Substitution reactions: from haloalkanes to amides

What substitution means

• In a substitution reaction an atom or group on a carbon is replaced by another; the carbon chain itself is unchanged.
• The carbon being attacked is slightly positive (δ+) because it is bonded to a more electronegative atom such as Cl, Br or O. The attacking species has a lone pair, like OH⁻, NH₃ or the O of an alcohol.
• At Level 3, esterification, condensation, hydrolysis and condensation polymerisation all count as substitution reactions.
• Always give the reagent and the conditions with the product: 'KOH(aq), heat' and 'KOH in alcohol, heat' give different products from the same haloalkane.

Try it: what does the reaction make?

Haloalkanes and alcohols

• Heated with aqueous KOH or NaOH, a haloalkane becomes an alcohol: CH₃CH₂CH₂Br + OH⁻ → CH₃CH₂CH₂OH + Br⁻.
• Heated with concentrated ammonia, a haloalkane becomes a primary amine. A second NH₃ takes the H⁺ that is released: CH₃CH₂Cl + 2NH₃ → CH₃CH₂NH₂ + NH₄Cl.
• Going the other way, an alcohol becomes a haloalkane with concentrated HCl or HBr, or with thionyl chloride: CH₃CH₂OH + SOCl₂ → CH₃CH₂Cl + SO₂ + HCl. Tertiary alcohols react fastest with concentrated HCl.
• If the KOH is dissolved in alcohol instead of water, the haloalkane mostly loses a hydrogen halide, such as HBr, to form an alkene instead. That is elimination, covered in the next lesson.

Amines are bases

• The N in an amine has a lone pair that can accept a proton, so amines are weak bases, like ammonia: CH₃NH₂ + H₂O ⇌ CH₃NH₃⁺ + OH⁻.
• Small amines are soluble in water, turn damp red litmus blue, and smell fishy.
• With an acid they form a salt: CH₃NH₂ + HCl → CH₃NH₃⁺Cl⁻ (methylammonium chloride), which is ionic, odourless and soluble.
• The same lone pair lets an amine attack the δ+ carbon of an acyl chloride, which is how N-substituted amides are made.

Acyl chlorides: the fast route

• A carboxylic acid becomes an acyl chloride with thionyl chloride: CH₃COOH + SOCl₂ → CH₃COCl + SO₂ + HCl.
• The C of -COCl is bonded to both O and Cl, so it is very δ+, and acyl chlorides react quickly and completely at room temperature.
• Each reaction swaps the Cl for another group and releases HCl, seen as steamy fumes in moist air: CH₃COCl + H₂O → CH₃COOH + HCl.
• With an alcohol it makes an ester; with ammonia an amide, CH₃COCl + 2NH₃ → CH₃CONH₂ + NH₄Cl; with a primary amine an N-substituted amide, CH₃COCl + CH₃NH₂ → CH₃CONHCH₃ + HCl.

Making esters and amides

• Esterification: a carboxylic acid and an alcohol heated under reflux with a few drops of concentrated H₂SO₄ give an ester and water: CH₃CH₂CH₂COOH + CH₃CH₂OH ⇌ CH₃CH₂CH₂COOCH₂CH₃ + H₂O.
• This makes ethyl butanoate, a fruity ester found in kiwifruit. The reaction is reversible and slow, so the yield is limited; H₂SO₄ is the catalyst and also removes some of the water.
• Using the acyl chloride instead, CH₃CH₂CH₂COCl + CH₃CH₂OH → CH₃CH₂CH₂COOCH₂CH₃ + HCl, is fast and goes to completion.
• Amides are made from an acyl chloride and ammonia or an amine. The ester or amide link joins the two pieces, and a small molecule (H₂O or HCl) is lost, which is why these are called condensation reactions.

Hydrolysis in acid and in base

• Hydrolysis uses water to split an ester or amide back into its two pieces. It needs heating under reflux with dilute acid or with a base such as NaOH(aq).
• In acid, the products are the carboxylic acid plus the alcohol (from an ester) or an ammonium ion (from an amide), because the amine or NH₃ takes a proton from the acid.
• In base, the acid part comes out as its carboxylate ion, because OH⁻ removes the proton; the other product is the alcohol, or NH₃ or the amine.
• Acid hydrolysis of an ester is reversible, so it is incomplete. Base hydrolysis goes to completion because the carboxylate ion cannot react back with the alcohol.

Try it: acid or base hydrolysis?

Planning a reaction scheme

• Start from the target and work backwards: an amide needs an acyl chloride and an amine; an acyl chloride needs a carboxylic acid; an amine can come from a haloalkane.
• Count carbons: substitution never changes the chain length, so the pieces of the product must already exist in the starting materials.
• Write every step with its reagent and conditions, and name or draw every intermediate.
• Check each step uses a reagent you are allowed: in the exam you are often given a short list and must choose from it.

What Achieved, Merit and Excellence look like

• Achieved gives correct products and names a reaction type. Merit explains what happens in each step and why the products form. Excellence links observations, reagents and products for every step and compares the alternatives.