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Organic synthesis is the discipline of assembling a defined target molecule from simpler, commercially available starting materials by a sequence of selective transformations. Every reaction encountered earlier in this course — addition to alkenes, nucleophilic substitution of halogenoalkanes, oxidation and reduction of carbonyls, esterification, electrophilic aromatic substitution, Friedel-Crafts acylation — is a tool in the synthetic chemist's toolkit. The skill that distinguishes a top A-Level answer is not memorising any single reaction in isolation, but planning a route: deciding which functional-group interconversions (FGIs) connect starting material to target, in what order, with what carbon-chain modifications, and with what trade-offs in selectivity, yield, and atom economy. This lesson develops a working method of retrosynthetic analysis — thinking backwards from the target — then applies it to canonical aliphatic and aromatic pathway problems, including chain extension via cyanide, oxidation cascades, and aromatic functionalisation sequences. The pathway diagrams introduced here are the single most valuable revision tool in organic chemistry; commit them to memory.
Spec mapping (AQA 7405): This lesson maps to §3.3.14 (organic synthesis) and synthesises every other organic section of the specification: §3.3.1 (nomenclature and isomerism), §3.3.2 (alkanes — free-radical halogenation), §3.3.3 (halogenoalkanes — nucleophilic substitution and elimination), §3.3.4 (alkenes — electrophilic addition), §3.3.5 (alcohols — oxidation, dehydration, esterification), §3.3.7 (optical isomerism — relevant to stereoselective synthesis), §3.3.8 (aldehydes and ketones — reduction, addition of HCN), §3.3.9 (carboxylic acids and derivatives — esters, acyl chlorides, amides), §3.3.10 (aromatic chemistry — nitration, Friedel-Crafts), §3.3.11 (amines — formation from halogenoalkanes, nitriles, nitroarenes). Refer to the official AQA specification document for the exact wording of each section.
Assessment objectives: Recall of standard reagents and conditions for key interconversions is AO1. Constructing multi-step synthesis routes from a given starting material to a named target — naming reagents, conditions, intermediates, and reaction types at every step — is AO2 and appears on every A-Level Paper 2. Evaluating alternative routes against criteria of atom economy, overall yield, selectivity, hazard, and chain length is AO3 and increasingly common in extended-response synthesis questions.
A synthesis problem is presented forwards: "convert A to B." The most efficient way to solve it is to think backwards. Retrosynthesis asks, at each stage, what immediate precursor could have been converted into this molecule using a reaction I know? The disconnection arrow (⇒) by convention points from product to precursor — the reverse of the synthetic arrow. The procedure is:
Two questions discipline every disconnection: (i) is there a real, A-Level-allowed reaction that performs this transformation? (ii) is the reaction selective enough that the desired isomer is the major product? Many "obvious" disconnections fail on selectivity grounds — for example, Markovnikov addition of HBr to propene gives the 2-bromo, not the 1-bromo, isomer; free-radical halogenation of an alkane gives a statistical mixture; oxidation of a primary alcohol gives the aldehyde or the acid depending on whether the apparatus is set up for distillation or reflux.
The table below is the master FGI map. Every A-Level synthesis is built from rows in this table. Reagents and conditions are written in the precise form expected by examiners — do not abbreviate "NaOH(aq), reflux" to "NaOH"; do not write "oxidise" without specifying the oxidant.
