Organic Synthesis Routes

This lesson brings together the functional group chemistry covered throughout A-Level organic chemistry and applies it to the design of multi-step synthetic routes. You will learn how to plan conversions between functional groups, select appropriate reagents and conditions, calculate atom economy and percentage yield, and apply practical techniques such as reflux, distillation, and recrystallisation. Green chemistry principles are also introduced. This material is essential for the synoptic questions that appear at A-Level and for the Required Practical assessments.

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Functional Group Interconversions — The Synthesis Map

At A-Level, you must be able to convert between the major functional groups using the correct reagents and conditions. The table below summarises the key transformations:

Starting material	Target product	Reagents and conditions	Notes
Alkene	Alcohol	Steam (H₂O), H₃PO₄ catalyst, 300 °C, 60 atm	Hydration; industrial route to ethanol
Alkene	Halogenoalkane	HBr or HCl (gas or concentrated solution)	Electrophilic addition; Markownikoff's rule applies
Alkene	Diol	Cold, dilute KMnO₄ (alkaline)	Oxidative addition across C=C
Alkene	Dihalide	Br₂ (in organic solvent or as bromine water)	Electrophilic addition
Alkane	Halogenoalkane	Cl₂ or Br₂, UV light	Free radical substitution; mixture of products
Halogenoalkane	Alcohol	NaOH(aq), heat under reflux	Nucleophilic substitution
Halogenoalkane	Nitrile	KCN in ethanol/water, heat under reflux	Nucleophilic substitution; extends carbon chain by 1
Halogenoalkane	Primary amine	Excess NH₃ in ethanol, heat in sealed tube	Nucleophilic substitution
Halogenoalkane	Alkene	KOH in ethanol, heat	Elimination
Primary alcohol	Aldehyde	K₂Cr₂O₇/H₂SO₄, distil immediately	Controlled oxidation
Primary alcohol	Carboxylic acid	K₂Cr₂O₇/H₂SO₄, heat under reflux (excess oxidant)	Full oxidation
Secondary alcohol	Ketone	K₂Cr₂O₇/H₂SO₄, heat under reflux	Oxidation
Tertiary alcohol	No oxidation product	—	Resistant to oxidation
Alcohol	Alkene	Conc. H₃PO₄ or conc. H₂SO₄, heat	Elimination (dehydration)
Alcohol + carboxylic acid	Ester	Conc. H₂SO₄ catalyst, heat under reflux	Esterification (reversible)
Aldehyde	Primary alcohol	NaBH₄ in water/ethanol	Reduction
Ketone	Secondary alcohol	NaBH₄ in water/ethanol	Reduction
Carboxylic acid	Primary alcohol	LiAlH₄ in dry ether	Strong reduction
Ester	Alcohol + carboxylic acid/salt	Dilute H₂SO₄ (acid) or NaOH(aq) (base), reflux	Hydrolysis
Nitrile	Carboxylic acid	Dilute HCl or dilute NaOH, heat under reflux	Hydrolysis
Nitrile	Primary amine	LiAlH₄ in dry ether, or H₂/Ni catalyst	Reduction
Acyl chloride + alcohol	Ester	Room temperature, no catalyst	Goes to completion
Acyl chloride + amine	Amide	Room temperature	Goes to completion
Carboxylic acid	Acyl chloride	SOCl₂ (thionyl chloride)	Produces HCl and SO₂ as by-products
Benzene	Nitrobenzene	Conc. HNO₃ + conc. H₂SO₄, 50 °C	Electrophilic substitution (nitration)
Nitrobenzene	Phenylamine	Sn + conc. HCl, reflux; then NaOH	Reduction
Phenylamine	Diazonium salt	NaNO₂ + HCl, below 10 °C	Diazotisation
Diazonium salt + phenol	Azo dye	Coupling in NaOH(aq)	Electrophilic substitution on activated ring

graph TD
    ALK["Alkene"] -->|"H₂O/H₃PO₄, 300°C"| ALC["Alcohol"]
    ALK -->|"HBr"| HA["Halogenoalkane"]
    HA -->|"NaOH(aq), reflux"| ALC
    HA -->|"KCN, ethanol/water"| NIT["Nitrile<br/>(chain +1C)"]
    HA -->|"Excess NH₃, sealed tube"| AM["Primary Amine"]
    HA -->|"KOH in ethanol, heat"| ALK
    ALC -->|"K₂Cr₂O₇/H₂SO₄<br/>distil"| ALD["Aldehyde"]
    ALD -->|"K₂Cr₂O₇/H₂SO₄<br/>reflux"| CA["Carboxylic Acid"]
    ALC -->|"K₂Cr₂O₇/H₂SO₄<br/>reflux (excess)"| CA
    ALD -->|"NaBH₄"| ALC
    CA -->|"LiAlH₄, dry ether"| ALC
    CA -->|"SOCl₂"| ACL["Acyl Chloride"]
    ACL -->|"+ alcohol"| EST["Ester"]
    CA -->|"+ alcohol<br/>conc. H₂SO₄ catalyst"| EST
    NIT -->|"Dilute HCl/NaOH, reflux"| CA
    NIT -->|"LiAlH₄ or H₂/Ni"| AM

Exam Tip: Memorise this synthesis map thoroughly. In the exam, you may be given a starting material and a target molecule and asked to plan a multi-step route. Always state the reagents, conditions, and type of reaction for each step.

