Chemistry 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 Section 21.4. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

The chemistry of acid anhydrides is similar to that of acid chlorides.. Although anhydrides react more slow ly than acid chlorides, the kinds of reactions the two groups undergo are the same. Thus, acid anhydrides react with water to form acids, wdth alcohols to form esters, with amines to form amides, and with UAIH4 to form primary alcohols. Only the ester and amide forming reactions are much used, however. 

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. 

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 I ylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts rather than the less nucleophilic -OH group. 

Notice in both of the previous reactions that only half of the anhydride molecule is used 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 to use, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups. 

Note that the diorganocopper reaction occurs only with acid chlorides. Carboxylic acids, esters, acid anhydrides, and amides do not react with diorganocopper reagents. 

Salicylic acid (o-Hydi-oxybe azoic acid) 

CHAPTER 21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitutions 

Problem 21.15 What product would you expect from reaction of 1 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 in this case  

Problem 21.16 Write the mechanism of the reaction shown above between p-hydroxyaniline and acetic anhydride to prepare acetaminophen. 

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