| Starting material | Product | Reagents and conditions | Reaction type |
|---|---|---|---|
| Alkane | Halogenoalkane | X₂ (Cl₂ or Br₂), UV light | Free-radical substitution |
| Alkene | Alkane | H₂, Ni catalyst, 150 °C | Catalytic hydrogenation |
| Alkene | Halogenoalkane | HBr, HCl or HI, room temp | Electrophilic addition (Markovnikov) |
| Alkene | 1,2-Dihalogenoalkane | Br₂ or Cl₂, room temp | Electrophilic addition |
| Alkene | Alcohol | H₂O(g), H₃PO₄ catalyst, 300 °C, 60 atm | Electrophilic addition (hydration) |
| Halogenoalkane | Alcohol | NaOH(aq), reflux | Nucleophilic substitution |
| Halogenoalkane | Nitrile | KCN in ethanol, reflux | Nucleophilic substitution (adds 1 C) |
| Halogenoalkane | Primary amine | Excess NH₃ in ethanol, sealed tube, heat | Nucleophilic substitution |
| Halogenoalkane | Alkene | NaOH in ethanol, reflux | Elimination (E2) |
| Alcohol (1°) | Aldehyde | K₂Cr₂O₇ / dilute H₂SO₄, distil off product | Oxidation |
| Alcohol (1°) | Carboxylic acid | Excess K₂Cr₂O₇ / dilute H₂SO₄, reflux | Oxidation |
| Alcohol (2°) | Ketone | K₂Cr₂O₇ / dilute H₂SO₄, reflux | Oxidation |
| Alcohol | Halogenoalkane | HX (or NaX + H₂SO₄, or SOCl₂ for Cl) | Substitution |
| Alcohol | Alkene | Conc. H₂SO₄ or H₃PO₄, heat | Dehydration (elimination) |
| Alcohol + carboxylic acid | Ester | Conc. H₂SO₄ catalyst, reflux | Esterification |
| Alcohol + acyl chloride | Ester | Room temperature | Acylation |
| Aldehyde | 1° Alcohol | NaBH₄ in methanol/water | Reduction |
| Ketone | 2° Alcohol | NaBH₄ in methanol/water | Reduction |
| Aldehyde | Carboxylic acid | K₂Cr₂O₇ / dilute H₂SO₄, reflux (or Tollens' to confirm) | Oxidation |
| Aldehyde or ketone | 2-Hydroxynitrile | KCN + dilute H₂SO₄ (HCN in situ) | Nucleophilic addition (adds 1 C) |
| Nitrile | Carboxylic acid | Dilute HCl or H₂SO₄, reflux | Acid hydrolysis |
| Nitrile | Primary amine | LiAlH₄ in dry ether (or H₂/Ni) | Reduction |
| Carboxylic acid | 1° Alcohol | LiAlH₄ in dry ether | Reduction |
| Carboxylic acid | Acyl chloride | SOCl₂ (or PCl₅, PCl₃) | Substitution |
| Acyl chloride + alcohol | Ester | Room temperature | Acylation |
| Acyl chloride + amine | N-substituted amide | Room temperature | Acylation |
| Benzene | Nitrobenzene | Conc. HNO₃ + conc. H₂SO₄, < 55 °C | Electrophilic substitution (nitration) |
| Nitrobenzene | Phenylamine | Sn + conc. HCl, reflux; then NaOH(aq) | Reduction |
| Benzene | Bromobenzene | Br₂ + FeBr₃ (or AlBr₃) catalyst | Electrophilic substitution (halogenation) |
| Benzene | Alkylbenzene | RCl + AlCl₃, reflux | Friedel-Crafts alkylation |
| Benzene | Aryl ketone | RCOCl + AlCl₃, reflux | Friedel-Crafts acylation |
| Methylbenzene (and side chains) | Benzoic acid | Hot acidified KMnO₄, reflux | Side-chain oxidation |
Memorise the conditions column in particular: aqueous vs ethanolic NaOH switches between substitution and elimination; distillation vs reflux switches between aldehyde and acid; dilute vs concentrated H₂SO₄ switches between hydration and dehydration. These are where examiners distribute marks.
ALKANE
|
X₂, UV (free-radical sub.)
v
ALKENE <--NaOH/ethanol-- HALOGENOALKANE --KCN/ethanol--> NITRILE
| (elimination) | |
| HBr | NaOH(aq) | dilute HCl, reflux
| (addition) | (nucleophilic sub.) | (hydrolysis)
| conc. H₂SO₄/heat v v
+----dehydration----------> ALCOHOL CARBOXYLIC ACID
| |
| K₂Cr₂O₇/H₂SO₄ |
| | + alcohol/H₂SO₄
distil | reflux | (esterification)
/ \ v
ALDEHYDE CARBOXYLIC ACID ESTER
| ^
| NaBH₄ | K₂Cr₂O₇/H₂SO₄ reflux
v |
1° ALCOHOL ---------+
Chain extension: HALOGENOALKANE --KCN--> NITRILE (adds 1 C)
NITRILE --LiAlH₄/dry ether--> 1° AMINE (adds 0 C, gains NH₂)
The diagram compresses fifteen interconversions onto one page. The "rule of three branches" from alcohol is worth highlighting: a primary alcohol can be (a) partially oxidised to aldehyde under distillation, (b) fully oxidised to carboxylic acid under reflux with excess oxidant, or (c) dehydrated to an alkene. The choice of conditions decides the product.
Target: CH₃CH₂COOH. Starting material: CH₃CH₂CH₂OH. Same carbon count; the OH is converted to COOH on the same terminal carbon.
Retrosynthesis: propanoic acid ⇒ full oxidation of propan-1-ol.
