11.6 Reactions of Carboxylic Acids

We commented earlier in this chapter that carboxylic acids are similar in some respects to both alcohols and ketones. Like alcohols, carboxylic acids can be deprotonated to give anions, which are good nucleophiles in S_N2 reactions. Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group. However, carboxylic acids also undergo other reactions characteristic of neither alcohols nor ketones. Figure 11.6 shows some of the general reactions of carboxylic acids.

Figure 11.6 Some general reactions of carboxylic acids.

Reactions of carboxylic acids can be grouped into the four categories indicated in Figure 11.6. Of the four, we’ve already discussed the acidic behavior of carboxylic acids in Section 11.2 through Section 11.4, and we mentioned reduction by treatment with LiAlH₄ in Section 9.5. The remaining two categories are examples of fundamental carbonyl-group reaction mechanisms—nucleophilic acyl substitution and α substitution. We will further discuss nucleophilic acyl substitution in this section.

The direct nucleophilic acyl substitution of a carboxylic acid is difficult because –OH is a poor leaving group (Section 7.3). Thus, it’s usually necessary to enhance the reactivity of the acid, either by using a strong acid catalyst to protonate the carboxyl and make it a better acceptor or by converting the –OH into a better leaving group. Under the right circumstances, however, acid chlorides, anhydrides, esters, and amides can all be prepared from carboxylic acids by nucleophilic acyl substitution reactions.

Conversion of Carboxylic Acids into Acid Chlorides

In the laboratory, carboxylic acids are converted into acid chlorides by treatment with thionyl chloride, SOCl₂.

This reaction occurs by a nucleophilic acyl substitution pathway in which the carboxylic acid is first converted into an acyl chlorosulfite intermediate, thereby replacing the –OH of the acid with a much better leaving group. The chlorosulfite then reacts with a nucleophilic chloride ion. You might recall from Section 9.7 that an analogous chlorosulfite is involved in the reaction of an alcohol with SOCl₂ to yield an alkyl chloride.

Conversion of Carboxylic Acids into Acid Anhydrides

Acid anhydrides can be derived from two molecules of carboxylic acid by heating to remove 1 equivalent of water. Because of the high temperatures needed, however, only acetic anhydride is commonly prepared this way.

Conversion of Carboxylic Acids into Esters

Perhaps the most useful reaction of carboxylic acids is their conversion into esters. There are many methods for accomplishing this, including the S_N2 reaction of a carboxylate anion with a primary alkyl halide that we saw in Section 7.3.

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need for an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters.

The mechanism of the Fischer esterification reaction is shown in Figure 11.7. Carboxylic acids are not reactive enough to undergo nucleophilic addition directly, but their reactivity is greatly enhanced in the presence of a strong acid such as HCl or H₂SO₄. The mineral acid protonates the carbonyl-group oxygen atom, thereby giving the carboxylic acid a positive charge and rendering it much more reactive toward nucleophiles. Subsequent loss of water from the tetrahedral intermediate yields the ester product.

Figure 11.7 MECHANISM: Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid.The net effect of Fischer esterification is substitution of an –OH group by –OR′. All steps are reversible, and the reaction typically has an equilibrium constant close to 1. Thus, the reaction can be driven in either direction by the choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present.

Worked Example 11.2: Synthesizing an Ester from an Acid
How might you prepare the following ester using a Fischer esterification reaction?

Strategy
Begin by identifying the two parts of the ester. The acyl part comes from the carboxylic acid and the –OR part comes from the alcohol. In this case, the target molecule is propyl o-bromobenzoate, so it can be prepared by treating o-bromobenzoic acid with 1-propanol.

SolutionProblem 11.14
How might you prepare the following esters from the corresponding acids?

(a)

(b)

(c)

Problem 11.15
If the following molecule is treated with acid catalyst, an intramolecular esterification reaction occurs. What is the structure of the product? (Intramolecular means within the same molecule.)

Conversion of Carboxylic Acids into Amides

Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions. Thus, the –OH must be replaced by a better, nonacidic leaving group to carry out a nucleophilic acyl substitution. In practice, amides are often prepared by activating the carboxylic acid with a carbodiimide (R–N═C═N–R), followed by addition of the amine.

Dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (EDEC) are commonly used.

As shown in Figure 11.8, the acid first adds to a C═N double bond of DCC, and nucleophilic acyl substitution by amine then ensues. Alternatively, and depending on the reaction solvent, the reactive acyl intermediate might also react with a second equivalent of carboxylate ion to generate an acid anhydride that then reacts with the amine. The product from either pathway is the same.

Figure 11.8 MECHANISM: Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexylcarbodiimide (DCC).

Conversion of Carboxylic Acids into Alcohols

We said in Section 9.5 that carboxylic acids are reduced by LiAlH₄ to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which –H replaces –OH to give an aldehyde that is further reduced by nucleophilic addition to produce a primary alcohol. The aldehyde intermediate is much more reactive than the starting acid, so it reacts instantly and is not isolated.

Because hydride ion is a base as well as a nucleophile, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic acid and gives a high-energy dianion intermediate. In this intermediate, the two oxygens are complexed to a Lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extended reaction times.

Alternatively, borane in tetrahydrofuran (BH₃/THF) is a useful reagent for reducing carboxylic acids to primary alcohols. Reaction of an acid with BH₃/THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with LiAlH₄ because of its relative ease and safety. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that on p– nitrophenylacetic acid. If the reduction of p-nitrophenylacetic acid were done with LiAlH₄, both the nitro and carboxyl groups would be reduced.

Problem 11.16
How might you prepare 2-phenylethanol from benzyl bromide? More than one step is needed.

Problem 11.17
How might you carry out the following transformation? More than one step is needed.

Biological Conversions of Carboxylic Acids

The direct conversion of a carboxylic acid to an acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry. As in the laboratory, the acid must first be activated by converting the –OH into a better leaving group. This activation is often accomplished in living organisms by reaction of the acid with adenosine triphosphate (ATP) to give an acyl adenosyl phosphate, or acyl adenylate, a mixed anhydride combining a carboxylic acid and adenosine monophosphate (AMP, also known as adenylic acid). In the biosynthesis of fats, for example, a long-chain carboxylic acid reacts with ATP to give an acyl adenylate, followed by subsequent nucleophilic acyl substitution of a thiol group in coenzyme A to give the corresponding acyl CoA (Figure 11.9).

Figure 11.9 MECHANISM: In fatty-acid biosynthesis, a carboxylic acid is activated by reaction with ATP to give an acyl adenylate, which undergoes nucleophilic acyl substitution with the –SH group on coenzyme A. (ATP = adenosine triphosphate; AMP = adenosine monophosphate.)