Carbonyl Group

Acyl Chlorides and Acid Anhydrides

Acyl Chlorides and Acid Anhydrides

Carboxylic acids are, in general, unreactive, however they will react with bases and alcohols. The ?+ve carbon atom is capable of attracting nucleophiles but, due to the stability of the -COOH group, this does not occur easily.

However, if the carboxylic acid group is converted into a more reactive derivative first of all, then nucleophilic attack can take place. Two of these derivatives include:

  • acyl chlorides
  • acid anhydrides

Structure of acyl chlorides and acid anhydrides

Acyl chlorides contain the following functional group:

Acyl Chlorides and Acid Anhydrides

The two electronegative atoms attached to the carbon atom makes it very ?+ve and so nucleophiles are readily attracted.

Acid anhydrides contain the following functional group:

Acyl Chlorides and Acid Anhydrides

As with acyl chlorides, the two electronegative atoms attached to the carbon atom makes it very ?+ve and so nucleophiles are readily attracted.

Therefore, both acyl chlorides and acid anhydrides readily react with nucleophiles.

Mechanism: nucleophilic addition-elimination

The mechanism used by acyl chlorides is nucleophilic addition-elimination.

  • If a nucleophile attacks an acyl chloride, addition takes place and the ?-bond breaks.
  • However, this causes the C-Cl bond to break which, in turn, leads to the ?-bond reforming. The additional H belonging to the nucleophile is lost too.
  • The free proton can then combine with the chloride ion or another nucleophile.

This mechanism takes place when acyl chlorides and acid anhydrides react with ammonia, primary amines, alcohols and water. The reaction is called acylation.

Acylation reactions of acyl chlorides

With water

Acyl Chlorides and Acid AnhydridesWhen acyl chlorides mix with water the reaction is very violent and results in white HCl fumes:

R-COCl + H2O ? R-COOH + HCl

The resulting organic product is a carboxylic acid and the mechanism is nucleophilic addition-elimination.

With ammonia

When acyl chlorides mix with water the reaction is also very violent and, again, results in white HCl fumes:

R-COCl + NH3 ? R-CONH2 + HCl

In excess ammonia it is possible for the left-over NH3 and HCl to react:

R-COCl + 2NH3 ? R-CONH2 + NH4Cl

The resulting organic product is an amide and the mechanism is nucleophilic addition-elimination.

With alcohols

When acyl chlorides mix with alcohols the reaction is also very violent and, again, results in white HCl fumes:

R1-COCl + R2-OH ? R1-COOR2 + HCl

The resulting organic product is an ester and the mechanism is nucleophilic addition-elimination.

With primary amines

When acyl chlorides mix with primary amines the reaction is also very violent and, again, results in white HCl fumes:

R1-COCl + R2-NH2 ? R1-CONHR2 + HCl

In excess amine it is possible for the left-over amine and HCl to react:

R1-COCl + 2R2-NH2 ? R1-CONHR2 + R2-NH3Cl

The resulting organic product is an N-substituted amide and the mechanism is nucleophilic addition-elimination.

Acylation reactions of acid anhydrides

Acid AnhydridesLike acyl chlorides, acid anhydrides react with ammonia, primary amines, alcohols and water. The reaction is also called nucleophilic addition-elimination.

However, the reactions are much slower and carboxylic acid, not HCl, is produced.

Due to the toxicity of HCl and the speed of the reactions, acid anhydrides in acylation reactions are favoured commercially over acyl chlorides.

With water

When warmed, acid anhydrides react slowly with water to produce two carboxylic molecules:

R1-COOCO-R2 + H2O ? R1-COOH + R2-COOH

With ammonia

When warmed, acid anhydrides react slowly with ammonia to produce a carboxylic acid and an amide:

R1-COOCO-R2 + NH3 ? R1-CONH2 + R2-COOH

With alcohols

When warmed, acid anhydrides react with alcohols to produce esters and a carboxylic acid:

R1-COOCO-R2 + R3-OH ? R1-COO-R3 + R2-COOH

With primary amines

When warmed, acid anhydrides react with primary amines to produce a carboxylic acid and N-substituted amides:

R1-COOCO-R2 + R3-NH2 ? R1-CONH-R3 + R2-COOH

Preparation of aspirin

Aspirin is an ester. It has the following formula:

It is created by reacting the -OH group located on the 2-hydroxybenzoic acid with either:

  • Ethanoic acid: the conditions must be very acidic and heat and reflux are required. The reaction only goes into equilibrium.
  • Ethanoyl chloride: the reaction is violent, hard to control, and the toxic gas hydrogen chloride is produced.
  • Ethanoic anhydride: when heated gently the reaction is quite fast and no toxic by-products are formed. Therefore, this is the favoured method for preparing aspirin.