Organic Synthesis Revision Notes for OCR A-Level Chemistry A

Further Synthetic Routes

Introduction

This topic brings together all the functional group chemistry you've studied throughout your organic chemistry course. You'll learn to identify multiple functional groups within complex molecules and plan multi-step synthetic routes to prepare target compounds from simple starting materials.

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Mastering synthetic routes requires combining knowledge from all areas of organic chemistry. Think of it as putting together a puzzle where each functional group transformation is a piece that connects to others.

Identifying functional groups in organic molecules

Being able to recognize functional groups within large molecules is essential for understanding their chemistry and planning synthesis routes. This skill forms the foundation of organic synthesis - you must identify where you're starting and where you need to go before planning your route.

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Worked Example: Aspartame

Aspartame is an artificial sweetener used in many food products. Its structure contains multiple functional groups that determine its properties:

The molecule contains:

An ester group ( $\ce{-COO-}$ ) on the left side
An amide group ( $\ce{-CONH-}$ ) in the centre, linking two parts of the molecule
An amine group ( $\ce{-NH2}$ ) attached to the carbon chain
A carboxylic acid group ( $\ce{-COOH}$ ) on the right side
A benzene ring (phenyl group) attached via a $\ce{-CH2-}$ bridge

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Worked Example: Capsaicin

Capsaicin is the compound responsible for the heat in chili peppers. Identifying its functional groups:

The molecule contains:

A phenol group (benzene ring with $\ce{-OH}$ attached) highlighted in orange
An ether group ( $\ce{-OCH3}$ , a methoxy substituent) highlighted in green
An amide group ( $\ce{-CONH-}$ ) highlighted in blue
An alkene group ( $\ce{C=C}$ double bond) highlighted in orange

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The ether group is beyond the scope of the A-Level specification but is included here for completeness. Focus on the functional groups you need to know: phenol, amide, and alkene.

The reactions of the main functional groups

Understanding how functional groups can be interconverted is crucial for planning synthetic routes. The comprehensive flow chart below maps out all the key transformations:

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Learn this flowchart thoroughly! It shows all the possible conversions between functional groups. When planning a synthesis, ask yourself: "Can I get from functional group A to functional group B directly, or do I need intermediate steps?"

Key transformations to remember

Alkene reactions:

Addition of hydrogen halide ( $\ce{HX}$ ) produces a haloalkane
Hydration with $\ce{H3PO4/H2O}$ produces a primary alcohol
Reaction with $\ce{H2SO4}$ also produces an alcohol

Haloalkane reactions:

Reaction with aqueous $\ce{NaOH}$ produces a primary alcohol
Reaction with $\ce{NaCN}$ in ethanol produces a nitrile (chain extension by one carbon)

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Nitrile formation is your go-to method for chain extension! Remember that $\ce{NaCN}$ adds one carbon atom to your chain.

Primary alcohol reactions:

Oxidation with $\ce{K2Cr2O7/H2SO4}$ produces an aldehyde (partial oxidation) or carboxylic acid (complete oxidation under reflux)
Reduction with $\ce{NaBH4/H2O}$ can reverse aldehyde back to alcohol
Esterification with carboxylic acid and $\ce{H2SO4}$ catalyst produces an ester

Aldehyde reactions:

Further oxidation with $\ce{K2Cr2O7/H+}$ produces a carboxylic acid
Nucleophilic addition with $\ce{NaCN/H+}$ produces a hydroxynitrile (chain extension)
Reduction with $\ce{NaBH4/H2O}$ produces a primary alcohol

Carboxylic acid reactions:

Esterification with alcohol and $\ce{H2SO4}$ produces an ester
Reaction with $\ce{SOCl2}$ (thionyl chloride) produces an acyl chloride
Reaction with $\ce{NH3}$ produces a primary amide (via acyl chloride intermediate)

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Acyl chlorides are highly reactive intermediates. They're the key to making both amides and esters from carboxylic acids efficiently.

