Acylation (Oxford AQA International A Level (IAL) Chemistry): Revision Note

Acyl Groups

• Acyl chlorides are derivatives of carboxylic acids by substitution of the -OH group by a chlorine atom

  • Acyl chlorides are named by identifying the parent hydrocarbon chain and adding the suffix -oyl chloride

• Acid anhydrides are also derivatives of carboxylic acids formed by substitution of the -OH group by an alkanoate

  • Acid anhydrides are named by identifying the parent hydrocarbon chain and adding the suffix -oic anhydride

• Amides are organic compounds with an -CONR₂ functional group

  • They can be prepared from the condensation reaction between an acyl chloride and ammonia or amine

Derivatives of ethanoic acid

Nucleophilic Addition–Elimination Mechanism

• Acyl chlorides are reactive organic compounds that undergo many reactions such as nucleophilic addition-elimination reactions

• In nucleophilic addition-elimination reactions, the nucleophilic addition of a small molecule across the C=O bond takes place followed by elimination of a small molecule

• Examples of these nucleophilic addition-elimination reactions include:

  • Hydrolysis

  • Reaction with alcohols to form esters

  • Reaction with ammonia and primary amines to form amides

Hydrolysis

• The hydrolysis of acyl chlorides results in the formation of a carboxylic acid and HCl molecule

• This is a nucleophilic addition-elimination reaction

• A water molecule adds across the C=O bond

• A hydrochloric acid (HCl) molecule is eliminated

• For example the hydrolysis of propanoyl chloride to form propanoic acid and HCl is:

Mechanism of hydrolysis of acyl chlorides

• In the hydrolysis of acyl chlorides, the water molecule acts as a nucleophile

  • Step 1 - Nucleophilic addition; the lone pair on the oxygen atoms carry out an initial attack on the carbonyl carbon

  • Step 2 - Elimination; this is followed by the elimination of a hydrochloric acid (HCl) molecule
    

Formation of esters

• Acyl chlorides can react with alcohols to form esters

• The esterification of acyl chlorides is also a nucleophilic addition-elimination reaction

  • The alcohol adds across the C=O bond

  • A HCl molecule is eliminated

Formation of esters: reaction mechanism

• In the esterification reaction of acyl chlorides, the alcohols act as a nucleophile

• Step 1 - Nucleophilic addition; the lone pair on the oxygen atoms carry out an initial attack on the carbonyl carbon

• Step 2 - Elimination; this is again followed by the elimination of an HCl molecule

Formation of amides

• Acyl chlorides react with ammonia or primary amines to form amides in a condensation reaction.

• A lone pair on the nitrogen atom attacks the carbonyl carbon in the acyl chloride.

• The reaction proceeds via a nucleophilic addition–elimination mechanism:

  • The nucleophile adds to the C=O bond

  • A chloride ion (Cl⁻) is eliminated

  • Hydrogen chloride (HCl) is formed

What happens to the HCl?

• The HCl formed does not remain unreacted.

• It is immediately neutralised by a second molecule of ammonia or amine present in excess.

• This forms an ammonium salt (e.g. NH₄Cl, CH₃NH₃Cl).

Why 2 molecules are needed

• The 1st molecule of ammonia/amine forms the amide

• The 2nd molecule of ammonia/amine neutralises the HCl and forms ammonium salt

Examples

• Reaction with ammonia

• Product: Primary amide (propanamide) and ammonium chloride

CH₃CH₂COCl + 2NH₃ → CH₃CH₂CONH₂ + NH₄Cl

• Reaction with methylamine

• Product: Secondary (substituted) amide and methylammonium chloride

CH₃COCl + 2CH₃NH₂ → CH₃CONHCH₃ + CH₃NH₃Cl

• Reaction with ethylamine

• Product: Secondary (substituted) amide and ethylammonium chloride

CH₃COCl + 2CH₃CH₂NH₂ → CH₃CONHCH₂CH₃ + CH₃CH₂NH₃Cl

Summary for formation of amides

• All reactions form HCl, which is not observed as a separate product

• The HCl is neutralised by excess ammonia or amine

• The final products are an amide and an ammonium salt

Formation of amides: reaction mechanism

• The nitrogen atom in ammonia and primary amines act as a nucleophile

  • Step 1 - Nucleophilic addition; the lone pair on the nitrogen atoms carry out an initial attack on the carbonyl carbon

  • Step 2 - Elimination; this is followed by the elimination of an HCl molecule

  • Step 3 - Acid-Base reaction; the HCl formed would immediately react with excess ammonia to give ammonium chloride in an acid-base reaction

Mechanism with ammonia

Mechanism with a primary amine

Manufacture of Aspirin

• Acylation reactions have many uses, such as in the pharmaceutical and textile industries for making drugs, e.g. aspirin, and textiles, e.g. cellulose acetate

• In the industrial manufacture of aspirin, salicylic acid and ethanoic anhydride are reacted together in an acylation reaction to form aspirin and ethanoic acid

salicylic acid + ethanoic anhydride aspirin + ethanoic acid

• The reaction of acyl chlorides with water or alcohols produces carboxylic acid and esters respectively

  • However it is normally a fast, exothermic process with a rapid production of highly corrosive hydrogen chloride gas

  • In general, acid anhydrides are preferred over acyl chlorides in the production of aspirin because they are also cheaper to produce, less reactive and the reactions can be more easily controlled

  • For acid anhydrides, the by-product is the less corrosive carboxylic acid compared to hydrogen chloride for acyl chlorides