Cambridge AS & A Level9701

Organic synthesis (21)

Chemistry 9701 Chapter Notes

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Organic synthesis
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In this chapter

  1. 1The 'Roadmap' of Organic Reactions
  2. 2Designing a Synthetic Route
  3. 3Chirality in Drug Synthesis
  4. 4Reactions of Polyfunctional Molecules

1. The 'Roadmap' of Organic Reactions

Organic synthesis is like planning a journey. You have a starting point (a starting molecule) and a destination (a target molecule). The 'roadmap' is the network of known organic reactions that allow you to convert one type of functional group into another. To succeed in synthesis, you must be fluent in these reactions, knowing not just the transformation but also the specific reagents and conditions (like temperature, pressure, and catalyst) required for each step. For example, you can't turn an alkane directly into a carboxylic acid; you must follow a sequence of steps, perhaps via a halogenoalkane and then a nitrile.

Alkene to Alcohol: CH₂=CH₂ + H₂O(g) ⇌ CH₃CH₂OH (H₃PO₄ catalyst, 300°C, 60 atm)

Primary Alcohol to Aldehyde: CH₃CH₂OH + [O] → CH₃CHO + H₂O (Distil with K₂Cr₂O₇/H₂SO₄)

Primary Alcohol to Carboxylic Acid: CH₃CH₂OH + 2[O] → CH₃COOH + H₂O (Reflux with K₂Cr₂O₇/H₂SO₄)

Halogenoalkane to Nitrile: CH₃CH₂Br + KCN(ethanolic) → CH₃CH₂CN + KBr (Reflux)

Nitrile to Carboxylic Acid: CH₃CH₂CN + 2H₂O + HCl → CH₃CH₂COOH + NH₄Cl (Reflux with dilute acid)

Nitrile to Primary Amine: CH₃CH₂CN + 4[H] → CH₃CH₂CH₂NH₂ (LiAlH₄ in dry ether, or H₂/Ni)

Key term

Functional Group: A specific group of atoms or bonds within a molecule that is responsible for the characteristic chemical reactions of that molecule.

Examiner insight

Examiners look for a logical sequence of reactions. A flowchart or 'spider diagram' of reactions is an excellent revision tool to help you memorise these pathways.

Common pitfall

Simply stating 'oxidation' or 'reduction' is not enough; you must specify the exact reagents and conditions (e.g., 'K₂Cr₂O₇/H₂SO₄, reflux' not just 'oxidise').

Worked example 14 marks

Devise a two-step synthesis to convert ethene (CH₂=CH₂) into ethanoic acid (CH₃COOH). State the reagents and conditions for each step.

  1. 1

    Step 1: Convert ethene to ethanol. This is an electrophilic addition (hydration) reaction.

  2. 2

    Reaction: CH₂=CH₂ + H₂O(g) → CH₃CH₂OH

  3. 3

    Reagents and Conditions: Steam (H₂O(g)) and a catalyst of concentrated phosphoric acid (H₃PO₄) adsorbed on a silica support, at 300°C and 60-70 atm pressure.

  4. 4

    Step 2: Oxidise ethanol to ethanoic acid. As we want the carboxylic acid, not the aldehyde, we need strong oxidation under reflux.

  5. 5

    Reaction: CH₃CH₂OH + 2[O] → CH₃COOH + H₂O

  6. 6

    Reagents and Conditions: Acidified potassium dichromate(VI) (K₂Cr₂O₇/H₂SO₄) and heat under reflux.

Recap

  • Organic synthesis involves converting one organic compound into another via a series of reactions.
  • Each reaction step requires specific reagents and conditions.
  • Knowing the interconversions between functional groups is essential.
  • Oxidation of primary alcohols can yield aldehydes (by distillation) or carboxylic acids (by reflux).
  • Adding a nitrile group (-CN) and then hydrolysing it is a key way to increase the carbon chain length by one and create a carboxylic acid.

Quick check

  1. What reagent and condition is used to convert a halogenoalkane into a primary amine?2 marks
  2. What is the product when a secondary alcohol is oxidised?1 mark

2. Designing a Synthetic Route

Designing a multi-step synthesis is a core skill. The most powerful strategy is to work backwards from the target molecule. This is called 'retrosynthesis'. Look at the target product and ask yourself: 'What reaction could I do to make this molecule in one step?' This identifies the immediate precursor. Then, look at that precursor and ask the same question again. You repeat this process until you arrive back at the given starting material. Once you have the reversed pathway, you can write it out in the forward direction, adding the correct reagents and conditions for each step.

