A Level Organic Synthesis: Multi-Step Routes with Aromatic Chemistry

This guide covers subtopic 36.1, Organic synthesis, from Topic 36, Organic synthesis, of Cambridge International AS & A Level Chemistry 9701, 2025–2027 series. This is A Level content — a skills capstone, the direct sequel to Organic Synthesis: Planning Multi-Step Routes at AS Level, now drawing on the full range of A Level organic reactions including benzene chemistry.

Before studying this

This resource assumes the AS-level synthesis skill itself from Organic Synthesis: Planning Multi-Step Routes, and draws on every A Level organic topic covered so far: Arenes and Halogenoarenes, Phenol: Reactions and Acidity, Carboxylic Acids and Acyl Chlorides, Amines: Aliphatic and Aromatic, Basicity and Azo Dyes, and Amides and Amino Acids.

Syllabus coverage

CAMBRIDGE INTERNATIONAL AS & A LEVEL CHEMISTRY 9701 — A Level, Topic 36

36.1 Organic synthesis — for a molecule containing several functional groups, identifying them using the reactions in the syllabus and predicting properties/reactions; devising multi-step synthetic routes using the reactions in the syllabus; analysing a given synthetic route in terms of reaction type and reagents for each step, and possible by-products.

What’s new at A Level

The AS-level approach — identify functional groups, work forwards from starting material or backwards from target, check every reagent and condition, watch for side reactions — is unchanged. What’s new is the reaction toolkit available to draw on, now including electrophilic aromatic substitution (with its directing-effect rules), phenol chemistry, acyl chloride addition-elimination reactions, diazonium salt chemistry, and amide/amine interconversions — considerably widening what a single synthesis route can achieve, and correspondingly widening what can go wrong if a step is misapplied.

Worked example: benzene to phenylethanoic acid derivatives

Devise a synthesis of 4-nitrophenyl ethanoate from benzene.

Work backwards from the target. 4-Nitrophenyl ethanoate is an ester, made from ethanoyl chloride and 4-nitrophenol (the ester linkage points directly at Phenol: Reactions and Acidity’s alcohol/phenol + acyl chloride reaction). 4-Nitrophenol itself is a nitrated phenol, which points at phenol’s own nitration reaction. Phenol, in turn, is made from phenylamine via a diazonium salt. Reading the route forwards:

Step 1: Benzene + concentrated HNO₃/H₂SO₄, 25–60 °C → nitrobenzene (electrophilic substitution, nitration)

Step 2: Nitrobenzene + Sn/concentrated HCl (heat), then NaOH(aq) → phenylamine (reduction of the nitro group)

Step 3: Phenylamine + NaNO₂/dilute acid, below 10 °C → benzenediazonium chloride

Step 4: Benzenediazonium chloride + H₂O (warm) → phenol

Step 5: Phenol + dilute HNO₃(aq), room temperature → a mixture of 2-nitrophenol and 4-nitrophenol (separated by, e.g., fractional distillation of the two isomers, which have different volatilities due to different degrees of intramolecular vs intermolecular hydrogen bonding — a detail beyond what’s tested, but worth knowing a real separation step exists)

Step 6: 4-Nitrophenol + ethanoyl chloride, room temperature → 4-nitrophenyl ethanoate + HCl (addition-elimination, ester formation from a phenol)

Analysing this route: six steps, spanning nitration, reduction, diazotisation, hydrolysis of a diazonium salt, a second nitration, and finally esterification. A possible by-product to flag at step 5 is the 2-nitrophenol isomer formed alongside the wanted 4-nitrophenol — the hydroxyl group’s 2,4-directing effect means both are produced together and must be separated, not that the reaction only makes the 4-isomer.

Worked example: analysing a given route

Analyse the following route, stating the type of reaction and reagents for each step, and any possible by-product: methylbenzene → benzoic acid → benzoyl chloride → benzamide.

Step 1 (methylbenzene → benzoic acid): oxidation of the side-chain, using hot alkaline KMnO₄ then dilute acid.

Step 2 (benzoic acid → benzoyl chloride): substitution, using PCl₃ (with heat), PCl₅, or SOCl₂.

Step 3 (benzoyl chloride → benzamide): condensation (addition-elimination), using excess ammonia at room temperature; the by-product is ammonium chloride, NH₄Cl, formed when the HCl released in the addition-elimination step is neutralised by the second equivalent of the excess ammonia used.

A checklist for building or analysing a route

For devising a route: identify every functional group in the target that isn’t present in the starting material, choose reactions from the syllabus that install each one (checking reagents and conditions are genuinely compatible with any functional groups already present from an earlier step — for example, don’t plan to nitrate a ring after installing a group that would itself react under nitrating conditions, unless that’s intended), and order the steps so nothing installed early is inadvertently destroyed or modified by a later step’s reagents.

For analysing a given route: work through each arrow in turn, name the reaction type (substitution, addition, elimination, addition-elimination, oxidation, reduction, condensation), state the specific reagents and conditions needed (not just “oxidise” or “reduce” — the actual reagent, since different oxidising/reducing agents are specified for different transformations throughout the syllabus), and check for a by-product at every step that releases a small molecule (H₂O, HCl, NH₄Cl and similar salts are the most common).

Common mistakes

Forgetting that nitration and other ring reactions must respect the existing substituent’s directing effect once one is already present. A route that nitrates an already-substituted ring needs to specify (or at least be consistent with) which position(s) the existing group directs to.

Quoting a generic reagent instead of the specific one required. “Oxidise the alcohol” is not a complete answer where the mark scheme wants K₂Cr₂O₇/dilute H₂SO₄ (or KMnO₄) with the correct heating/distillation detail — the same precision expected throughout every individual topic carries over into synthesis questions.

Missing a by-product that changes the practical yield or purity of the target. Directing effects producing an isomer mixture (as in the phenol nitration example above) and HCl-neutralisation salts (as in the amide example) are the two most frequently tested by-product situations.

Assuming every synthesis has only one correct route. Multiple valid routes to the same target often exist — a route is correct if every step uses a genuine reaction from the syllabus with compatible reagents and conditions, not because it matches one specific “intended” answer.

Quick revision checklist

• Same planning method as AS: identify functional-group changes needed, choose reactions, check compatibility and order
• New A Level tools: electrophilic aromatic substitution + directing effects, phenol chemistry, acyl chloride addition-elimination, diazonium chemistry, amide/amine interconversion
• Always state the specific reagent and condition, not a generic description
• Always check for isomer mixtures (directing effects) and small-molecule by-products (H₂O, HCl, ammonium/aminium salts) at each step

Related resources

• Organic Synthesis: Planning Multi-Step Routes — the AS-level synthesis skill this topic extends
• Arenes and Halogenoarenes: Electrophilic Substitution and Reactivity — directing effects used throughout the worked examples
• Phenol: Reactions and Acidity and Amines: Aliphatic and Aromatic, Basicity and Azo Dyes — the phenol/diazonium route used above
• Carboxylic Acids and Acyl Chlorides — the acyl-chloride steps used above
• Cambridge AS & A Level Chemistry hub

Written against Cambridge International AS & A Level Chemistry 9701, 2025–2027 series. Always check the current syllabus for your examination year.