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Organic Chemistry

21.5 Chemistry of Acid Anhydrides

Organic Chemistry21.5 Chemistry of Acid Anhydrides

21.5 • Chemistry of Acid Anhydrides

Preparation of Acid Anhydrides

Acid anhydrides are typically prepared by nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion, as we saw in the previous section. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way.

Benzoyl chloride reacts with sodium acetate in ether, forming acetic benzoic anhydride. In the product structure, a benzoyl group and an acetyl group are single-bonded to an oxygen atom.

Reactions of Acid Anhydrides

The chemistry of acid anhydrides is similar to that of acid chlorides, although anhydrides react more slowly. Thus, acid anhydrides react with water to form acids, with alcohols to form esters, with amines to form amides, and with LiAlH4 to form primary alcohols. Only the ester- and amide-forming reactions are commonly used, however.

The reaction scheme shows conversion of an acid anhydride to a carboxylic acid using water (hydrolysis), ester using alcohol (alcoholysis), amide using ammonia (aminolysis), aldehyde and primary alcohol using hydride ions (reduction).

Conversion of Acid Anhydrides into Esters

Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetylsalicylic acid) is prepared commercially by the acetylation of o-hydroxybenzoic acid (salicylic acid) with acetic anhydride.

Salicylic acid reacts with acetic anhydride in aqueous sodium hydroxide, giving aspirin and acetate ion. The aspirin structure comprises of a benzene ring with carboxylic acid and methyl acetate groups attached ortho to each other.

Conversion of Acid Anhydrides into Amides

Acetic anhydride is also commonly used to prepare N-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Only the more nucleophilic –NH2 group reacts rather than the less nucleophilic –OH group.

The reaction of p-hydroxyaniline and acetic anhydride in the presence of aqueous sodium hydroxide forms an acetate ion and acetaminophen, where the para position of phenol is attached to an acetamide group.

Notice in both of the previous reactions that only “half” of the anhydride molecule is used, while the other half acts as the leaving group during the nucleophilic acyl substitution step and produces acetate ion as a by-product. Thus, anhydrides are inefficient, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups.

Problem 21-14
Write the mechanism of the reaction between p-hydroxyaniline and acetic anhydride to prepare acetaminophen.
Problem 21-15

What product would you expect from reaction of one equivalent of methanol with a cyclic anhydride, such as phthalic anhydride (1,2-benzenedicarboxylic anhydride)? What is the fate of the second “half” of the anhydride?

The structure shows phthalic anhydride where a benzene ring is fused with a cyclopentane-2,5-dione ring where the carbon atom in between the carbonyl groups is replaced by an oxygen atom.
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