Acid anhydrides, acyl chlorides and acylationAQA A-Level Chemistry: Revision notes

Acid derivatives are made by replacing the OH of a carboxylic acid:

• Acyl chloride: RCOCl, for example ethanoyl chloride, CH₃COCl.
• Acid anhydride: (RCO)₂O, for example ethanoic anhydride, (CH₃CO)₂O.
• Amide: RCONH₂, or an N-substituted amide RCONHR′ if a primary amine was used, for example ethanamide, CH₃CONH₂, and N-methylethanamide, CH₃CONHCH₃.

In all of them the carbonyl carbon is δ+ and is attacked by nucleophiles. Acyl chlorides are the most reactive, because chlorine is a good leaving group and the carbon is strongly δ+.

Acyl chlorides react with nucleophiles that have an –OH or –NH group. Each reaction gives HCl as a by-product (seen as misty fumes):

• Water: CH₃COCl + H₂O → CH₃COOH + HCl (carboxylic acid)
• Alcohol: CH₃COCl + C₂H₅OH → CH₃COOC₂H₅ + HCl (ester)
• Ammonia: CH₃COCl + NH₃ → CH₃CONH₂ + HCl (amide); with excess ammonia the HCl forms NH₄Cl
• Primary amine: CH₃COCl + CH₃NH₂ → CH₃CONHCH₃ + HCl (N-substituted amide)

These reactions are acylation: an acyl group, RCO–, is added to the nucleophile.

Acid anhydrides follow the same pattern but are less reactive, and the by-product is a carboxylic acid, not HCl:

• Water: (CH₃CO)₂O + H₂O → 2CH₃COOH
• Alcohol: (CH₃CO)₂O + C₂H₅OH → CH₃COOC₂H₅ + CH₃COOH
• Ammonia: (CH₃CO)₂O + 2NH₃ → CH₃CONH₂ + CH₃COONH₄
• Primary amine: (CH₃CO)₂O + CH₃NH₂ → CH₃CONHCH₃ + CH₃COOH

Aspirin is made by acylating the OH group of 2-hydroxybenzoic acid: C₇H₆O₃ + (CH₃CO)₂O → C₉H₈O₄ + CH₃COOH.

Ethanoic anhydride is preferred to ethanoyl chloride in industry because it:

• is cheaper
• is less corrosive and less hazardous to handle
• reacts more slowly with water, so it is less readily hydrolysed by moisture and is easier to store and control
• gives ethanoic acid as the by-product, not corrosive HCl fumes

A good answer gives two clear advantages and avoids vague statements such as 'it is safer' on its own.

Acylation by an acyl chloride is nucleophilic addition–elimination. For ammonia:

1. Addition: the lone pair on N attacks the δ+ carbon. The C=O π electrons move to O, giving an intermediate with O⁻ and N⁺.
2. Elimination: the lone pair on O⁻ reforms the C=O bond and the Cl⁻ leaves, taking the electrons of the C–Cl bond.
3. The positively charged nitrogen loses H⁺ (to Cl⁻ or another molecule of NH₃), giving the amide.

For water, an alcohol or an amine, the mechanism has the same three steps. In each case show the lone pair on the attacking atom and a curly arrow to the carbon.

Pure organic solid (aspirin): warm 2-hydroxybenzoic acid with ethanoic anhydride, then add water to crystallise the crude solid. Recrystallise: dissolve in the minimum volume of hot solvent, filter hot, cool slowly, filter under reduced pressure, wash with cold solvent and dry. Test purity by melting point: a pure sample melts sharply at the known value, an impure one melts lower and over a range.

Pure organic liquid: wash the crude liquid with sodium carbonate solution in a separating funnel to remove acid, dry with an anhydrous salt such as anhydrous sodium sulfate, then distil and collect the fraction at the boiling point range. Check purity from the boiling point.

Percentage yield = actual mass ÷ theoretical mass × 100. For 3.00 g 2-hydroxybenzoic acid (0.0217 mol), the theoretical aspirin mass is 3.91 g.