3.9.3 Acylation

3.9.3 Acylation: Name acyl chlorides, acid anhydrides and amides, describe the nucleophilic addition–elimination mechanism, and compare acyl chlorides and anhydrides in making esters, amides and aspirin.

Acid derivatives are made by replacing the –OH of a carboxylic acid with another group.

Acyl chlorides

The –OH is replaced by –Cl, giving names ending -oyl chloride, such as ethanoyl chloride, CH₃COCl.

Acid anhydrides

Two acyl groups share one oxygen, giving names ending -oic anhydride, such as ethanoic anhydride, (CH₃CO)₂O.

Amides

The –OH is replaced by an amino group, giving –CONH₂ or –CONHR, such as ethanamide, CH₃CONH₂.

Reactivity

Acyl chlorides are very reactive because the carbonyl carbon is bonded to two electronegative atoms, so it is strongly δ+.

Leaving group

The chloride ion is a good leaving group, which helps the elimination step to happen quickly.

Acyl chlorides react with water, alcohols, ammonia and amines by the same two-stage mechanism.

The nucleophile (the lone pair on O or N) attacks the δ+ carbonyl carbon and the C=O π bond moves onto oxygen.

This forms an unstable intermediate with a negative oxygen and a positive nucleophile atom.

The C=O bond reforms by electron movement from oxygen, and the chloride ion leaves.

A proton is lost from the attacking atom, producing HCl or, with excess amine or ammonia, an ammonium chloride.

The overall result is that Cl is replaced by the nucleophile group.

Products and Equations

Observation

Acyl chlorides react vigorously with water, giving steamy white fumes of hydrogen chloride.

Two moles of amine

The second mole of ammonia or amine reacts with HCl, so the ammonium salt forms with the amide.

Esters

Reaction with an alcohol is faster and goes to completion, unlike esterification with a carboxylic acid.

Anhydrides

Anhydrides react in the same way but give a carboxylic acid instead of HCl as the by-product.

Nucleophile	Product	Equation for ethanoyl chloride
Water	Carboxylic acid	CH₃COCl + H₂O → CH₃COOH + HCl
Alcohol	Ester	CH₃COCl + CH₃OH → CH₃COOCH₃ + HCl
Ammonia	Primary amide	CH₃COCl + 2NH₃ → CH₃CONH₂ + NH₄Cl
Methylamine	N-methylamide	CH₃COCl + 2CH₃NH₂ → CH₃CONHCH₃ + CH₃NH₃Cl

Aspirin and Industrial Choice

Making aspirin

Salicylic acid is acylated by ethanoic anhydride at its –OH group to give aspirin and ethanoic acid.

Why anhydride

Ethanoic anhydride is cheaper, reacts less violently, and does not give corrosive hydrogen chloride.

Safer by-product

The by-product ethanoic acid is less hazardous and can be recovered and reused.

Other uses

Acylation is also used in making dyes, plasticisers and fibres such as cellulose ethanoate.

Question: Write the equation for the reaction of propanoyl chloride with ethylamine and explain why two moles of ethylamine are needed.

Propanoyl chloride is CH₃CH₂COCl and ethylamine is CH₃CH₂NH₂.
The N-substituted amide formed is CH₃CH₂CONHCH₂CH₃, with HCl as the other product.
HCl reacts with a second mole of ethylamine to give the salt CH₃CH₂NH₃Cl.
Equation: CH₃CH₂COCl + 2CH₃CH₂NH₂ → CH₃CH₂CONHCH₂CH₃ + CH₃CH₂NH₃Cl.

Answer: CH₃CH₂COCl + 2CH₃CH₂NH₂ → CH₃CH₂CONHCH₂CH₃ + CH₃CH₂NH₃Cl; the second amine neutralises the HCl formed.

3.9.3 – Key Points for the Exam

Acyl chloride: A carboxylic acid derivative with the –COCl group.
Acid anhydride: A compound with two acyl groups joined by an oxygen atom.
Amide: A compound containing the –CON group.
Acylation: A reaction that introduces an acyl group (RCO–) into a molecule.

Common Mistakes

Writing only one mole of ammonia or amine in the equation, so that HCl is not accounted for.
Saying the acyl chloride reacts with water by a simple substitution without showing the addition step.
Naming CH₃COCl as ethanoic chloride instead of ethanoyl chloride.
Claiming acyl chlorides are preferred industrially for aspirin, when the anhydride is the cheaper and safer choice.