AQA A-Level› Organic Chemistry› 3.3.14 Organic Synthesis› Synthesis Routes
3.3.14

Designing Synthesis Routes

Planning multi-step organic synthesis pathways, retrosynthetic analysis, and functional group interconversions.

Designing multi-step organic synthesis pathways requires a systematic approach. You must integrate your knowledge of all organic reaction mechanisms, reagents, and conditions to map out the conversion of a starting material into a desired target molecule.

🔑 Key Principle

The core of designing synthesis routes lies in identifying the functional group changes needed and choosing selective reagents that avoid undesired side-reactions, all while maintaining the maximum possible atom economy and yield.

Retrosynthetic Analysis

Retrosynthetic analysis is the standard method for designing synthetic pathways. Instead of trying to build the target molecule forward from the starting material, you work backward: beginning with the target molecule and breaking it down step-by-step into simpler precursors (synthons or intermediates) until you reach readily available starting materials.

Retrosynthetic Analysis

A method of planning a chemical synthesis by working backwards from the target molecule to simpler precursor structures.

Target Molecule

The desired end product of a multi-step organic synthesis.

Synthesis Intermediate

A stable compound formed during one step of a multi-step reaction that is then used as a reactant in the subsequent step.

📝 AQA Examiner Tip

A crucial first step in any synthesis question is to count the number of carbon atoms in both the starting material and the target molecule. If the carbon chain increases in length, you must incorporate a carbon-carbon bond forming step. At A-Level, this typically means using KCN in ethanol to convert a halogenoalkane to a nitrile, or using HCN in nucleophilic addition with an aldehyde or ketone.

The Organic Synthesis Roadmap

The diagram below shows the major functional group interconversions required for the AQA specification, linking both aliphatic and aromatic chemistry pathways.

AQA Organic Synthesis Roadmap Functional Group Interconversions Alkene Halogenoalkane Nitrile Ketone / Aldehyde Alcohol Carboxylic Acid Primary Amine Benzene Nitrobenzene Phenylamine N-Phenylethanamide HBr (g) / room temp KOH in ethanol, reflux KCN in ethanol, reflux Steam, H3PO4, heat/press Conc. H2SO4, heat NaOH (aq), reflux NaBr + H2SO4 K2Cr2O7/H2SO4, distil/reflux NaBH4 (aq) K2Cr2O7/H2SO4, reflux Dilute HCl / H2O, reflux LiAlH4 in dry ether Excess NH3 in ethanol, heat Conc. HNO3 + conc. H2SO4, 50-60 °C Sn, conc. HCl, reflux then NaOH CH3COCl, R.T.
📝 AQA Examiner Tip

When stating the reagents for the conversion of nitrobenzene to phenylamine, you must mention both the metals and the acids: write Sn and concentrated HCl, followed by neutralisation with NaOH. Do not write "reduction" or "[H]" as the reagent, as you will lose marks.

Worked Examples of Synthesis Design

✏️ Worked Example 1
Plan a two-step synthesis to convert propene into propanone. Identify the intermediate, reagents, and conditions for each step.

Step 1: Convert propene (alkene) to propan-2-ol (secondary alcohol)

  • Reagents and Conditions: Steam (\(\text{H}_2\text{O(g)}\)), concentrated phosphoric acid (\(\text{H}_3\text{PO}_4\)) catalyst, high temperature (300 °C) and pressure (60 atm).
  • Intermediate: Propan-2-ol, \(\text{CH}_3\text{CH(OH)CH}_3\) (formed as the major product via electrophilic addition according to Markovnikov's rule).

Step 2: Convert propan-2-ol to propanone (ketone)

  • Reagents and Conditions: Acidified potassium dichromate(VI) (\(\text{K}_2\text{Cr}_2\text{O}_7 / \text{H}_2\text{SO}_4\)), heat under reflux.

Equations:

1. \(\text{CH}_3\text{CH=CH}_2 + \text{H}_2\text{O} \xrightarrow{\text{H}_3\text{PO}_4} \text{CH}_3\text{CH(OH)CH}_3\)

2. \(\text{CH}_3\text{CH(OH)CH}_3 + [\text{O}] \rightarrow \text{CH}_3\text{COCH}_3 + \text{H}_2\text{O}\)

✏️ Worked Example 2
Design a synthesis pathway to prepare propanoic acid starting from bromoethane. Outline the intermediate and the reagents/conditions for each step.

Analysis: Bromoethane has 2 carbons. Propanoic acid has 3 carbons. The carbon chain must increase by 1.

Step 1: Convert bromoethane to propanenitrile

  • Reagent and Conditions: Potassium cyanide (\(\text{KCN}\)) in ethanol/water solvent, heat under reflux.
  • Intermediate: Propanenitrile, \(\text{CH}_3\text{CH}_2\text{CN}\).

Step 2: Convert propanenitrile to propanoic acid

  • Reagent and Conditions: Dilute hydrochloric acid (\(\text{HCl(aq)}\)), heat under reflux (acidic hydrolysis).

Equations:

1. \(\text{CH}_3\text{CH}_2\text{Br} + \text{CN}^- \rightarrow \text{CH}_3\text{CH}_2\text{CN} + \text{Br}^-\)

2. \(\text{CH}_3\text{CH}_2\text{CN} + \text{HCl} + 2\text{H}_2\text{O} \rightarrow \text{CH}_3\text{CH}_2\text{COOH} + \text{NH}_4\text{Cl}\)

✏️ Worked Example 3
Outline a synthesis to prepare N-phenylethanamide starting from benzene. Show the structures of the intermediates and the reagents/conditions for all steps.

Step 1: Nitration of Benzene to Nitrobenzene

  • Reagents and Conditions: Concentrated nitric acid (\(\text{HNO}_3\)) and concentrated sulfuric acid (\(\text{H}_2\text{SO}_4\)) catalyst, heat at 50 to 55 °C.
  • Intermediate 1: Nitrobenzene, \(\text{C}_6\text{H}_5\text{NO}_2\).

Step 2: Reduction of Nitrobenzene to Phenylamine

  • Reagents and Conditions: Tin (\(\text{Sn}\)) and concentrated hydrochloric acid (\(\text{HCl}\)), heat under reflux, followed by the addition of sodium hydroxide (\(\text{NaOH}\)) solution to liberate the amine.
  • Intermediate 2: Phenylamine, \(\text{C}_6\text{H}_5\text{NH}_2\).

Step 3: Acylation of Phenylamine to N-phenylethanamide

  • Reagent and Conditions: Ethanoyl chloride (\(\text{CH}_3\text{COCl}\)), room temperature.

Equations:

1. \(\text{C}_6\text{H}_6 + \text{HNO}_3 \xrightarrow{\text{H}_2\text{SO}_4} \text{C}_6\text{H}_5\text{NO}_2 + \text{H}_2\text{O}\)

2. \(\text{C}_6\text{H}_5\text{NO}_2 + 6[\text{H}] \rightarrow \text{C}_6\text{H}_5\text{NH}_2 + 2\text{H}_2\text{O}\)

3. \(\text{C}_6\text{H}_5\text{NH}_2 + \text{CH}_3\text{COCl} \rightarrow \text{C}_6\text{H}_5\text{NHCOCH}_3 + \text{HCl}\)

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