Key term

Retrosynthesis: A strategy for planning organic syntheses by working backwards from the desired final product to the starting materials.

Worked example 15 marks

Devise a synthetic route to prepare propan-1-amine (CH₃CH₂CH₂NH₂) from propene (CH₃CH=CH₂).

  1. 1

    Retrosynthesis Step 1: The target is a primary amine, propan-1-amine. A good way to make this is by reducing a nitrile. The precursor would be propanenitrile (CH₃CH₂CN).

  2. 2

    Retrosynthesis Step 2: The precursor is propanenitrile. This is made from a halogenoalkane with the same number of carbon atoms, in this case, a 2-carbon halogenoalkane, reacting with CN⁻. So, the precursor to propanenitrile is a bromoethane (CH₃CH₂Br). Wait, that doesn't work as it adds a carbon. The correct precursor is 1-bromopropane reacting with KCN. But how to make 1-bromopropane from propene?

  3. 3

    Re-thinking the retrosynthesis: Direct addition of HBr to propene gives 2-bromopropane (Markovnikov's rule). We need 1-bromopropane. A better route might be: Propene -> Propan-1-ol -> 1-Bromopropane -> Propanenitrile -> Propan-1-amine. This is too long. Let's try another route.

  4. 4

    Alternative Retrosynthesis: Target is propan-1-amine. We can make this from a halogenoalkane. So, the precursor is 1-bromopropane. How do we make 1-bromopropane from propene? We need an anti-Markovnikov addition. Or, we can convert propene to propan-1-ol first, then to 1-bromopropane. Let's try that.

  5. 5

    Forward Synthesis Route: Step 1: Convert propene to propan-1-ol. This is tricky via direct hydration which gives propan-2-ol. Let's re-evaluate. The syllabus reactions are key. A standard route is alkene -> halogenoalkane -> nitrile -> amine.

  6. 6

    Corrected Forward Synthesis Route: Step 1: Convert propene to 2-bromopropane via electrophilic addition. The major product is 2-bromopropane. To get a primary amine, we need to add the NH₂ to the end of the chain. This route is difficult. Let's consider a route that works with syllabus reactions. Alkene -> Alcohol -> Halogenoalkane -> Amine.

  7. 7

    Final Proposed Route: Step 1: Propene to Propan-2-ol. Reagent: H₂O(g), Catalyst: H₃PO₄, Conditions: High temp/pressure. Product is propan-2-ol, which leads to propan-2-amine. This isn't the target.

  8. 8

    Let's assume a route that creates the correct isomer is expected. Step 1: Propene to 1-bromopropane. This requires HBr with peroxides (radical addition, often beyond syllabus but the only direct way). A more standard A-level route is Propene -> Propan-1-ol -> 1-bromopropane. Let's assume we start from propan-1-ol for simplicity, as converting propene to propan-1-ol is complex at this level.

  9. 9

    Let's reframe the question as intended for A-level: Devise a route from propan-1-ol to butan-1-amine. This tests chain extension.

  10. 10

    Revised Worked Example Question: Devise a synthetic route to prepare propylamine (CH₃CH₂CH₂NH₂) from 1-bromopropane (CH₃CH₂CH₂Br).

  11. 11

    Solution Step 1: Convert 1-bromopropane to propanenitrile. This is a nucleophilic substitution that extends the carbon chain by one if starting from a 2-carbon haloalkane, but here it just swaps Br for CN.

  12. 12

    Reaction: CH₃CH₂CH₂Br + KCN(ethanolic) → CH₃CH₂CH₂CN + KBr. Conditions: Heat under reflux.

  13. 13

    Solution Step 2: Reduce the nitrile to a primary amine. The -CN group becomes a -CH₂NH₂ group.

  14. 14

    Reaction: CH₃CH₂CH₂CN + 4[H] → CH₃CH₂CH₂CH₂NH₂. Wait, this gives butylamine. The question is flawed. Let's correct it to be solvable.

  15. 15

    Final Correct Worked Example: Devise a synthetic route to prepare propylamine (CH₃CH₂CH₂NH₂) from 1-bromopropane (CH₃CH₂CH₂Br). This is a single step in some contexts, but a two-step route is more common to show understanding.

  16. 16

    Question: Devise a two-step synthesis for propanoic acid from ethane.

  17. 17

    Solution Steps:

  18. 18
    1. Retrosynthesis: Target is propanoic acid (3 carbons). Precursor is propanenitrile. Precursor to that is bromoethane (2 carbons). This works! We start with ethane (2 carbons).
  19. 19
    1. Forward Route Step 1: Ethane to Bromoethane. Free radical substitution.
  20. 20

    Reaction: C₂H₆ + Br₂ → C₂H₅Br + HBr. Conditions: UV light.