Acyl chloride reactions:

Reaction with $\ce{NH3}$ produces a primary amide
Reaction with primary amine produces a secondary amide
Reaction with alcohol produces an ester

Ester reactions:

Hydrolysis with $\ce{NaOH(aq)}$ (alkaline conditions) produces sodium salt of carboxylic acid and alcohol
Hydrolysis with dilute acid produces carboxylic acid and alcohol

Nitrile reactions:

Reduction with $\ce{H2/Ni}$ or $\ce{LiAlH4}$ produces a primary amine (chain extended by one carbon)
Hydrolysis with $\ce{H2O/HCl}$ produces a carboxylic acid (chain extended by one carbon)

The reactions of benzene and its derivatives

Benzene undergoes electrophilic aromatic substitution reactions. Understanding these transformations is essential for aromatic synthesis:

Key benzene reactions

Nitration:

Reagents: Concentrated $\ce{HNO3}$ and concentrated $\ce{H2SO4}$
Product: Nitrobenzene
The $\ce{H2SO4}$ acts as a catalyst to generate the $\ce{NO2+}$ electrophile

Alkylation (Friedel-Crafts):

Reagents: Alkyl halide (e.g., $\ce{CH3Cl}$ ) with $\ce{AlCl3}$ catalyst
Product: Methylbenzene (toluene)
$\ce{AlCl3}$ is a halogen carrier that helps generate the electrophile

Acylation (Friedel-Crafts):

Reagents: Acyl chloride (e.g., $\ce{CH3COCl}$ ) with $\ce{AlCl3}$ catalyst
Product: Ketone (e.g., acetophenone/phenylethanone)
More reliable than alkylation as it avoids polysubstitution

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Friedel-Crafts acylation is preferred over alkylation because it stops after one substitution. Alkylation can continue to give multiple substitutions, making the product mixture difficult to separate.

Halogenation:

Chlorination: $\ce{Cl2}$ with $\ce{AlCl3}$ catalyst produces chlorobenzene
Bromination: $\ce{Br2}$ with $\ce{FeBr3}$ catalyst produces bromobenzene
The halogen carrier catalysts are essential for these reactions

Reactions of benzene derivatives

Reduction of nitrobenzene:

Reagents: $\ce{Sn}$ and concentrated $\ce{HCl}$ , followed by neutralisation
Alternative: $\ce{H2}$ with nickel catalyst
Product: Aniline (phenylamine)

Tribromination of aniline:

Reagents: $\ce{Br2(aq)}$ at room temperature (no catalyst needed)
Product: 2,4,6-tribromoaniline
The $\ce{-NH2}$ group activates the benzene ring strongly

chatImportant

Notice that aniline reacts with bromine water WITHOUT a catalyst. This is because the $\ce{-NH2}$ group is so activating that it makes the benzene ring much more reactive than benzene itself. This is a common exam question!

Reduction of ketones:

Reagents: $\ce{NaBH4}$ in methanol
Converts carbonyl group to alcohol group

The reactions of phenol and its derivatives

Phenol shows enhanced reactivity compared to benzene due to the electron-donating effect of the $\ce{-OH}$ group:

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Phenol is much more reactive than benzene because the lone pair of electrons on the oxygen atom is donated into the benzene ring, increasing the electron density. This means phenol can react under much milder conditions than benzene.

Key phenol reactions

Nitration:

Reagents: Dilute $\ce{HNO3}$ (much milder conditions than benzene)
Product: Mixture of 2-nitrophenol and 4-nitrophenol
Further nitration produces 2,4-dinitrophenol
The $\ce{-OH}$ group is a 2,4-directing group

Bromination:

Reagents: $\ce{Br2(aq)}$ at room temperature (no catalyst needed)
Product: 2,4,6-tribromophenol (white precipitate)
Immediate reaction showing how activated the benzene ring is

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The bromination of phenol happens so readily that it occurs immediately at room temperature with bromine water. The white precipitate of 2,4,6-tribromophenol is a distinctive test for phenol.

