Planning a Synthetic Route
A concise revision guide to multi-step organic synthesis: the reaction map that joins every functional group, how to plan a multi-step route backwards from the target, worked routes for aliphatic and aromatic targets, and how to analyse a given route for its reaction types, reagents and by-products.
Before You Start
A synthesis question joins reactions from the whole course. Nothing new is taught here: the skill is choosing and ordering reactions you already know.
- Adding a carbon to a chain or a ring: Carbon–Carbon Bond Formation.
- Nucleophilic substitution of halogenoalkanes by OH⁻, CN⁻ and NH₃: Nucleophilic Substitution Reactions.
- Oxidation of alcohols, reduction of carbonyl compounds, HCN addition: Reduction and Nucleophilic Addition.
- Acyl chlorides with water, alcohols, ammonia and amines: Acyl Chlorides.
- Nitration of benzene, reduction of nitrobenzene and the directing effects of groups on the ring: Topic 30 Hydrocarbons and Topic 34 Nitrogen Compounds.
- Identifying each intermediate by its tests and spectra: Identifying Functional Groups by Chemical Tests and Deducing Formulae from Analytical Data.
The Reaction Map
Every functional group is joined to its neighbours by a reaction with a known reagent. Learn the map as a web of arrows: each arrow is one step, one reagent and one set of conditions.
| From | To | Reagent and conditions |
|---|---|---|
| alkene | halogenoalkane | HBr at room temperature (electrophilic addition) |
| alkene | alcohol | steam, H₃PO₄ catalyst, 300 °C, 60 atm (hydration) |
| halogenoalkane | alcohol | NaOH(aq), heat under reflux (nucleophilic substitution) |
| halogenoalkane | nitrile | KCN in ethanol, heat under reflux (+1 carbon) |
| halogenoalkane | primary amine | excess concentrated NH₃ in ethanol, heated under pressure |
| halogenoalkane | alkene | KOH in ethanol, heat under reflux (elimination) |
| alcohol | halogenoalkane | PCl₅ (chloro-) or NaBr with concentrated H₂SO₄ (bromo-) |
| primary alcohol | aldehyde | K₂Cr₂O₇ / dilute H₂SO₄, distil the aldehyde as it forms |
| primary alcohol | carboxylic acid | K₂Cr₂O₇ / dilute H₂SO₄, heat under reflux |
| secondary alcohol | ketone | K₂Cr₂O₇ / dilute H₂SO₄, heat under reflux |
| aldehyde or ketone | alcohol | NaBH₄ in water or ethanol (reduction) |
| aldehyde or ketone | hydroxynitrile | HCN with KCN (nucleophilic addition, +1 carbon) |
| nitrile | carboxylic acid | dilute HCl, heat under reflux (hydrolysis) |
| nitrile | primary amine | LiAlH₄ in dry ether, or H₂ with a nickel catalyst (reduction) |
| carboxylic acid | acyl chloride | PCl₅ (or SOCl₂) at room temperature |
| carboxylic acid | ester | alcohol with concentrated H₂SO₄ catalyst, heat under reflux |
| acyl chloride | ester / amide | alcohol / ammonia or amine, room temperature (addition-elimination) |
| ester | carboxylic acid | dilute acid under reflux, or NaOH(aq) under reflux then acidify |
| benzene | nitrobenzene | concentrated HNO₃ and concentrated H₂SO₄ at about 50 °C, below 60 °C (nitration) |
| nitrobenzene | phenylamine | Sn and concentrated HCl under reflux, then NaOH(aq) |
| benzene | alkyl- or acylbenzene | halogenoalkane or acyl chloride with an AlCl₃ catalyst (Friedel–Crafts) |
The map drawn as structures: the two-carbon web from ethene, with the nitrile and hydroxynitrile branches, and the benzene row underneath, reagents on every arrow.
The same map as named boxes: use it to trace any route with your finger before writing it down.
Exam focus: Oxidising agent and conditions are both needed: K₂Cr₂O₇ / H₂SO₄ with distil for an aldehyde and with reflux for the acid. Reflux and distil are different answers.
How to Plan a Route
Work backwards from the target, one step at a time, until the starting material appears. Routes in questions can have several steps.
- Compare the carbon skeletons: same number of carbons, one more, or a ring? One more carbon means a nitrile step somewhere.
- Name the functional group of the start and of the target and find the arrows that join them on the map.
- Ask what the target can be made from in one step; then what that intermediate can be made from; stop at the start.
- Write the reagent and conditions for every step and name the type of reaction.
- Check the route: no step over the limit, every intermediate named, side reactions and excess reagents considered.
Working backwards: ethanoic acid from ethene
The five planning steps as a checklist, with the ethene to ethanoic acid example worked underneath.
