Preparing Carboxylic Acids

Let s review briefly the methods for preparing carboxylic acids that we ve seen in past chapters  

Oxidation of a primary alcohol or an aldehyde yields a carboxylic acid (Sections 13.5 and 14.3). Both oxidations are often carried ont with CrOa in aqueous acid. 

Carboxylic acids can he prepared from nitriles by heating with aqueous acid or base by a mechanism that we ll see in Section 15.7. Since nitriles themselves are easily made by Sn2 reaction of a primary or secondary alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr RC=N RCO2H). Note that the product acid has one more carbon than the starting alkyl halide. An example occurs in one commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. 

As noted previously, there are no Grignard reagents inside living cells, but there are other types of stabilized carbanions that are often carboxylated. One of the initial steps in fatty-acid biosynthesis, for instance, involves formation of a carbanion from acetyl CoA, followed by carboxylation to yield malonyl CoA. 

WORKED EXAMPLE 15.2 Devising a Synthesis Route for a Carboxylic Acid 

Rank the following compounds in order of increasing acidity. Don t look at a table of p/Cg data to help with your answer. 

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Among the methods for preparing carboxylic acids carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO2H The malonic ester synthesis converts RBr to RCH2CO2H... 

Section 19.10 Several of the reactions introduced in earlier chapters can be used to prepare carboxylic acids (See Table 19.4). 

Strategy We ve seen two methods for preparing carboxylic acids from alkyl halides ... 

Some preparations of alkene and acetylenic compounds from alkene and acetylenic starting materials can, in principle, be classified in either the monofunctional or difunctional sections for example, the transformation RCH=CHBr — RCH=CHCOOH could be considered as preparing carboxylic acids from halides (Section 25, monofunctional compounds) or preparing a carboxylic acid-alkene (Section 322, difunctional compounds). The choice usually depends on the focus of the particular paper where this reaction was found. In such cases both sections should be consulted. 

A closely related example involving a seven-membered transition state (6) hydrogen atom abstraction in the crystalline state is shown in Scheme 9. Based on earlier work by Wagner and coworkers [38], Cheung, Rademacher, Scheffer, and Trotter prepared carboxylic acid 41a and treated it with a variety of optically pure amines to form chiral salts 41b [39]. Irradiation of crystalline samples of the salts followed by workup with ethereal diazomethane afforded the chiral in-... 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R"CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.1500... 

The above prepared carboxylic acid (0.2 g) thus obtained was dissolved in 5% hydrochloric acid, and the solution was concentrated to dryness under reduced pressure. The residue was crystallized from water to give a hydrochloride of the (0.21 g), m.p. above 300°C. On the other hand, the above free carboxylic acid (0.2 g) was dissolved in 7% methanesulfonic acid solution under heating. After cooling, the precipitate was recrystallized from diluted methanol to give a methanesulfonic acid salt of the carboxylic acid (0.22 g), mp above 300°C (dec.). 

Decide which synthesis to use. The acetoacetic ester synthesis is used to prepare methyl ketones, and the malonic ester synthesis is used to prepare carboxylic acids. Both syntheses provide a method to add alkyl groups to the a-carbon. Therefore, next identify the group or groups that must be added to the a-carbon. Remember that the a-carbon is the nucleophile, so the groups to be attached must be the electrophile in the Sn2 reaction they must have a leaving group bonded to the carbon to which the new bond is to be formed. 

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. 

Where have we encountered carboxylic acids as reaction products before The carbonyl carbon is highly oxidized, because it has three C-O bonds, so carboxylic acids are typically prepared by oxidation reactions. Three oxidation methods are summarized below. Two other useful methods to prepare carboxylic acids are presented in Chapter 20. 

The malonic ester iq ithesis prepares carboxylic acids having two general structures ... 

The reaction is used to prepare carboxylic acids with one or two alkyl groups on the cc carbon. 

On the other hand, potassium permanganate is frequently used to prepare carboxylic acids from both aliphatic [86S] and aromatic aldehydes [555]. High yields of carboxylic acids are also obtained by oxidation with tetrabutylammonium permanganate [599] or benzyltriethylammonium permanganate [903] (equation 350). Recently, doubts about the safety of work with quaternary ammonium permanganates have been raised [967]. 

Like /3-hydroxyaldehydes and -ketones, jS-hydroxyesters and -acids are readily dehydrated. The unsaturated compounds thus obtained (chiefly a,]3-unsaturated) can be hydrogenated to saturated carboxylic acids. Extended in this way, the Reformatsky reaction is a useful general method for preparing carboxylic acids, paralleling the aldol route to alcohols. 

One of the most valuable methods of preparing carboxylic acids makes use of ethyl malonate (malonic ester), CH2(COOC2H5)>, and is called the malonic ester synthesis. This synthesis depends upon (a) the high acidity of the a-hydrogens of malonic ester, and (b) the extreme ease with which malonic acid and substituted malonic acids undergo decarboxylation. (As we shall sec, this combination of properties is more than a happy accident, and can be traced to a single underlying cause.)... 

An alternative method for preparing carboxylic acids is by reaction of] Grignard reagent with CO2 to yield a metal carboxylate, followed by protonation to give the carboxylic acid. This carboxylation reaction is carried... 

A combination of two of the reactions discussed in this chapter—alkylation of an a-carbon and decarboxylation of a j8-dicarboxylic acid—can be used to prepare carboxylic acids of any desired chain length. The procedure is called the malonic ester synthesis because the starting material for the synthesis is the diethyl ester of malonic acid. The first two carbons of the carboxylic acid come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the reaction. 

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