Organic Synthesis (AS Level) - The Chemical Construction Game

Hello future chemists! Welcome to Organic Synthesis. Don't worry, this isn't a chapter full of brand new reactions. Instead, it's the chapter where you put on your architect hat and learn how to link all the reactions you studied on alkenes, alcohols, and halogenoalkanes into one big, strategic plan.

Think of learning individual reactions as learning how to use individual Lego bricks. Organic synthesis is the skill of taking those bricks and building a complex structure—a new molecule! This skill is essential for producing everything from common plastics to life-saving pharmaceuticals.

Key Learning Objectives (The Goal)

  • Identify all functional groups in a complex molecule.
  • Predict the outcome of a reaction based on the functional groups present.
  • Devise multi-step synthetic routes (chemical pathways).
  • Analyse and understand a given synthetic route.

1. The Synthesis Mindset: Working Backwards

When you are asked to design a synthetic route (a chemical pathway) to make a molecule, the worst thing you can do is stare at the starting material and guess the first step. The secret weapon of every organic chemist is Retrosynthesis.

What is Retrosynthesis?

Retrosynthesis means working backwards from your Target Molecule (the one you want to make) to your Starting Material (the one you are given).

Analogy: Imagine you want to climb a tall mountain (your target molecule). It's easier to start at the top and figure out the step just before the top, then the step before that, and so on, until you reach the ground (your starting material).

Step-by-Step Strategy:

  1. Look at the Target Molecule. What is its main functional group?
  2. Identify the reaction that creates this functional group in the *last step*. What precursor molecule would you need?
  3. Look at that precursor molecule. How can you make *that* from the step before?
  4. Repeat this process until the precursor required is your Starting Material.

Memory Tip: Always use a long arrow, sometimes with two lines (\(\rightarrow\)), to represent a multi-step synthesis route. Clearly state the reagents and conditions above and below the arrow for *each* step.

2. The AS Organic Reaction Toolkit

The core challenge of synthesis is knowing exactly which reaction converts Functional Group A to Functional Group B. Here is a summary of the most useful AS conversions (Topics 14-19).

Quick Review: Functional Group Conversions

A. Alkenes (\(\text{C=C}\)) - The Starting Point

Alkenes are highly versatile because the \(\pi\) bond makes them susceptible to electrophilic addition.

  • Alkene \(\rightarrow\) Alkane: Hydrogenation. Reagent: \(\text{H}_2\). Conditions: \(\text{Pt}\) or \(\text{Ni}\) catalyst, heat. (Addition)
  • Alkene \(\rightarrow\) Halogenoalkane: Add hydrogen halide. Reagent: \(\text{HX}(\text{g})\). Conditions: Room temperature. (Addition, follow Markovnikov's Rule)
  • Alkene \(\rightarrow\) Alcohol: Add steam. Reagent: \(\text{H}_2\text{O}(\text{g})\). Conditions: \(\text{H}_3\text{PO}_4\) catalyst, heat. (Electrophilic Addition)
  • Alkene \(\rightarrow\) Diol: Mild oxidation. Reagent: Cold, dilute, acidified \(\text{KMnO}_4\). Conditions: Cold, dilute acid. (Addition, the purple \(\text{KMnO}_4\) decolourises to brown precipitate)
B. Halogenoalkanes (\(\text{R-X}\)) - The Conversion Hub

Halogenoalkanes typically undergo nucleophilic substitution or elimination reactions.

  • Halogenoalkane \(\rightarrow\) Alcohol: Nucleophilic substitution (hydrolysis). Reagent: \(\text{NaOH}(\text{aq})\) or \(\text{KOH}(\text{aq})\). Conditions: Heat.
  • Halogenoalkane \(\rightarrow\) Alkene: Elimination. Reagent: \(\text{NaOH}\) or \(\text{KOH}\) in ethanol. Conditions: Heat. (The key is using ethanolic base, not aqueous!)
  • Halogenoalkane \(\rightarrow\) Nitrile: Reagent: \(\text{KCN}\) in ethanol. Conditions: Heat. (This adds a carbon atom—a chain lengthening step!)
  • Halogenoalkane \(\rightarrow\) Amine: Reagent: Excess \(\text{NH}_3\) in ethanol. Conditions: Heat under pressure.
C. Alcohols (\(\text{R-OH}\)) - Oxidation and Reduction

Alcohols are defined by their classification (Primary, Secondary, Tertiary), which determines their oxidation pathway.