Forward synthesis (one step):
CH₃CH₂CH₂OH + 2[O] → CH₃CH₂COOH + H₂O
Reagents and conditions: excess K₂Cr₂O₇ acidified with dilute H₂SO₄, heat under reflux. The reflux apparatus is critical — it returns volatile intermediates (the aldehyde propanal) to the flask for further oxidation. If the apparatus were set up for distillation, propanal would distil out before reaching the acid stage. The orange dichromate(VI) reduces to green chromium(III) as the reaction proceeds.
Target: CH₃CH₂COOH (3 C). Starting material: CH₃CH₂Br (2 C). One extra carbon required — the signal to use the cyanide route.
Retrosynthesis:
Forward synthesis (two steps):
Step 1: CH₃CH₂Br + KCN → CH₃CH₂CN + KBr. Conditions: KCN dissolved in ethanol, reflux. Ethanol is the solvent because aqueous KCN would favour hydroxide attack and give ethanol (substitution by OH⁻) as a competing product. The nitrile carbon is the new C; the chain has grown from 2 to 3.
Step 2: CH₃CH₂CN + 2H₂O + HCl → CH₃CH₂COOH + NH₄Cl. Conditions: dilute HCl (or dilute H₂SO₄), heat under reflux. The nitrile is hydrolysed to the carboxylic acid via an amide intermediate; under acidic conditions the nitrogen leaves as ammonium ion.
This is the canonical chain-extension route. Examiners explicitly test whether students see "chain grows by one carbon" as a trigger for CN⁻.
Target: CH₃COOC₂H₅. Starting material: ethanol only.
Retrosynthesis: the ester disconnects to ethanoic acid + ethanol; the acid is itself made from ethanol by full oxidation.
Forward synthesis (two steps from a single starting material):
Step 1 (oxidation): CH₃CH₂OH + 2[O] → CH₃COOH + H₂O. Conditions: excess K₂Cr₂O₇ / dilute H₂SO₄, reflux. Convert roughly half of the ethanol to ethanoic acid (use stoichiometric quantities).
Step 2 (esterification): CH₃COOH + CH₃CH₂OH ⇌ CH₃COOC₂H₅ + H₂O. Conditions: concentrated H₂SO₄ catalyst, heat under reflux. The equilibrium can be driven to the right by using excess alcohol or by distilling off the ester. Yield is typically 60–70 %, a consequence of the reversible nature of the reaction; an industrial preparation would use an acyl chloride for higher yield and irreversibility.
Target: (CH₃)₂CHNH₂. Starting material: (CH₃)₂CHOH. The OH is replaced by NH₂ at the same secondary carbon.
Retrosynthesis:
Forward synthesis (two steps):
Step 1: (CH₃)₂CHOH + HBr → (CH₃)₂CHBr + H₂O. Conditions: HBr generated in situ from NaBr + 50 % H₂SO₄, warm, or alternatively use PBr₃. The acid protonates the OH, making H₂O a good leaving group; bromide then substitutes.
Step 2: (CH₃)₂CHBr + 2 NH₃ → (CH₃)₂CHNH₂ + NH₄Br. Conditions: excess concentrated NH₃ in ethanol, sealed tube, heat. Excess ammonia is essential to minimise further alkylation of the product amine (which is itself a nucleophile and would give secondary and tertiary amines as by-products). The sealed tube prevents loss of volatile NH₃ at the reflux temperature.
A point of stereochemistry: 2-bromopropane is not chiral (the central C carries two identical methyl groups), so SN1 vs SN2 selectivity is academic here. For a chiral substrate such as 2-bromobutane, SN2 would invert the configuration and SN1 would racemise — a consideration flagged in Going Further.
Target: C₆H₅NH₂. Starting material: C₆H₆.
Retrosynthesis:
Forward synthesis (two steps):
Step 1 (nitration): C₆H₆ + HNO₃ → C₆H₅NO₂ + H₂O. Conditions: concentrated HNO₃ + concentrated H₂SO₄, below 55 °C. The mixed acid generates the nitronium ion NO₂⁺, which is the electrophile. Temperature control is critical — above 55 °C a second nitration to dinitrobenzene becomes significant, and a 1,3-dinitro by-product appears.
Step 2 (reduction): C₆H₅NO₂ + 6[H] → C₆H₅NH₂ + 2 H₂O. Conditions: tin (Sn) + concentrated HCl, heat under reflux; then NaOH(aq) to liberate the free amine from its salt. The Sn/HCl reduces NO₂ through nitroso and hydroxylamine intermediates to the primary amine. Industrial syntheses use catalytic hydrogenation (H₂/Ni or H₂/Pt) at scale; Sn/HCl remains the A-Level standard.