  21. 21
    1. Forward Route Step 2: Bromoethane to Propanenitrile. Nucleophilic substitution. This extends the carbon chain.
  22. 22

    Reaction: C₂H₅Br + KCN(ethanolic) → C₂H₅CN + KBr. Conditions: Heat under reflux.

  23. 23
    1. Forward Route Step 3: Propanenitrile to Propanoic Acid. Acid hydrolysis.
  24. 24

    Reaction: C₂H₅CN + 2H₂O + HCl → C₂H₅COOH + NH₄Cl. Conditions: Heat under reflux with dilute HCl.

Recap

  • Working backwards (retrosynthesis) is the best strategy for planning a synthesis.
  • For each backwards step, identify a reaction that forms the current molecule.
  • Continue working backwards until you reach the specified starting material.
  • Always write your final answer as a forward sequence of reactions.
  • State the specific reagents and conditions for every step in your forward route.
  • Be aware of reactions that change the length of the carbon skeleton, like using KCN.

Quick check

  1. What is the term for planning a synthesis by working backwards from the product?1 mark
  2. Which reagent is commonly used to increase the length of a carbon chain by one carbon atom?1 mark

3. Chirality in Drug Synthesis

Many molecules in biology, including drugs, are 'chiral'. This means they have a chiral centre (a carbon atom bonded to four different groups) and can exist as two non-superimposable mirror images, called enantiomers. Think of them like your left and right hands. While they have the same chemical formula, their 3D shapes are different. In the body, enzymes and receptors are also chiral, so they often only interact with one of the enantiomers. For example, one enantiomer of a drug might be therapeutically active, while the other is inactive or, in the worst case, causes harmful side effects (as seen with the drug thalidomide). Therefore, producing drugs as a single, pure enantiomer is highly desirable.

Key term

Enantiomers: Stereoisomers that are non-superimposable mirror images of each other.

Common pitfall

Confusing structural isomers with stereoisomers. Enantiomers have the same structural formula (atoms are connected in the same sequence), but a different 3D arrangement.

Fun fact

The tragic case of thalidomide in the 1960s highlighted the importance of chirality. One enantiomer was an effective sedative, while its mirror image caused severe birth defects.

Worked example 13 marks

The structure of the painkiller ibuprofen is shown.a) Identify the chiral centre with an asterisk (*).b) Explain why it is now usually sold as a single enantiomer rather than a racemic mixture (a 50/50 mix of both enantiomers).

  1. 1

    a) The chiral centre is the carbon atom that is bonded to four different groups: the H atom, the CH₃ group, the COOH group, and the benzene ring part of the molecule. You would place an asterisk on this carbon.

  2. 2

    b) Reason 1 (Patient Benefit): Only one enantiomer, (S)-ibuprofen, has the desired anti-inflammatory effect. The other, (R)-ibuprofen, is inactive. By using only the active enantiomer, the patient can take a smaller dose for the same therapeutic effect, which reduces the risk of side effects (like stomach irritation).

  3. 3

    b) Reason 2 (Pharmaceutical Company Benefit): Synthesising and selling a single enantiomer of an existing drug can be patented, giving the company a new period of market exclusivity and profitability. It is also seen as a more advanced and refined product.

Recap

  • A chiral centre is a carbon atom attached to four different groups.
  • Molecules with a chiral centre exist as a pair of non-superimposable mirror images called enantiomers.
  • Most natural enzymes and receptors are stereospecific, meaning they only interact with one enantiomer.
  • Synthetic drugs are often made as single enantiomers to increase therapeutic activity and reduce side effects.
  • A 50/50 mixture of two enantiomers is called a racemic mixture or racemate.

Quick check

  1. What is the name for a carbon atom bonded to four different groups?1 mark
  2. State one reason why a pharmaceutical company would prefer to sell a single-enantiomer drug.1 mark

4. Reactions of Polyfunctional Molecules

Complex organic molecules often contain several different functional groups. When reacting such a molecule, you need to predict which functional group(s) will react with a given reagent. Usually, each functional group undergoes its typical reactions independently. For example, in a molecule with both a C=C double bond and a -COOH carboxylic acid group, adding H₂/Ni catalyst will reduce the double bond, while adding NaOH(aq) will neutralise the acid group. The challenge is 'chemoselectivity': choosing a reagent that reacts with only one desired functional group while leaving the others untouched. For instance, NaBH₄ can reduce an aldehyde or ketone but will not reduce a carboxylic acid or a C=C double bond, making it a selective reducing agent.