  • Alcohol \(\rightarrow\) Halogenoalkane: Substitution. Reagent: \(\text{HBr}\), \(\text{PCl}_5\), or \(\text{SOCl}_2\). Conditions: Heat (varies).
  • Primary Alcohol \(\rightarrow\) Aldehyde: Partial oxidation. Reagent: Acidified \(\text{K}_2\text{Cr}_2\text{O}_7\). Conditions: Distillation (to remove aldehyde before further oxidation).
  • Primary Alcohol \(\rightarrow\) Carboxylic Acid: Full oxidation. Reagent: Acidified \(\text{K}_2\text{Cr}_2\text{O}_7\). Conditions: Reflux (ensuring all is oxidised).
  • Secondary Alcohol \(\rightarrow\) Ketone: Oxidation (cannot be oxidised further). Reagent: Acidified \(\text{K}_2\text{Cr}_2\text{O}_7\). Conditions: Reflux.
  • Alcohol \(\rightarrow\) Alkene: Dehydration (elimination). Reagent: Excess concentrated \(\text{H}_2\text{SO}_4\) or heated \(\text{Al}_2\text{O}_3\). Conditions: Heat.
D. Carbonyls (\(\text{C=O}\)) and Nitriles (\(\text{C}\equiv\text{N}\))

These groups allow you to move between alcohols and carboxylic acids.

  • Aldehyde/Ketone \(\rightarrow\) Alcohol: Reduction. Reagent: \(\text{NaBH}_4\) (sodium tetrahydridoborate). (Mild reducing agent)
  • Aldehyde/Ketone \(\rightarrow\) Hydroxynitrile: Addition. Reagent: \(\text{HCN}\), \(\text{KCN}\) catalyst. Conditions: Heat. (This is another chain lengthening step!)
  • Carboxylic Acid \(\rightarrow\) Primary Alcohol: Strong reduction. Reagent: \(\text{LiAlH}_4\) (Lithium tetrahydridoaluminate) in dry ether. (Note: \(\text{NaBH}_4\) is too weak for carboxylic acids!)
  • Nitrile \(\rightarrow\) Carboxylic Acid: Hydrolysis. Reagent: Dilute acid (\(\text{H}_2\text{SO}_4(\text{aq})\)) or dilute alkali (\(\text{NaOH}(\text{aq})\)) followed by acidification. Conditions: Heat.
  • Nitrile \(\rightarrow\) Amine: Reduction. Reagent: \(\text{LiAlH}_4\) or \(\text{H}_2/\text{Ni}\).
Quick Review Box: The Magic Reagents for AS Synthesis

Struggling students often confuse these conditions. Focus on these distinctions:

  • \(\text{NaOH}(\text{aq})\) + Heat: Substitution (Halogenoalkane $\rightarrow$ Alcohol).
  • \(\text{NaOH}(\text{ethanolic})\) + Heat: Elimination (Halogenoalkane $\rightarrow$ Alkene).
  • Acidified \(\text{K}_2\text{Cr}_2\text{O}_7\): Oxidation. Use Distillation for Aldehyde. Use Reflux for Carboxylic Acid or Ketone.
  • \(\text{LiAlH}_4\): Strongest reducing agent (Carboxylic Acid $\rightarrow$ Alcohol).
  • \(\text{NaBH}_4\): Milder reducing agent (Aldehyde/Ketone $\rightarrow$ Alcohol).

3. Devising Multi-Step Synthetic Routes

Now let's apply the Retrosynthesis strategy to a common exam-style problem.

Example Route: Propane to Propanenitrile (A 2-Step Synthesis)

Target Molecule: $\text{CH}_3\text{CH}_2\text{C}\equiv\text{N}$ (Propanenitrile). Note: This molecule has 3 carbon atoms.

Starting Material: $\text{CH}_3\text{CH}_3$ (Ethane). Note: This molecule has 2 carbon atoms.

Wait! The target has more carbons than the starting material. This MUST involve a chain-lengthening step. The AS syllabus only has two ways to add a carbon atom: the use of $\text{KCN}$ to form a nitrile, or the use of Friedel-Crafts acylation/alkylation (which is A-Level arene chemistry, so we stick to KCN).

Working Backwards (Retrosynthesis):

Step R2: Final Step (\(\text{Precursor} \rightarrow \text{Propanenitrile}\))

How do we make a nitrile ($\text{R-C}\equiv\text{N}$)?

