Topic 20 · page 10 of 15

Planning a route

Compare the carbon count and the functional groups of the start and the target, work backwards from the target using the reaction maps, and write each step as a reagent, a condition and a named product. Unfamiliar reactions come with the information to use them.

15 min read20.3(ii)

Read first: The reaction map

Work backwards 20.3(ii)

A synthesis question may ask for up to four steps. You do not need to remember a route. You find it, using the same maps every time.

MethodPlanning a synthesis

  1. Compare the start and the target. Count the carbon atoms and name the functional groups.
  2. Carbon count. If the target has more carbons, choose a step that adds carbon: KCN, HCN, or a Grignard reagent.
  3. Work backwards. Ask: what makes the target in one step? Then what makes that compound? Stop when you reach the starting compound.
  4. Write each step in order: reagent, conditions, named product.
  5. Check that no reagent attacks another group in the molecule, and that the route has no more than four steps.

Worked exampleEthene to propanoic acid

Ethene has two carbons and propanoic acid has three, so a C–C bond must be made.

  1. Working backwards: propanoic acid is made from a nitrile (hydrolysis) or from a Grignard reagent with CO₂. The nitrile, propanenitrile, is made from bromoethane with KCN. Bromoethane is made from ethene with HBr.
  2. Step 1: ethene with HBr at room temperature gives bromoethane.
  3. Step 2: bromoethane with KCN in ethanol, heated under reflux, gives propanenitrile, CH₃CH₂CN.
  4. Step 3: propanenitrile heated under reflux with dilute HCl gives propanoic acid, CH₃CH₂COOH.
Two routes from ethene to propanoic acid. Route A: ethene with HBr at room temperature gives bromoethane; with KCN in ethanol under reflux this gives propanenitrile; with dilute HCl under reflux this gives propanoic acid. Route B: ethene with HBr gives bromoethane; with magnesium in dry ether this gives ethylmagnesium bromide; with carbon dioxide in dry ether and then dilute acid this gives propanoic acid.
Two three-step routes. Both go through bromoethane and add one carbon. Route B avoids cyanide.

The second route, through the Grignard reagent, is also three steps. Both routes score full marks if every reagent and condition is correct.

Worked exampleEthanol to propylamine

Ethanol has two carbons and propylamine has three, so the route needs the cyanide step.

  1. Step 1: ethanol with PCl₅ at room temperature gives chloroethane.
  2. Step 2: chloroethane with KCN in ethanol, heated under reflux, gives propanenitrile.
  3. Step 3: propanenitrile with LiAlH₄ in dry ether gives propylamine, CH₃CH₂CH₂NH₂.

Worked exampleEthene to 2-hydroxypropanoic acid, four steps

  1. Step 1: ethene with steam, H₃PO₄ catalyst, high temperature and pressure gives ethanol.
  2. Step 2: ethanol with acidified K₂Cr₂O₇, heated and distilled as the product forms, gives ethanal, CH₃CHO.
  3. Step 3: ethanal with HCN and a little KCN gives 2-hydroxypropanenitrile, CH₃CH(OH)CN. This step adds the carbon.
  4. Step 4: heat under reflux with dilute HCl to hydrolyse the nitrile: 2-hydroxypropanoic acid, CH₃CH(OH)COOH.

Worked examplePropan-1-ol to propyl propanoate

The ester is made from propanoic acid and propan-1-ol, so only part of the alcohol is oxidised.

  1. Step 1: oxidise some of the propan-1-ol with excess acidified K₂Cr₂O₇, heating under reflux, to give propanoic acid.
  2. Step 2: heat the acid under reflux with more propan-1-ol and a few drops of concentrated H₂SO₄ to give propyl propanoate.

Unfamiliar reactions 20.3(ii)

Some steps in a question are not in the specification. The question gives you the information. Read it, find the group that changes, and apply it to the compound in front of you.

Worked exampleMaking aspirin from methyl 2-hydroxybenzoate

Information given. Alcohols and phenols react with ethanoic anhydride, (CH₃CO)₂O, to form ethanoate esters, –OCOCH₃, and ethanoic acid.