Target: C₆H₅Br. Starting material: C₆H₆.
Forward synthesis (one step): C₆H₆ + Br₂ → C₆H₅Br + HBr. Conditions: Br₂ with FeBr₃ (or anhydrous AlBr₃) as halogen-carrier catalyst, room temperature, no UV light. The catalyst polarises Br–Br to generate Br⁺ as the effective electrophile; without it, benzene's delocalised π system is too unreactive for Br₂ alone. The distinction from alkene bromination — which proceeds with Br₂ alone in the cold — is a frequent examiner discriminator.
The direct target "4-methylbenzoic acid" cannot be made from methylbenzene by a single side-chain oxidation, because there is only one methyl group on the ring. The standard A-Level transformation is methylbenzene to benzoic acid:
C₆H₅CH₃ + 3[O] → C₆H₅COOH + H₂O. Conditions: hot acidified KMnO₄ (potassium manganate(VII) with dilute H₂SO₄), reflux for several hours. The benzylic C–H bonds are oxidised; any alkyl side chain longer than CH₃ is also oxidised down to COOH (e.g. ethylbenzene → benzoic acid). The aromatic ring itself is inert to KMnO₄ under these conditions. The mark scheme commonly demands "hot" — cold KMnO₄ does not oxidise the side chain.
To make 4-methylbenzoic acid (one methyl, one COOH at para positions), start from 1,4-dimethylbenzene (para-xylene) and partially oxidise — controlling stoichiometry to stop at the mono-acid. Industrially the analogous oxidation of para-xylene to terephthalic acid uses Co/Mn/Br catalysts in acetic acid solvent (the Amoco MC process), which oxidises both methyl groups; selective mono-oxidation is more difficult and is beyond A-Level. Recognising this limitation — and proposing the para-xylene route — is precisely the AO3 evaluative move that earns top-band marks.
Selectivity governs whether a route works in practice. Three families of selectivity matter at A-Level:
Regioselectivity — which position on the molecule reacts. Markovnikov's rule for HX addition to alkenes (H to the carbon with more H atoms; X to the more-substituted carbon) determines that propene + HBr gives 2-bromopropane as the major product. Free-radical halogenation of an alkane gives an unselective mixture of isomers — a reason to avoid this route when planning targeted syntheses. In aromatic chemistry, directing effects govern regioselectivity: existing substituents on the ring direct incoming electrophiles to particular positions. Electron-donating groups (–NH₂, –OH, alkyl) are 2,4-directors (ortho/para); electron-withdrawing groups (–NO₂, –COOH, –COR) are 3-directors (meta). This is examined explicitly in the Friedel-Crafts lesson (L4 of this course).
Chemoselectivity — which of several functional groups reacts. A molecule containing both an alcohol and a C=C double bond cannot be hydrogenated without also being oxidised by chromate; protecting groups (Going Further) are the strategic answer.
Stereoselectivity — which stereoisomer is produced. Nucleophilic substitution by SN2 mechanism inverts the configuration at a chiral centre (Walden inversion); SN1 proceeds via a planar carbocation and produces a racemic mixture. Reduction of an unsymmetrical ketone by NaBH₄ generates a chiral alcohol as a racemate, because hydride attacks both faces of the planar carbonyl with equal probability. Producing a single enantiomer (asymmetric synthesis) requires chiral reagents or catalysts — covered in Lesson 9.
Carbon counting is a discipline that catches every wasted minute on synthesis questions. Before drafting any route, count carbons in the starting material and target. There are exactly two A-Level methods to extend a carbon chain by one:
At university level, a third method — Grignard reagent + carbonyl — adds arbitrary chain lengths (signposted in Going Further). At A-Level, if your target has more carbons than the starting material, the answer is almost always cyanide.
To shorten a carbon chain, the A-Level toolbox is sparse: the iodoform reaction (positive triiodomethane test) cleaves a methyl ketone to give a carboxylate one carbon shorter — outside the AQA spec but historically examined elsewhere. AQA students should assume chain length is preserved unless explicitly extended by CN⁻.
Almost every synthesis at A-Level produces either an achiral product or a racemate; producing a single enantiomer is an asymmetric-synthesis problem reserved for Lesson 9. Three rules cover the AQA exam scope:
For a synthesis question that explicitly asks about stereochemistry, name the mechanism, identify whether a new stereocentre is created, and state whether the product is a single enantiomer, a racemate, or a mixture of diastereomers.
When two viable routes exist, examiners increasingly ask students to compare them on green-chemistry grounds. The relevant criteria:
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