Synthetic Routes and Retrosynthesis
Synthetic Routes and Retrosynthesis
What Is Organic Synthesis?
Organic synthesis is the step-by-step construction of a target molecule from simpler starting materials, using a series of reactions with specified reagents and conditions. At A-Level, you need to be able to plan synthetic routes across the full range of organic reactions studied.
Retrosynthesis
Retrosynthesis (retrosynthetic analysis) is the strategy of working backwards from the target molecule to available starting materials. At each step, you ask: "What could this molecule have been made from?" and identify the bond that was formed in the last step.
The symbol ⇒ (a double-stemmed open arrow) represents a retrosynthetic step ("can be made from").
Key Functional Group Interconversions
The core of synthesis planning is knowing how to convert one functional group into another. Here is a summary of the major transformations:
From Alkanes
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Free radical substitution | X₂ (Cl₂ or Br₂), UV light | Halogenoalkane |
From Alkenes
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Electrophilic addition of HBr | HBr, room temperature | Halogenoalkane |
| Addition of H₂ | H₂, Ni catalyst, 150 °C | Alkane |
| Addition of H₂O (hydration) | H₂O, H₃PO₄ catalyst, 300 °C, 60 atm | Alcohol |
| Addition of Br₂ | Br₂ in organic solvent, room temperature | Dibromoalkane |
| Oxidation | Cold, dilute KMnO₄ | Diol |
| Polymerisation | High pressure, catalyst | Poly(alkene) |
From Halogenoalkanes
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Nucleophilic substitution (OH⁻) | NaOH(aq), reflux | Alcohol |
| Nucleophilic substitution (CN⁻) | KCN in ethanol/water, reflux | Nitrile (extends C chain by 1) |
| Nucleophilic substitution (NH₃) | Excess NH₃ in ethanol, sealed tube, heat | Primary amine |
| Elimination | NaOH in ethanol, reflux | Alkene |
From Alcohols
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Oxidation of primary alcohol | K₂Cr₂O₇/H₂SO₄, distil | Aldehyde |
| Oxidation of primary alcohol | K₂Cr₂O₇/H₂SO₄, reflux | Carboxylic acid |
| Oxidation of secondary alcohol | K₂Cr₂O₇/H₂SO₄, reflux | Ketone |
| Dehydration | Conc. H₂SO₄, 170 °C (or Al₂O₃ catalyst, heat) | Alkene |
| Substitution with HBr | NaBr/H₂SO₄, reflux | Halogenoalkane |
| Esterification | Carboxylic acid, conc. H₂SO₄ catalyst, reflux | Ester |
From Aldehydes
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Reduction | NaBH₄ in water/methanol | Primary alcohol |
| Oxidation | K₂Cr₂O₇/H₂SO₄, reflux | Carboxylic acid |
| Nucleophilic addition (HCN) | HCN + KCN catalyst | Hydroxynitrile |
From Nitriles
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Hydrolysis | Dilute HCl or NaOH, reflux | Carboxylic acid (+ NH₃/NH₄⁺) |
| Reduction | LiAlH₄ in dry ether, then H₂O | Primary amine (with extra CH₂) |
From Carboxylic Acids
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Esterification | Alcohol, conc. H₂SO₄ catalyst, reflux | Ester |
| Reduction | LiAlH₄ in dry ether | Primary alcohol |
| With SOCl₂ | SOCl₂ (thionyl chloride), room temp | Acyl chloride |
From Acyl Chlorides
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| With alcohol | R'OH, room temperature | Ester + HCl |
| With water | H₂O, room temperature | Carboxylic acid + HCl |
| With ammonia | NH₃ (excess), room temperature | Amide + NH₄Cl |
| With amine | R'NH₂ (excess), room temperature | N-substituted amide |
| Friedel-Crafts acylation | Benzene, AlCl₃ catalyst | Aryl ketone |
From Benzene
| Reaction | Reagents & Conditions | Product |
|---|---|---|
| Nitration | Conc. HNO₃ + conc. H₂SO₄, 50 °C | Nitrobenzene |
| Halogenation | Br₂, AlBr₃ catalyst | Bromobenzene |
| Friedel-Crafts alkylation | RCl, AlCl₃ catalyst | Alkylbenzene |
| Friedel-Crafts acylation | RCOCl, AlCl₃ catalyst | Aryl ketone |
Extending the Carbon Chain
A crucial skill in synthesis is knowing when and how to add carbon atoms:
- Nitrile synthesis: RBr + CN⁻ → RCN (adds 1 carbon). Hydrolysis gives RCOOH; reduction gives RCH₂NH₂.
- Nucleophilic addition of HCN to carbonyls: RCHO + HCN → RCH(OH)CN (adds 1 carbon).
- Grignard reagents (extension): RMgBr + R'CHO → secondary alcohol (adds the R chain to the carbonyl).
Worked Example: Synthesise Propanoic Acid from Ethanol
Target: CH₃CH₂COOH (3 carbons). Starting material: CH₃CH₂OH (2 carbons). Need to add 1 carbon.
Step 1: Convert ethanol to bromoethane
- Reagents: NaBr + conc. H₂SO₄, reflux
- CH₃CH₂OH → CH₃CH₂Br
Step 2: Introduce CN to extend the chain
- Reagents: KCN in ethanol/water, reflux
- CH₃CH₂Br + CN⁻ → CH₃CH₂CN + Br⁻
Step 3: Hydrolyse the nitrile to the carboxylic acid
- Reagents: dilute HCl, reflux
- CH₃CH₂CN + 2H₂O + HCl → CH₃CH₂COOH + NH₄Cl
Tips for Planning Synthetic Routes
1. Compare the target and starting material — count carbons (do you need to extend the chain?), identify which functional groups must be introduced or removed
2. Work backwards from the target — what is the last step? What immediate precursor gives the target?
3. Consider multiple routes — there may be more than one viable pathway; choose the one with fewest steps and highest selectivity
4. State reagents and conditions for every step — examiners require this
5. Watch stereochemistry — if a specific enantiomer is needed, consider which steps preserve or create chirality
Exam Tips
- Multi-step synthesis questions are worth many marks — draw out each intermediate clearly
- Always specify reagents, conditions (temperature, solvent, catalyst), and state whether you heat under reflux or distil
- If the carbon count changes, you almost certainly need a nitrile step
- When converting an alcohol to a halogenoalkane, state the specific reagent (NaBr/H₂SO₄, or SOCl₂, or PCl₅ — not just "HBr")
- For two-step oxidation of a primary alcohol (alcohol → aldehyde → acid), distinguish: distil immediately for aldehyde, reflux for acid