We use nucleophilic substitution of a halogenoalkane ($\text{R-X}$) using \(\text{KCN}\).

Therefore, the precursor must be a Halogenoalkane with two carbons: Chloroethane ($\text{CH}_3\text{CH}_2\text{Cl}$) or Bromoethane ($\text{CH}_3\text{CH}_2\text{Br}$).

Step R1: First Step (\(\text{Ethane} \rightarrow \text{Halogenoalkane}\))

How do we turn the starting material Ethane ($\text{CH}_3\text{CH}_3$) into a Halogenoalkane ($\text{CH}_3\text{CH}_2\text{X}$)?

We use Free-Radical Substitution.

Therefore, $\text{Ethane} \rightarrow \text{Halogenoalkane}$ is the first step.

Writing the Synthesis Route (Working Forwards):

Step 1: Free-Radical Substitution

\(\text{CH}_3\text{CH}_3 + \text{Cl}_2 \rightarrow \text{CH}_3\text{CH}_2\text{Cl} + \text{HCl}\)

Reagents/Conditions: $\text{Cl}_2$ (or $\text{Br}_2$), Ultraviolet (UV) light.

Step 2: Nucleophilic Substitution (Chain Lengthening)

\(\text{CH}_3\text{CH}_2\text{Cl} + \text{KCN} \rightarrow \text{CH}_3\text{CH}_2\text{C}\equiv\text{N} + \text{KCl}\)

Reagents/Conditions: $\text{KCN}$ in ethanol, heat.

Common Mistake Alert!

When you see a change in the carbon chain length (e.g., from 2 carbons to 3), you must use one of the carbon-adding reactions, usually reaction with $\text{KCN}$. If you forget the KCN step, your carbon count will be wrong!

4. Analysis of Synthetic Routes

The syllabus also requires you to analyze a given route. This means identifying three things for every arrow in the reaction scheme:

  1. The Type of Reaction (e.g., Oxidation, Nucleophilic Substitution, Elimination).
  2. The exact Reagents and Conditions.
  3. Possible By-products (though usually focusing on the main organic product).

Focus on Reaction Types

It is crucial to use the correct terminology from Topic 13.2 when describing the reaction types:

  • Substitution: An atom or group is replaced by another atom or group.
    • Examples: Free-radical substitution (alkanes), Nucleophilic substitution (halogenoalkanes).
  • Addition: Atoms are added across a double bond, resulting in a saturated molecule.
    • Examples: Electrophilic addition (alkenes), Nucleophilic addition (carbonyls).
  • Elimination: A small molecule (like \(\text{H}_2\text{O}\) or \(\text{HX}\)) is removed from a molecule, resulting in an unsaturated product (often an alkene).
    • Examples: Dehydration of alcohols, elimination of \(\text{HX}\) from halogenoalkanes.
  • Hydrolysis: Breaking a bond using water (or acid/alkali).
    • Examples: Hydrolysis of esters, nitriles, or halogenoalkanes.
  • Oxidation/Reduction:
    • Oxidation: Increase in C-O bonds or decrease in C-H bonds (e.g., alcohol to aldehyde). Reagents often include $\text{[O]}$ (like $\text{K}_2\text{Cr}_2\text{O}_7$).
    • Reduction: Decrease in C-O bonds or increase in C-H bonds (e.g., aldehyde to alcohol). Reagents often include $\text{[H]}$ (like $\text{NaBH}_4$).

The Challenge of Multi-Functional Groups

In the A-Level extension of synthesis (which is often tested in AS synthesis problems), you may encounter molecules with multiple functional groups. Your task is to select a reagent that reacts selectively with only *one* of those groups.

Did you know? Many real drugs contain multiple functional groups. Chemists often have to protect one group with a ‘guard’ chemical so that the reagent only attacks the desired part of the molecule!

Example: Reducing a molecule containing both an aldehyde ($\text{C=O}$) and a $\text{C=C}$ double bond.

  • If you use \(\text{H}_2/\text{Ni}\), both the aldehyde and the $\text{C=C}$ bond will be reduced.
  • If you use \(\text{NaBH}_4\), only the aldehyde will be reduced (to an alcohol), leaving the $\text{C=C}$ bond untouched. This is selective reduction.
Key Takeaway for Organic Synthesis

Mastering synthesis is about rote memorisation AND clever strategy. Always use Retrosynthesis (working backward from the product) and memorize the functional group interconversions and their specific reagents/conditions. The ability to switch between functional groups is the heart of organic chemistry.