Acyl chlorides

Acyl chlorides (R–COCl) are made from a carboxylic acid using thionyl chloride (SOCl₂) (or PCl₅): $\text{CH}_3\text{COOH} + \text{SOCl}_2 \rightarrow \text{CH}_3\text{COCl} + \text{SO}_2 + \text{HCl}$ SOCl₂ is convenient because the by-products (SO₂, HCl) are gases that escape, leaving pure acyl chloride.

Acyl chlorides are the most reactive carboxylic acid derivative. Two features make them so:

• The carbonyl carbon is strongly δ+ — both the C=O oxygen and the electronegative Cl withdraw electron density, so nucleophiles are strongly attracted to it.
• Cl⁻ is a good leaving group, so it departs easily once the nucleophile has added.

The result is that acyl chlorides react with nucleophiles rapidly and irreversibly.

Acyl chlorides react fast with oxygen nucleophiles, always releasing HCl:

• Water (vigorous hydrolysis) → carboxylic acid: $\text{CH}_3\text{COCl} + \text{H}_2\text{O} \rightarrow \text{CH}_3\text{COOH} + \text{HCl}$
• Alcohol → ester: $\text{CH}_3\text{COCl} + \text{C}_2\text{H}_5\text{OH} \rightarrow \text{CH}_3\text{COOC}_2\text{H}_5 + \text{HCl}$
• Phenol → phenyl ester: $\text{CH}_3\text{COCl} + \text{C}_6\text{H}_5\text{OH} \rightarrow \text{CH}_3\text{COOC}_6\text{H}_5 + \text{HCl}$

Note that an acyl chloride can acylate a phenol, even though a phenol will not esterify with a carboxylic acid — a sign of how reactive acyl chlorides are.

With nitrogen nucleophiles, acyl chlorides form amides:

• Ammonia → a primary amide: $\text{CH}_3\text{COCl} + \text{NH}_3 \rightarrow \text{CH}_3\text{CONH}_2 + \text{HCl}$
• Primary amine → an N-substituted amide: $\text{CH}_3\text{COCl} + \text{CH}_3\text{NH}_2 \rightarrow \text{CH}_3\text{CONHCH}_3 + \text{HCl}$

This is the standard way to make amides (and, with amino acids, to form the peptide/amide bond). In every case the nucleophile replaces Cl and HCl is released.