Organic Chemistry: Concepts and Applications - Headley Allan D. 2020

Nucleophilic Substitution Reactions at Acyl Carbons
16.7 Substitution Reactions Involving Carboxylic Acids

As you can imagine, carboxylic acids are not very reactive since the OH group is a very poor leaving group as shown in Reaction (16-91).

(16-91)

It is possible to carry out a substitution reaction in the presence of acid, which will protonate the ─OH group and convert it to a good leaving group as shown in the general reaction given in Reaction (16-92).

(16-92)

The mechanism for the acid-catalyzed reaction is shown below. In the first step, the carbonyl oxygen is protonated to give a resonance-stabilized carbocation as shown in Reaction (16-93).

(16-93)

In the next step of the reaction mechanism, the nucleophile attacks the protonated carboxylic acid, as shown in Reaction (16-94), to produce a tetrahedral intermediate.

(16-94)

In the next step of the mechanism, protonated hydroxide leaves to produce water, as shown in Reaction (16-95) and an acid catalyst is regenerated to give the products.

(16-95)

16.7.1 Substitution Reactions of Carboxylic Acids with Alcohols

A typical acid-catalyzed reaction of a benzoic acid with ethanol is shown in Reaction (16-96).

(16-96)

Note that the product of an acid-catalyzed reaction of a carboxylic acid and an alcohol is a new molecule with a different functional group, an ester.

Problem 16.25

Give esters that result from each of the esterification reactions shown below.

16.7.2 Substitution Reactions of Carboxylic Acid with Ammonia and Amines

Let us now examine the substitution reaction of carboxylic acids with ammonia and amines. These reactions are very similar to those that we have seen before, except as mentioned, an acidic catalyst must be used as shown in Reaction (16-97) for the acid-catalyzed reaction of benzoic acid with ammonia.

(16-97)

Reaction (16-98) shows the reaction of benzoic acid with a primary amine, methylamine.

(16-98)

Reaction (16-99) shows the reaction of an ester with a secondary amine, dimethylamine.

(16-99)

Since ammonia and amines are nucleophilic molecules, they will react with carboxylic acids to form the corresponding primary amide (with ammonia); secondary amide (with primary amines); and tertiary amide (with secondary amines).

Problem 16.26

Give the organic products of the following reactions.

16.7.3 Substitution Reactions of Carboxylic Acids with Hard Metallic Hydrides

Carboxylic acids can be reduced to form the corresponding alcohol by the supply of electrons and hydrogens, i.e. the hydride ion (H⁻). Owing to the polarity of the carbonyl bond of carboxylic acids, hydride ions can be added, from strong reducing agents, such as LiAlH₄, to the polarized carbonyl bond of carboxylic acids. Reaction (16-100) gives an example of the reduction of a carboxylic acid by LAH.

(16-100)

Since carboxylic acids are fairly acidic and LiAlH₄ is an extremely strong base, the first step of the reaction is an acid—base reaction as shown in Reaction (16-101).

(16-101)

Once deprotonation occurs to form the carboxylate salt, a reduction takes place. In the first step, a hydride ion from LiAlH₄ is delivered to the carbonyl carbon as shown in Reaction (16-102) to form the aldehyde.

(16-102)

In the next step of the mechanism, the aldehyde is reduced by another mole of LiAlH₄ to form the alkoxide salt. In a separate reaction involving an acid—base reaction, the alkoxide anion is neutralized to give the final alcohol product as shown in Reaction (16-103).

(16-103)

Problem 16.27

Give the reduction products of the following reactions.