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Multi-Step Synthesis Planning

When planning a multi-step synthesis, it is often helpful to work backwards from the target molecule (retrosynthetic analysis):

1. Identify the functional group in the target molecule.
2. Ask: "What could I make this from in one step?" Identify the immediate precursor.
3. Repeat for the precursor until you reach the given starting material.
4. Write the route forwards, specifying reagents and conditions for each step.

graph RL
    A["TARGET MOLECULE<br/>Identify functional group"] -->|"What makes this<br/>in one step?"| B["Immediate Precursor"]
    B -->|"What makes THIS<br/>in one step?"| C["Earlier Precursor"]
    C -->|"Repeat until you<br/>reach..."| D["STARTING MATERIAL"]
    style A fill:#d4edda
    style D fill:#cce5ff

Worked Example 1: Propan-1-ol to Propanoic Acid to Propyl Propanoate

Target: Propyl propanoate (an ester, CH₃CH₂COOCH₂CH₂CH₃)

Starting material: Propan-1-ol (CH₃CH₂CH₂OH)

Retrosynthetic analysis:

Step backwards from the ester: propyl propanoate is formed from propanoic acid + propan-1-ol. We need propanoic acid.

Step backwards from propanoic acid: propanoic acid is formed by oxidation of propanal, which comes from oxidation of propan-1-ol.

Forward route:

Step 1: Oxidise propan-1-ol to propanoic acid.

Reagents: Excess K₂Cr₂O₇ / dilute H₂SO₄, heat under reflux.

CH₃CH₂CH₂OH + 2[O] → CH₃CH₂COOH + H₂O

Step 2: React propanoic acid with propan-1-ol to form the ester.

Reagents: Concentrated H₂SO₄ catalyst, heat under reflux.

CH₃CH₂COOH + CH₃CH₂CH₂OH ⇌ CH₃CH₂COOCH₂CH₂CH₃ + H₂O

Note: some of the propan-1-ol starting material is used in Step 1 and some is reserved for Step 2.

Worked Example 2: Ethanol to 2-Hydroxypropanenitrile (Extending the Carbon Chain)

Target: 2-Hydroxypropanenitrile, CH₃CH(OH)CN

Starting material: Ethanol, CH₃CH₂OH

Forward route:

Step 1: Oxidise ethanol to ethanal.

Reagents: K₂Cr₂O₇ / dilute H₂SO₄, distil immediately to collect the aldehyde.

CH₃CH₂OH + [O] → CH₃CHO + H₂O

Step 2: React ethanal with HCN (nucleophilic addition).

Reagents: KCN + dilute H₂SO₄ (HCN generated in situ for safety).

CH₃CHO + HCN → CH₃CH(OH)CN

This extends the chain from 2 carbons (ethanol) to 3 carbons (2-hydroxypropanenitrile). The nitrile can then be hydrolysed to 2-hydroxypropanoic acid (lactic acid) if desired.

Worked Example 3: Benzene to an Azo Dye

Target: An azo dye (e.g. 4-hydroxyazobenzene)

Starting material: Benzene, C₆H₆

Forward route:

Step 1: Nitrate benzene to form nitrobenzene.

Reagents: Conc. HNO₃ + conc. H₂SO₄, 50 °C.

Step 2: Reduce nitrobenzene to phenylamine.

Reagents: Sn + conc. HCl, heat under reflux; then add NaOH to liberate free amine.

Step 3: Diazotise phenylamine to form benzenediazonium chloride.

Reagents: NaNO₂ + dilute HCl, below 10 °C.

Step 4: Couple with phenol in alkaline solution.

Reagents: Phenol dissolved in NaOH(aq).

Product: 4-Hydroxyazobenzene (an orange azo dye).

graph LR
    A["Benzene<br/>C₆H₆"] -->|"Step 1: Nitration<br/>conc. HNO₃ + H₂SO₄<br/>50°C"| B["Nitrobenzene<br/>C₆H₅NO₂"]
    B -->|"Step 2: Reduction<br/>Sn + conc. HCl<br/>reflux, then NaOH"| C["Phenylamine<br/>C₆H₅NH₂"]
    C -->|"Step 3: Diazotisation<br/>NaNO₂ + HCl<br/>below 10°C"| D["Diazonium Salt<br/>C₆H₅N₂⁺Cl⁻"]
    D -->|"Step 4: Coupling<br/>Phenol in NaOH(aq)"| E["Azo Dye<br/>(orange)"]

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Practical Techniques in Organic Synthesis

Reflux