Neutralisation:

Reagents: $\ce{NaOH(aq)}$
Product: Sodium phenoxide ( $\ce{C6H5O-Na+}$ )
Phenol is a weak acid ( $\ce{pK_a} \approx 10$ ) due to resonance stabilization of the phenoxide ion

Organic synthesis and multi-step synthetic routes

Planning a synthesis requires systematic thinking about how to convert a starting material into a target molecule. This is where all your functional group knowledge comes together.

Approach to synthesis problems

Identify functional groups in both the starting material and target molecule
Work backwards from the target molecule (retrosynthetic analysis)
Select appropriate reagents and conditions for each step
Write balanced equations showing all intermediates

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Retrosynthetic analysis is the professional chemist's approach. Instead of asking "What can I make from this?", ask "What could I make this from?" This backwards thinking makes complex syntheses much easier to plan.

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Worked Example: Synthesis of Ethanamide from Chloroethane

Let's plan the conversion of an alcohol to a primary amide:

Step 1: Identify functional groups

Starting molecule: Alcohol ( $\ce{-OH}$ group)
Target molecule: Primary amide ( $\ce{-CONH2}$ group)
Both molecules have the same carbon skeleton (2 carbons)

Step 2: Plan the synthetic route

Working backwards from the target:

Primary amides are prepared from acyl chlorides (reaction with $\ce{NH3}$ )
Acyl chlorides are made from carboxylic acids (reaction with $\ce{SOCl2}$ )
Carboxylic acids can be prepared by oxidation of alcohols (using $\ce{K2Cr2O7/H2SO4}$ under reflux)

Step 3: Complete synthesis scheme

$\ce{CH3CH2OH ->[K2Cr2O7/H2SO4][reflux] CH3COOH ->[SOCl2] CH3COCl ->[NH3] CH3CONH2}$

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Worked Example: Synthesis of Butanoic Acid from Propanal

This example requires carbon chain extension:

Step 1: Identify functional groups

Starting molecule: Aldehyde (3 carbons)
Target molecule: Carboxylic acid (4 carbons)
Note: The target has one more carbon than the starting material

Step 2: Plan the synthesis

The key insight is that we need to extend the carbon chain by one carbon. The best route uses:

Convert aldehyde to haloalkane (via alcohol intermediate)
Nucleophilic substitution with cyanide to form nitrile (adds one carbon)
Hydrolysis of nitrile to form carboxylic acid

Step 3: Detailed synthesis

Reduction of aldehyde:

$\ce{CH3CH2CHO + 2[H] -> CH3CH2CH2OH}$

Reagents: $\ce{NaBH4}$ in water

Formation of bromoalkane:

$\ce{CH3CH2CH2OH + NaBr + H2SO4 -> CH3CH2CH2Br + NaHSO4 + H2O}$

Reagents: $\ce{NaBr}$ with concentrated $\ce{H2SO4}$ , heat (produces $\ce{HBr}$ in situ)

Nucleophilic substitution to form nitrile:

$\ce{CH3CH2CH2Br + NaCN ->[ethanol] CH3CH2CH2CN + NaBr}$

This is the chain extension step - the carbon in the cyanide group adds to the chain.

Hydrolysis of nitrile:

$\ce{CH3CH2CH2CN + 2H2O + HCl -> CH3CH2CH2COOH + NH4Cl}$

Reagents: Heat with dilute aqueous $\ce{HCl}$

The nitrile is hydrolysed to a carboxylic acid with the same carbon skeleton.