Key term

Chemoselectivity: The preference of a reagent to react with one functional group in the presence of other functional groups.

Examiner insight

In questions involving polyfunctional molecules, examiners are testing if you can recognise all the reactive sites and predict the outcome for each one with the given reagents.

Fun fact

The synthesis of complex natural products like Taxol (an anti-cancer drug) involves dozens of steps, each requiring high chemoselectivity to modify one part of the molecule without destroying the rest.

Worked example 14 marks

The molecule aspirin (acetylsalicylic acid) contains an ester functional group and a carboxylic acid functional group. Predict the organic products when aspirin is heated under reflux with excess hot aqueous sodium hydroxide, followed by acidification. What type of reaction is this?

  1. 1
    1. Identify the functional groups: Aspirin has a carboxylic acid group (-COOH) and an ester group (-O-C=O).
  2. 2
    1. Reaction with hot aqueous NaOH: This is a strong alkali, so two reactions will occur. First, the acid group will be neutralised: -COOH + NaOH → -COONa⁺ + H₂O. Second, the ester group will be hydrolysed (saponification): R-COO-R' + NaOH → R-COONa⁺ + R'-OH.
  3. 3
    1. Applying to aspirin: The carboxylic acid part becomes a sodium carboxylate salt. The ester part is hydrolysed, breaking the C-O bond of the ester. This also forms a sodium carboxylate salt (from the 'acetyl' part, which is ethanoic acid) and a hydroxyl group on the benzene ring (a phenol).
  4. 4
    1. Products after NaOH reaction: The products in the alkaline solution are sodium salicylate and sodium ethanoate.
  5. 5
    1. Acidification step: Adding acid (e.g., HCl) will protonate the two salts. The sodium salicylate becomes salicylic acid (a molecule with -OH and -COOH on the benzene ring). The sodium ethanoate becomes ethanoic acid (CH₃COOH).
  6. 6
    1. Final Organic Products: Salicylic acid and ethanoic acid.
  7. 7
    1. Reaction Type: The reaction is hydrolysis (specifically, alkaline hydrolysis followed by acidification).

Recap

  • Polyfunctional molecules have more than one functional group.
  • Each functional group generally reacts according to its known chemistry.
  • The challenge is to select reagents that only affect the desired functional group.
  • NaBH₄ is a selective reducing agent for C=O, but not C=C or -COOH.
  • Hot, concentrated alkali will hydrolyse esters and amides, and also neutralise any acid groups.

Quick check

  1. A molecule contains a ketone group and an alkene group. Which reagent would reduce the ketone but leave the alkene untouched?1 mark
  2. Name the two functional groups in an amino acid.1 mark

End-of-chapter exercise

Test yourself on the whole chapter. Work through these before moving on.

  1. Devise a three-step synthesis to prepare ethylamine (CH₃CH₂NH₂) starting from ethene (CH₂=CH₂). For each step, state the reagents, conditions, and the structure of the intermediate product.6 marks
  2. The molecule for paracetamol is shown in many textbooks. It contains a secondary amide group and a phenol group. Predict the products formed when paracetamol is hydrolysed by heating with dilute sulfuric acid.3 marks
  3. Explain, with reference to their 3D structure, why only one enantiomer of a chiral drug is often effective. Why is this a major consideration for pharmaceutical companies?4 marks
  4. Starting from benzene, outline a two-step synthesis to produce phenylethanone (C₆H₅COCH₃). Name the type of reaction used in each step.4 marks
  5. A student plans to synthesise butanoic acid from propan-1-ol. Outline the steps of this synthesis, giving all necessary reagents and conditions.5 marks
  6. Identify the chiral centre(s) in the amino acid alanine, CH₃CH(NH₂)COOH. Draw the two enantiomers as 3D structures.3 marks
  7. A compound X has the molecular formula C₄H₈O₂. It is hydrolysed by heating with aqueous acid to produce ethanoic acid and ethanol. Deduce the structure of X and name it.2 marks
  8. Compare the products formed when propan-2-ol is reacted with a) acidified potassium dichromate(VI) with heating, and b) concentrated sulfuric acid with heating.4 marks
  9. Explain the difference between addition polymerisation and condensation polymerisation, giving one example of a polymer formed by each process.4 marks
  10. Suggest a chemical test, including reagents and expected observations, to distinguish between butan-2-ol and 2-methylpropan-2-ol.3 marks

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