of chromic acid and a stoi-chiometric amount of sulfuric acid which is needed in the redox process to keep the solution at near a pH of 7. This technique is fast, easy, and efficient and the reagent solution is easily prepared from chromium trioxide and sulfuric acid in acetone. The oxidation can be carried out by adding the Jones reagent by burette to the alcohol. Oxidation is instantaneous and the addition can be stopped pre-cisely when all the alcohol has been consumed. Using a stoichiometric amount of chromic acid usually leaves other functional groups untouched. This is the method of choice for the synthesis of carboxylic acids from primary alcohols.

The oxidation of alkyl benzenes to benzoic acids [reaction (7.3)] is still carried out occasionally, and this oxidation is most likely the only one where potassium permanganate is the reagent of choice. Any carbon group attached to the aromatic ring is degraded to the carboxylic acid group under the very vigorous conditions of this oxidation.

An interesting twist on the oxidation of aromatic compounds forms the basis of a new and very useful synthesis of carboxylic acids. Normally the aromatic ring is resistant to oxidation and the side chains are oxidatively degraded to car-boxylic acids, as in reaction (7.3). It has been found that ruthenium tetroxide is a mild and selective oxidant of aromatic rings and completely degrades the ring to the carboxylic acid but leaves aliphatic groups unoxidized. This is essentially the reverse of the chemoselectivity seen in potassium permanganate oxidations of arenes, where the side chains are oxidized but the aromatic ring is left intact. The selectivity and mildness is seen in the following example in which no amide or silyl ether (OTMS) oxidation was observed and there was no epimerization of either chiral center:

Another common way to install a carboxylic acid group is to hydrolyze a carboxylic acid derivative. Such hydrolyses do not require a change in oxidation level (carboxylic acid derivatives are at the oxidation level of the acid itself), but they do normally require acid or base catalysis. Nitriles [reaction (7.4)] often require vigorous conditions for hydrolysis mainly because they are only weakly electrophilic. Either concentrated hydrochloric acid or sodium hydroxide can be used to hydrolyze nitriles. The first stage of the hydrolysis produces an amide and the amide is subsequently hydrolyzed to the acid. Each step of the hydrolysis requires strenuous conditions and is useful mainly for nitriles that lack other functional groups that would be destroyed by the stringent conditions. It has been found that a mixture of sodium hydroxide and hydrogen peroxide can be used to hydrolyze nitriles more efficiently than sodium hydroxide alone and is the reagent of choice, although many other reagent combinations have been reported.

Amides are stabilized by resonance and are thus difficult to hydrolyze. Like nitriles they can be hydrolyzed by concentrated hydrochloric acid or concentrated sodium hydroxide. These are powerful reagents that tend to react with many other functional groups as well. Thus hydrolysis is not a satisfactory method for amides with many other functional groups present. As with nitriles, a mixture of sodium hydroxide and hydrogen peroxide is one of the more effective reagents for hydrolysis.

Esters, on the other hand, are very common hydrolytic precursors to carboxylic acids. The traditional reaction for the hydrolysis of esters is basic saponification using sodium hydroxide or potassium hydroxide. While acid catalysis can also be employed, preparative methods usually use base catalysis because formation of the carboxylate salt drives the reaction to the right and gives high yields of products.

While esters are much more easily hydrolyzed than amides, traditional saponi-fication suffers from the fact that most esters are not soluble in aqueous base and so the rate of the hydrolysis is limited by the solubility, not by the reactivity. This limitation is overcome by the use of lithium hydroxide in aqueous THF, the reagent of choice for basic hydrolysis of esters. Methyl and ethyl esters are cleaved readily by this combination as most esters are soluble in this solvent mixture.

If structural constraints prevent the use of basic hydrolysis of the ester group, acid hydrolysis must be used. Nowadays it is much more common, in such instances, to use tert-butyl esters because they are cleaved rapidly and efficiently by trifluoroacetic acid (TFA) to the carboxylic acid and isobutylene. This cleav-age is different from the normal acid-catalyzed hydrolysis of esters in that the alkyl– oxygen bond is broken rather than the acyl– oxygen bond. This change in mechanism is brought about by the stability of the tert-butyl cation which is produced upon alkyl– oxygen cleavage. As an added benefit, the isobutylene by-product is a gas which escapes from the reaction mixture.

If neither acidic nor basic conditions are compatible with other groups present in the ester to be hydrolyzed, then β -trimethylsilylethyl esters are often prepared. Trimethylsilylethyl esters are cleaved easily by fluoride under mild, neutral con-ditions. Typical sources of fluoride are cesium fluoride (CsF) or the more soluble tetrabutylammonium fluoride (TBAF).

Current methods for the hydrolysis of esters are fast, efficient, and sufficiently mild that they are compatible with the presence of a variety of other func-tional groups and/or stereocenters in the molecule. For example, protected amino acid esters are hydrolyzed quantitatively without racemization or deprotection by LiOH in aqueous THF.

Carboxylic acid groups can also be installed in molecules using the reaction of an organometallic compound with carbon dioxide. This is a reductive method since the carbon dioxide is reduced to a carboxylic acid by formation of a new car-bon – carbon bond. Both Grignard reagents and organolithium compounds work well in this reaction.

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