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Worked Example: Synthesis of 1-(3-aminophenyl)ethanol from Benzene

This complex synthesis combines aromatic chemistry with functional group transformations:

Step 1: Identify functional groups

Starting material: Benzene (simple aromatic ring)
Target molecule: Contains amine group ( $\ce{-NH2}$ ) at position 3 (meta) and secondary alcohol side chain ( $\ce{-CH(OH)CH3}$ )

Step 2: Plan the synthesis

Key considerations:

The amine group must be in the meta position (position 3)
To get meta-substitution, we need a meta-directing group
The $\ce{-NO2}$ group is meta-directing, so nitration should come first
The side chain can be added via Friedel-Crafts acylation
The ketone can be reduced to an alcohol
The nitro group can be reduced to an amine

Step 3: Complete synthesis scheme

Nitration: $\ce{C6H6 + HNO3 ->[conc. H2SO4] C6H5NO2 + H2O}$
Friedel-Crafts acylation: $\ce{C6H5NO2 + CH3COCl ->[AlCl3] C6H4(NO2)(COCH3) + HCl}$
- The $\ce{-NO2}$ group directs the incoming acyl group to position 3 (meta)
Reduction of nitro group: $\ce{C6H4(NO2)(COCH3) ->[Sn/HCl] C6H4(NH2)(COCH3)}$
- This converts $\ce{-NO2}$ to $\ce{-NH2}$
Reduction of ketone: $\ce{C6H4(NH2)(COCH3) ->[NaBH4] C6H4(NH2)(CH(OH)CH3)}$
- This converts the carbonyl to a secondary alcohol

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Critical Point About Directing Groups:

The nitro group must be introduced first because it is a meta-directing group. The $\ce{-NH2}$ group is a 2,4-directing group.

If we reduced the nitro group first, the ketone would be directed to the wrong positions (2 and 4) instead of position 3. The order of steps is crucial in aromatic synthesis - always consider the directing effects of your functional groups!

Exam tips for synthesis questions

Planning your answer:

Always identify functional groups in starting material and target first
Count carbons - if the numbers don't match, you need chain extension or shortening
Work backwards from the target molecule
Show all intermediate structures clearly
State reagents and conditions for each step

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Common Mistakes to Avoid:

Forgetting to state conditions (e.g., "reflux", "heat", "concentrated")
Incorrect order of steps (especially with directing groups in benzene chemistry)
Not recognizing when chain extension is needed
Missing intermediate steps in multi-step syntheses
Confusing similar reagents (e.g., $\ce{NaBH4}$ vs $\ce{LiAlH4}$ )

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Key Reagents to Remember:

Oxidation: $\ce{K2Cr2O7/H2SO4}$ under reflux
Reduction: $\ce{NaBH4}$ (mild, for aldehydes/ketones), $\ce{LiAlH4}$ (strong, for everything), $\ce{Sn/HCl}$ (for nitro groups)
Acyl chloride formation: $\ce{SOCl2}$
Chain extension: $\ce{NaCN}$ in ethanol, then hydrolyse
Benzene reactions: Need halogen carriers ( $\ce{AlCl3}$ , $\ce{FeBr3}$ ) or concentrated acids

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Key Points to Remember:

Functional group identification is the first step in any synthesis problem - know your functional groups thoroughly (ester, amide, amine, carboxylic acid, phenol, aldehyde, ketone, nitrile, acyl chloride, haloalkane)
The flowchart of functional group interconversions is your roadmap for synthesis - learn how to convert between all major functional groups using appropriate reagents and conditions
Work backwards from the target molecule (retrosynthetic analysis) - this makes complex syntheses much easier to plan. Ask yourself: "What molecule could I make this from in one step?"
Carbon chain extension uses cyanide chemistry - reaction with $\ce{NaCN}$ adds one carbon atom via nitrile formation, which can then be hydrolysed to a carboxylic acid or reduced to an amine
Benzene chemistry requires careful planning of directing groups - nitro groups are meta-directing (positions 3,5), while amino and hydroxyl groups are 2,4-directing. The order of substitution matters for multi-step aromatic syntheses!

Organic Synthesis (OCR A-Level Chemistry A): Revision Notes

Further Synthetic Routes

Introduction

Identifying functional groups in organic molecules

The reactions of the main functional groups

Key transformations to remember

The reactions of benzene and its derivatives

Key benzene reactions

Reactions of benzene derivatives

The reactions of phenol and its derivatives

Key phenol reactions

Organic synthesis and multi-step synthetic routes

Approach to synthesis problems

Exam tips for synthesis questions

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