A Level Chemistry: Multi-Step Synthesis Routes — Revision Notes

Condensed for the final weeks. For the full explanation, use the Organic Synthesis: Multi-Step Routes study guide.

How to plan a route

Work backwards from the target. Ask what single reaction could produce that functional group, then treat its starting material as the new target. Repeat until you reach something you were given.

Three questions for every step:

1. Does the carbon skeleton change? Only a few reactions add carbon — CN⁻ substitution and the Friedel–Crafts reactions. If the target has more carbons than the start, one of those must appear.
2. What is the oxidation level? Alcohol → aldehyde → carboxylic acid is a ladder; you must specify distillation to stop at the aldehyde.
3. Are the conditions compatible? You cannot use a reagent that would destroy a group already present.

The essential interconversions

alkene   ->  halogenoalkane      HBr, room temp
alkene   ->  alcohol             steam, H3PO4 catalyst, 300 C, 60 atm
halogenoalkane -> alcohol        NaOH(aq), reflux
halogenoalkane -> nitrile        KCN in ethanol, reflux      [ADDS A CARBON]
halogenoalkane -> amine          excess NH3 in ethanol, heat under pressure
nitrile  ->  carboxylic acid     dilute HCl(aq), reflux
nitrile  ->  amine               LiAlH4 in dry ether, or H2/Ni
alcohol  ->  aldehyde            K2Cr2O7/H2SO4, DISTIL OFF
alcohol  ->  carboxylic acid     K2Cr2O7/H2SO4, REFLUX
alcohol  ->  alkene              conc. H2SO4, 170 C (dehydration)
aldehyde ->  carboxylic acid     K2Cr2O7/H2SO4, reflux
ketone/aldehyde -> alcohol       NaBH4, or LiAlH4
carboxylic acid -> acyl chloride SOCl2
acyl chloride -> ester           alcohol, room temp
acid + alcohol -> ester          conc. H2SO4 catalyst, reflux

Distil versus reflux is the single most commonly dropped mark. Distilling removes the aldehyde as it forms, before it can be oxidised further; refluxing returns it to the flask so oxidation continues to the acid.

Aromatic routes

benzene   ->  nitrobenzene       conc. HNO3 / conc. H2SO4, 25-60 C
nitrobenzene -> phenylamine      Sn / conc. HCl, then NaOH
benzene   ->  alkylbenzene       RCl / AlCl3
benzene   ->  phenylketone       RCOCl / AlCl3
methylbenzene -> benzoic acid    hot alkaline KMnO4, then dilute acid (side chain oxidised)
phenylamine -> diazonium salt    NaNO2 / dilute HCl, BELOW 10 C
diazonium salt -> phenol         H2O, warm

Temperature control in nitration matters: mononitration is favoured across 25-60 °C, but above about 60 °C you get dinitration. Diazonium salt formation needs below 10 °C — above this the salt decomposes before it can be used.

Worked example: analysing a route

Analyse: methylbenzene → benzoic acid → benzoyl chloride → benzamide.

Step 1  oxidation of the side chain    hot alkaline KMnO4, then dilute acid
Step 2  substitution                   PCl5, PCl3, or SOCl2
Step 3  condensation (addn-elim)       excess NH3, room temp
                                        by-product: NH4Cl

Always check for a by-product that releases a small molecule at each step — H₂O, HCl and NH₄Cl are the most common, and naming it is frequently a separate mark from naming the reaction type itself.

Reagents that add a carbon

Only three, and questions are built around them:

• KCN in ethanol with a halogenoalkane → nitrile, one carbon longer.
• HCN with an aldehyde or ketone → hydroxynitrile, one carbon longer.
• Friedel–Crafts with RCl or RCOCl → attaches an alkyl or acyl group to the ring.

If a question’s product has one more carbon than the starting material, a nitrile step is almost certainly required — and the nitrile then needs hydrolysing to an acid or reducing to an amine.

Reducing agents

Reagent	Reduces	Does not reduce
NaBH₄	Aldehydes, ketones	Carboxylic acids, nitriles, esters
LiAlH₄ (dry ether)	Everything above, plus acids, esters, nitriles	Isolated C=C double bonds
H₂ / Ni	Alkenes, the benzene ring, and nitriles	Carboxylic acids, esters, amides

Choosing NaBH₄ when a nitrile must be reduced is a common error.

Exam traps

• Writing “oxidise” without naming the reagent and the conditions.
• Reflux where distillation is needed, so the aldehyde over-oxidises.
• NaOH(aq) and heat (gives the alcohol) versus NaOH in ethanol and heat (gives the alkene) — the solvent decides the product.
• Forgetting the second stage of nitrobenzene reduction: NaOH is needed to liberate the free amine from its salt.
• Using NaBH₄ on a nitrile or carboxylic acid.
• Routes that lose or gain carbons with no reaction that could account for it.
• Forgetting the below-10°C condition for diazonium salt formation.
• Naming a reaction type without also naming the by-product released.

Self-test

1. How do you convert a halogenoalkane into a carboxylic acid with one extra carbon?
2. What single difference gives an aldehyde rather than a carboxylic acid from an alcohol?
3. A halogenoalkane is heated with NaOH. What decides whether the product is an alcohol or an alkene?
4. Name the reagents for converting benzene into phenylamine.
5. Which reducing agent would you use for a nitrile, and why not the other?
6. What condition is essential for forming a diazonium salt, and why?
7. In the route benzoic acid → benzoyl chloride → benzamide, name the reaction type and by-product of the final step.

Answers: 1. KCN in ethanol under reflux to form the nitrile, then dilute HCl(aq) under reflux to hydrolyse it to the carboxylic acid. 2. Distil the aldehyde off as it forms rather than refluxing, so it cannot be oxidised further. 3. The solvent — NaOH(aq) and heat gives nucleophilic substitution to the alcohol; NaOH in ethanol and heat gives elimination to the alkene. 4. Conc. HNO₃ with conc. H₂SO₄ between 25 and 60 °C, then Sn with conc. HCl, then NaOH to liberate the amine. 5. LiAlH₄ in dry ether (or H₂/Ni); NaBH₄ is not powerful enough to reduce a nitrile. 6. The temperature must stay below 10°C, since the diazonium salt decomposes above this temperature before it can be used. 7. Condensation (addition-elimination), using excess ammonia at room temperature; the by-product is ammonium chloride, NH₄Cl.