Common mistake: Writing a reagent without conditions, or two changes in one arrow. One arrow is one reaction: an alcohol does not become an ester in a single step from an acyl chloride and an acid at once.
Check: Reading the Reaction Map
Supply the missing reagent and conditions on a route, name the type of each reaction and decide whether the number of carbons changes.
Worked Routes 1: Aliphatic Targets
Three routes of two or three steps, each written as a question would expect it: intermediate, reagent, conditions and type of reaction.
Route (a): ethene to ethanoic acid through ethanal
Step 1. Ethene + steam, H₃PO₄ catalyst, 300 °C and 60 atm → ethanol (hydration, electrophilic addition).
Route (b): 1-bromopropane to butanoic acid or butylamine
Route (c): propan-2-ol to 2-hydroxy-2-methylpropanoic acid
Step 1. Propan-2-ol + K₂Cr₂O₇ / dilute H₂SO₄, heat under reflux → propanone (oxidation of a secondary alcohol to a ketone).
Step 2. Propanone + HCN with KCN → 2-hydroxy-2-methylpropanenitrile, (CH₃)₂C(OH)CN (nucleophilic addition, one carbon added).
Routes (a), (b) and (d) drawn as structures with the reagent and conditions over every arrow and the reaction type beneath it.
Exam focus: When a route branches, as in (b), the question usually asks for one product: read which, and give only that final step.
Quick Check: Which Proposed Route Works?
Pick the one route in each set that would work.
Worked Routes 2: Aromatic Targets and Choosing the Alcohol
Aromatic routes start from benzene. The ring is kept and its substituent is changed step by step; the order of steps decides where new groups go.
Route (d): benzene to N-phenylethanamide
Step 1. Benzene + concentrated HNO₃ and concentrated H₂SO₄ at about 50 °C (below 60 °C) → nitrobenzene (nitration, electrophilic substitution).
- Nitrate first, then reduce: phenylamine itself is too reactive to nitrate cleanly, and NH₂ directs new groups to the 2 and 4 positions. See Topic 30 Hydrocarbons.
- Protecting the amine as an amide (step 3) is used industrially before further ring substitution: the amide is less activating.
- Keep the nitration at about 50 °C, below 60 °C, to avoid dinitration.
Route (f): but-1-ene to butanone, and which alcohol forms
Remember: Which alcohol an unsymmetrical alkene gives decides the whole route: a secondary alcohol leads to a ketone, a primary alcohol to an aldehyde or acid.
Check: Writing Multi-Step Routes
Plan routes of two to 4 steps from a given start to a given target, name every intermediate and give the reagent, conditions and reaction type for each step.
Unfamiliar Reactions Given in the Question
Questions often supply a reaction you have not met, with its reagents and conditions. Treat it as one more arrow on the map and use it exactly as given.
- Read what the new reagent does to the functional group: which bond breaks, which forms, and whether the carbon count changes.
- Use the reagents and conditions printed in the question, word for word; do not swap in a familiar reagent.
- Apply the reaction to the molecule in the question, not to the example given: the same change on a different skeleton.
- Check the other groups in the molecule: would they react with the same reagent? A question may ask you to protect one.
Exam focus: Marks for an unfamiliar step go to applying the pattern correctly to the new molecule and keeping the reagents and conditions as printed.
Analysing a Given Route: Reaction Types and By-Products
A question may give a complete route and ask you to analyse it: name the type of reaction and the reagent at each step, and spot the by-products each step can give.
| Step in a route | Type of reaction | Possible by-product |
|---|---|---|
| acyl chloride + alcohol or amine | nucleophilic addition-elimination (acylation) | HCl fumes; with excess amine the amine salt |
| nitrile + dilute acid, reflux | hydrolysis | an ammonium salt, NH₄⁺ |
| halogenoalkane + KOH in ethanol, reflux | elimination | the alcohol by substitution alongside the alkene; two alkenes from an unsymmetrical halide |
| benzene + acyl chloride, AlCl₃ | electrophilic substitution (Friedel–Crafts) | polysubstitution of the ring, especially in alkylation |
| benzene + HNO₃/H₂SO₄ above 60 °C | electrophilic substitution (nitration) | dinitrobenzene |
| primary alcohol + K₂Cr₂O₇ / H₂SO₄, reflux | oxidation | the aldehyde if oxidation is incomplete; the acid if an aldehyde was wanted |
| halogenoalkane + NH₃ | nucleophilic substitution | secondary and tertiary amines and a quaternary salt |
Step 1. For each arrow write the reagent, the conditions and the type of reaction (substitution, addition, elimination, oxidation, reduction, hydrolysis, condensation).
