The reactions of acyl chlorides and acid anhydrides

Acyl chlorides and acid anhydrides are both more reactive than carboxylic acids, reacting with a wide range of nucleophiles and so are widely used in organic synthesis.

The mechanism is nucleophilic acyl substitution which can be neatly divided into nucleophilic addition of the nucleophile to the 𝛅+ carbon of the carbonyl group, followed by elimination of a leaving group (Cl^– or ROCO^–).

Both acyl chlorides and acid anhydrides are reactive enough to react with neutral nucleophiles at room temperature (usually in the presence of a weak base such as triethylamine, (C₂H₅)₃N).

Nucleophilic acyl substitution in acyl chlorides

• with water (hydrolysis) to form a carboxylic acid and hydrogen chloride

• with an alcohol (alcholysis) to form an ester and hydrogen chloride

• with ammonia (aminolysis) to form a primary amide and ammonium chloride, NH₄⁺Cl^–

• with a primary amine to form a secondary amide and the chloride salt of a primary amide, in this example methyl ammonium chloride, CH₃NH₃⁺Cl^–

[See note that accompanies the answer to Q.3 below – it applies to the reaction between ammonia or an amine with either an acyl chloride or an acid anhydride]

Nucleophilic acyl substitution in acid anhydrides

The mechanism is the same as for acyl chlorides as shown above except of course the by-product is a carboxylate ion / carboxylic acid rather than a chloride ion / hydrogen chloride. If the acid anhydride is symmetrical then the initial attack by the nucleophile could be at either 𝛅+ carbon (see the first stage below), but if the acid anhydride is unsymmetrical then the nucleophile will attack the more 𝛅+ carbon – remember that alkyl groups are electron donating.

• with water to form carboxylic acids

• with an alcohol to form an ester and a carboxylic acid

• with ammonia to form a primary amide and an ammonium carboxylate salt

In practical terms, acid anhydrides are often preferred reagents compared with acyl chlorides because they don’t react violently with water and the by-product of their reactions is a carboxylic acid rather than hydrogen chloride.

Practice questions

1. Write equations to show the reaction between

(a) benzoyl chloride, C₆H₅COCl, and propan-2-ol

(b) propanoic anhydride, CH₃CH₂COOCOCH₂CH₃, and ammonia

2. Write an equation to show how this ester is formed from the reaction between an acyl chloride and an alcohol. Name the reactants in your reaction.

3. Ethanol chloride reacts with ethylamine according to the equation shown below. Explain why ethylamine can be considered to be both a nucleophile and a base in this reaction.

Answers

1. (a)

1. (b)

2.

3. The first molecule of ethylamine uses the lone pair of electrons on the nitrogen to attack the 𝛅+ carbon of the carbonyl group, C=O, making a new bond between the nitrogen and carbon atoms. The second molecule of ethylamine behaves as a base because it removes a proton from the positively charged nitrogen atom in the first intermediate in the reaction mechanism (bases are proton acceptors) forming a by-product of CH₃CH₂NH₃⁺ Cl^– .

[A simpler way of looking at this reaction mechanism is to assume that H⁺ is lost / kicked out by the positively charged nitrogen atom in the first intermediate and it forms HCl with the Cl^– ion that is the leaving group from the second intermediate. HCl is an acid and ethylamine is a base so they react together to form the salt as the by-product.]