21.5 Chemistry of Acid Anhydrides

Acid anhydrides are versatile compounds in organic synthesis. They're less reactive than acid chlorides but more reactive than carboxylic acids, making them useful intermediates in many reactions. Their balanced reactivity allows for controlled transformations in various synthetic processes.

Acid anhydrides play a crucial role in pharmaceutical synthesis. They're used to make common drugs like aspirin and acetaminophen through nucleophilic acyl substitution reactions. Understanding their reactivity and mechanisms is key for designing efficient synthetic routes in drug development.

Synthesis and Reactivity of Acid Anhydrides

Preparation of acid anhydrides

• React carboxylic acids with acyl chlorides in a nucleophilic acyl substitution reaction
  • Carboxylic acid acts as the nucleophile attacking the electrophilic carbonyl carbon of the acyl chloride
  • Chloride ion serves as the leaving group
• React a carboxylic acid with a carbodiimide dehydrating agent (DCC, dicyclohexylcarbodiimide)
  • Reaction proceeds through the formation of an O-acylisourea intermediate
  • Intermediate undergoes nucleophilic attack by another carboxylic acid molecule forming the acid anhydride and dicyclohexylurea (DCU) as a byproduct
  • This is an example of a dehydration reaction

Acid anhydrides vs acid chlorides

• Acid anhydrides are less reactive than acid chlorides in nucleophilic acyl substitution reactions due to the better leaving group ability of the chloride ion compared to the carboxylate ion
• Acid anhydrides are more reactive than carboxylic acids because the additional carbonyl group makes them more electrophilic
• Acid anhydrides undergo slower hydrolysis to form carboxylic acids compared to the hydrolysis of acid chlorides
• Acid anhydrides react with alcohols to form esters at a slower rate than the corresponding reaction with acid chlorides
• Acid anhydrides react with amines to form amides with lower reactivity than acid chlorides but higher than carboxylic acids

Acetic anhydride in pharmaceuticals

• Aspirin (acetylsalicylic acid) synthesized using acetic anhydride
  1. Salicylic acid treated with acetic anhydride to acetylate the phenolic hydroxyl group
  2. Nucleophilic acyl substitution reaction where the phenoxide ion acts as the nucleophile
  3. Reaction typically carried out in the presence of a weak base (sodium acetate) to catalyze the reaction
• Acetaminophen (paracetamol) synthesized using acetic anhydride
  1. p-Aminophenol acetylated using acetic anhydride to form acetaminophen
  2. Nucleophilic acyl substitution reaction with the amino group acting as the nucleophile
  3. Reaction usually performed in the presence of a weak base (sodium acetate) to catalyze the reaction and neutralize the acetic acid byproduct

Reaction Mechanism of Acid Anhydrides

• Acid anhydrides contain two carbonyl groups (carbonyl group) connected by an oxygen atom
• In nucleophilic acyl substitution reactions:
  • The carbonyl carbon acts as the electrophile
  • The incoming reactant acts as the nucleophile
  • The carboxylate group serves as the leaving group