Task. Make aspirin (2-ethanoyloxybenzoic acid) from methyl 2-hydroxybenzoate in two steps.

  1. Compare the two compounds. The start has –COOCH₃ and –OH. Aspirin has –COOH and –OCOCH₃. The ester has become an acid, and the phenol –OH has become an ethanoate ester.
  2. Step 1 is a reaction you know: hydrolysis of an ester. Heat under reflux with NaOH(aq), then add dilute HCl. This gives 2-hydroxybenzoic acid. The acid is needed to turn the sodium salt back into –COOH.
  3. Step 2 uses the information given: the –OH reacts with ethanoic anhydride (with an H₃PO₄ catalyst, warm) to give aspirin and ethanoic acid.
A two-step route drawn with skeletal formulae. Methyl 2-hydroxybenzoate has a methyl ester group and an OH group on neighbouring carbons of a benzene ring. Heating with sodium hydroxide solution under reflux and then adding dilute hydrochloric acid gives 2-hydroxybenzoic acid, with a carboxylic acid group and an OH group. Ethanoic anhydride with phosphoric acid catalyst then gives aspirin, with a carboxylic acid group and an ethanoate ester group.
Step 1 is ester hydrolysis, step 2 uses the information in the question. The ring positions of the two groups do not change.

Worked exampleUsing information on amines

Information given. Primary amines react with ethanoic anhydride to form N-substituted amides, –NHCOCH₃, and ethanoic acid.

Task. Make N-phenylethanamide from nitrobenzene in two steps.

  1. The start has –NO₂ on a ring; the target has –NHCOCH₃. The nitrogen is already attached, but it must first become –NH₂.
  2. Step 1: tin and concentrated HCl, heat under reflux, then excess NaOH(aq): phenylamine.
  3. Step 2: phenylamine with ethanoic anhydride, as in the information: N-phenylethanamide, CX6HX5NHCOCHX3\ce{C6H5NHCOCH3}.

Check yourself

  1. Plan a three-step synthesis of butylamine from propan-1-ol. Give reagents, conditions and each intermediate.
  2. Plan a two-step synthesis of 2-hydroxypropanoic acid from ethanal.
  3. Using bromoethane and ethanal as the only organic compounds, plan a route to butan-2-ol.
  4. Plan a three-step synthesis of propanoic acid from ethanol.
  5. Information: primary amines react with ethanoic anhydride to form N-substituted amides and ethanoic acid. Plan a two-step synthesis of N-phenylethanamide from nitrobenzene, showing which step uses the information.
  6. A student suggests turning ethanol into propylamine by converting it to chloroethane and heating that with ammonia. Explain why this fails and give a correct step.

Answers cover these until you have tried the questions

  1. Step 1: propan-1-ol with KBr and 50% H₂SO₄, heat under reflux, gives 1-bromopropane. Step 2: KCN in ethanol, heat under reflux, gives butanenitrile, CH₃CH₂CH₂CN. Step 3: LiAlH₄ in dry ether gives butylamine. (3 C to 4 C: the nitrile step adds the carbon.)
  2. Step 1: HCN with a little KCN gives 2-hydroxypropanenitrile. Step 2: dilute HCl, heat under reflux, gives 2-hydroxypropanoic acid.
  3. Step 1: bromoethane with Mg in dry ether gives ethylmagnesium bromide. Step 2: add ethanal in dry ether, then dilute acid, to give butan-2-ol, CH₃CH(OH)CH₂CH₃. (2 C + 2 C = 4 C.)
  4. Step 1: ethanol with PCl₅ gives chloroethane. Step 2: KCN in ethanol, reflux, gives propanenitrile. Step 3: dilute HCl, reflux, gives propanoic acid.
  5. Step 1: tin and concentrated HCl, heat under reflux, then excess NaOH(aq), reduces nitrobenzene to phenylamine. Step 2 uses the information: phenylamine with ethanoic anhydride gives N-phenylethanamide and ethanoic acid.
  6. Ammonia would substitute the chlorine and give ethylamine, CH₃CH₂NH₂, which has two carbons, not three. The route needs one more carbon. Use KCN in ethanol, heat under reflux, to give propanenitrile, then LiAlH₄ in dry ether to give propylamine.