Part 3: Acyl chlorides, anhydrides and acylation mechanisms

Predict the products of all required acylation reactions and draw a charged tetrahedral intermediate accurately.

Find the group attached to the acyl carbon

The acyl group is R–C(=O)–. An acyl chloride is RCOCl; an acid anhydride contains RCO–O–COR; an amide contains RCONH₂ or an N-substituted version such as RCONHR′. CH₃COCl is ethanoyl chloride, (CH₃CO)₂O ethanoic anhydride and CH₃CONHCH₃ N-methylethanamide. The N-prefix places a substituent on nitrogen rather than on the carbon chain.

Acyl chlorides are reactive towards nucleophiles because carbonyl carbon is electrophilic and chloride can leave. Acid anhydrides also transfer an acyl group, generally less vigorously. Unlike aldehydes and ketones, these compounds have a leaving group that allows the carbonyl to reform after addition.

Four nucleophiles, four predictable product classes

Moist air can produce steamy acidic fumes when an acyl chloride hydrolyses. Ammonia can give white ammonium chloride smoke; the appearance depends on whether reagents are gaseous, concentrated or in solution. State the observed phase rather than assuming every dissolved salt precipitates. Two ammonia/amine molecules are used in the full excess-reagent equation: one supplies the amide nitrogen and the other accepts the proton.

Addition, elimination and proton transfer

For water or an alcohol, the oxygen lone pair attacks acyl carbon while the C=O π pair moves onto oxygen. The tetrahedral intermediate contains the original O⁻, the incoming oxygen with three bonds and a positive charge, and the Cl still bonded to carbon. An O⁻ lone pair reforms C=O while the C–Cl bond pair goes to chloride. Loss of a proton from the incoming group completes the neutral product.

For ammonia or a primary amine, start the attack arrow from the nitrogen lone pair. After attachment, nitrogen has four bonds and a positive charge. Carbonyl reformation and chloride loss are followed by deprotonation, commonly by a second ammonia/amine molecule. Never draw an uncharged N with four ordinary bonds or an intermediate carbon with five bonds.

These are nucleophilic addition–elimination mechanisms. You may encounter a representation combining collapse and proton loss in one drawn step; whichever sequence is used, every arrow must start from an electron pair/bond and all intermediate valencies and charges must be valid. June 2023 Paper 2 Q03.1 explicitly assessed the addition and intermediate arrows.

Anhydrides produce a carboxylic acid or carboxylate

With water, ethanoic anhydride forms two ethanoic acid molecules. With an alcohol, it gives an ester plus ethanoic acid. With excess ammonia or primary amine, the acid by-product is neutralised to an ammonium or alkylammonium carboxylate. The product class is the same as acyl chloride acylation, but chloride is absent.

Choose an acylating agent for the actual process

In aspirin preparation, the phenolic OH of 2-hydroxybenzoic acid is acylated by ethanoic anhydride to make an ester; the carboxylic acid group remains. The product is 2-ethanoyloxybenzoic acid, commonly called aspirin. Ethanoic acid is the by-product.

Compared with ethanoyl chloride, ethanoic anhydride is generally cheaper, less corrosive, less readily hydrolysed and avoids HCl fumes in this preparation. It remains a hazardous reagent requiring controlled handling. Industrial choice also depends on yield, waste treatment and energy; a faster reaction is not the only criterion. RP10 solid and liquid preparation methods are covered in Organic Synthesis.

Quick checks

Original Finesse questions. Reveal the indicative worked solutions after attempting each question; these are not official AQA mark allocations.

Sources