Step 2. Ask what else the reagent could do to that molecule, and what small molecule is released: these are the by-products.
Exam focus: A by-product answer needs a named compound and a reason: “dinitrobenzene, because the temperature rose above 60 °C”, not just “side reactions”.
Chirality in Drug Synthesis
Many drug molecules are chiral: they have a carbon with four different groups and exist as two enantiomers (Optical Activity and Racemic Mixtures). The two enantiomers can behave differently in the body.
- Enzymes and receptors are themselves chiral, so one enantiomer may fit and act while the other is inactive or harmful. Thalidomide is the standard example.
- An ordinary synthesis, such as HCN adding to an aldehyde, attacks either face of the planar C=O equally and gives a racemic mixture.
- The racemic mixture must then be separated into the two pure enantiomers: resolution is costly and slow, and half of the product is the unwanted form.
- Modern routes use a chiral catalyst or an enzyme to make a single pure enantiomer, or start from a natural single-enantiomer compound.
| Approach | Advantage | Disadvantage |
|---|---|---|
| make the racemic mixture, then separate | simple reagents | extra separation step, half the material wasted, higher cost |
| chiral catalyst or enzyme | one enantiomer directly, less waste, lower dose, fewer side effects | catalyst must be developed for each reaction |
Why a single enantiomer is the aim: different activity of the two forms, the cost of separating a racemic mixture, and the chiral catalyst route.
Remember: Three points earn the marks: enantiomers can have different biological activity; a racemic product needs separating; a chiral catalyst gives a single enantiomer and avoids the waste.
Check: Analysing Routes and Unfamiliar Steps
Apply a reaction given in a question to a new molecule, complete a route with an unfamiliar step in it, and compare two routes to the same target.
Common Exam Points
- One arrow is one reaction: give the reagent AND the conditions for every step, and name the type of reaction.
- Count carbons first: one more carbon in the target means a nitrile step; the same count means functional group changes only.
- Oxidation of a primary alcohol: distil for the aldehyde, reflux for the carboxylic acid; a secondary alcohol gives a ketone under reflux.
- Aromatic routes: nitrate benzene at about 50 °C (below 60 °C), reduce nitrobenzene with Sn and concentrated HCl then NaOH, acylate phenylamine with an acyl chloride.
- Routes can have several steps; a shorter correct route is preferred when the question sets a limit.
- Unfamiliar reactions: use the reagents and conditions as printed and apply the same change to the molecule in the question.
- Analyse a given route by naming the reaction type and reagent at each step and the by-products: HCl from acyl chlorides, NH₄⁺ from nitrile hydrolysis, dinitration, polysubstitution.
- Enantiomers of a drug can differ in activity; a racemic product must be separated; a chiral catalyst gives one pure enantiomer.
- Show every intermediate by name or structure; a route with a missing intermediate loses the mark for that step.
FAQs
Use these quick answers to check how to plan a multi-step route from the reaction map, the order of steps in aromatic syntheses, the by-products to look for and why drugs are made as single enantiomers.
How do I start planning a synthetic route?
Compare the target with the starting material: which functional groups change, and does the carbon skeleton stay the same, gain a carbon or need a ring? Then work backwards step by step, asking which compound could make the target, until you reach the start.
How do I make ethanoic acid from ethene?
Two steps. Hydrate ethene with steam over a phosphoric(V) acid catalyst at about 300 °C and 60 atm to give ethanol. Then heat the ethanol under reflux with excess acidified potassium dichromate(VI), which oxidises it through ethanal to ethanoic acid.
In what order do I carry out the steps from benzene to N-phenylethanamide?
Nitrate first: concentrated nitric and sulfuric acids at about 50 °C give nitrobenzene. Reduce the nitro group with tin and concentrated hydrochloric acid under reflux, then add sodium hydroxide to free phenylamine. Finally react the amine with ethanoyl chloride to give N-phenylethanamide.
What by-products should I look for when I analyse a given route?
Acyl chloride steps release HCl; nitrile hydrolysis in acid gives an ammonium salt; ethanolic KOH causes elimination alongside substitution; Friedel–Crafts reactions can substitute the ring more than once; nitration above 60 °C gives dinitro compounds. Name each by-product and say why it forms.
Why does it matter whether a drug is made as a single enantiomer?
The two enantiomers of a chiral drug can have different biological activity; one may be harmful, as with thalidomide. A route giving a racemic mixture needs the enantiomers separating, which is costly and wastes half the product, so modern syntheses use chiral catalysts or enzymes.
Copyright notice: This OLS revision content, including the explanations, layout, diagrams, tables and embedded learning structure, is authored for Online Learning System by Dr. Mohammed Al-Fatah. It may not be copied, reproduced, redistributed or adapted without written permission.
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