Organic Synthesis — IAL Edexcel Modular (Chemistry) Revision Notes & Topical Questions

Section 1 of 23Deducing structures from analytical data

Deducing structures from analytical data

Progression

• Progression empirical formula, molecular formula, functional groups, then overall structure.
  • (using Mr from mass spectrometry)

Combustion analysis

• Combustion analysis a known mass burned in excess dry oxygen gives masses of CO₂ and H₂O.
• Mass of C = 12.0/44.0 x mass of CO₂ and mass of H = 2.0/18.0 x mass of H₂O.
• Percentage O = 100 - percentage C - percentage H.

Group tests

• Br₂ for C=C;
  • acidified dichromate(VI) for primary and secondary alcohols;
  • Fehling's or Tollens' for aldehydes;
  • 2,4-DNPH for C=O;
  • Na₂CO₃ for carboxylic acids;
  • iodoform for CH₃ next to C=O.

Spectra

• IR for functional groups, mass spectrometry for formula and fragments, 13C and 1H NMR for structure.

Section 2 of 23Interconversions of functional groups

Interconversions of functional groups

Alkene

• Alkene to haloalkane with X₂ or HX, to alcohol with steam and H₂SO₄, to alkane with H₂/Ni at 150 °C.

Alcohol

• Alcohol to alkene with Al₂O₃ or concentrated H₂SO₄ (elimination), to haloalkane with NaX + H₂SO₄ under reflux.

Haloalkane

• Haloalkane to alcohol with NaOH(aq), to nitrile with KCN, to amine with NH₃ in ethanol;
  • alkane to haloalkane with halogen and UV light.

Oxidation

• Oxidation primary alcohol to aldehyde (distil) or acid (reflux) and secondary alcohol to ketone with K₂Cr₂O₇/H₂SO₄.

Reduction and addition

• NaBH₄ reduces aldehydes and ketones to alcohols;
  • NaCN/H⁺ converts an aldehyde to a hydroxynitrile;
  • H₂O/HCl hydrolyses a nitrile to a carboxylic acid.

Acyl chlorides

• Acyl chlorides made with SOCl₂;
  • hydrolysed by H₂O;
  • give primary amides with NH₃ and secondary amides with primary amines by nucleophilic addition-elimination.

Esters

• Esters made by esterification;
  • hydrolysed by NaOH(aq) to the carboxylate or by dilute acid to the carboxylic acid.

Section 3 of 23Aromatic reaction pathways

1Benzene

• Benzene to methylbenzene with CH₃Cl/AlCl₃, to bromobenzene with Br₂/FeBr₃, to nitrobenzene with HNO₃/H₂SO₄ and to phenylethanone with CH₃COCl/AlCl₃.

2Nitrobenzene

• Nitrobenzene to phenylamine with Sn/HCl.

3Phenylamine

• Phenylamine to 2,4,6-tribromophenylamine with bromine.

4Phenylethanone

• Phenylethanone to 1-phenylethanol with NaBH₄.

Section 4 of 23Designing a synthetic route

• Target molecule
  • design the route with few steps and good yield, up to four steps.

1

Draw the target and the starting molecule.

2

Compare the numbers of carbon atoms.

3

Decide which functional groups to introduce or change and in what order.

4

Choose reagents and conditions for each step.

5

Identify control measures to reduce risk from the hazards.

• Lengthening the chain
  • add a nitrile (one carbon) or use a Grignard reagent.

Section 5 of 23Grignard reagents

Preparation

• Preparation a halogenoalkane in dry ether with magnesium, as in CH₃CH₂I + Mg → CH₃CH₂MgI.
• Grignard reagents are destroyed by water, so conditions must be dry.

Reactions

• Reactions the R group is a nucleophile that adds to C=O, then dilute acid hydrolyses the product.
• Methanal gives a primary alcohol and other aldehydes give secondary alcohols.
• Ketones give tertiary alcohols.
• CO₂ gives a carboxylic acid.

Section 6 of 23Distillation, steam distillation and reflux

Simple distillation

• Simple distillation separates by boiling point;
  • an aldehyde distils off as it forms because it has no hydrogen bonding.
• Use a heating mantle, anti-bumping granules, greased joints and water entering the condenser at the bottom.
• Collect distillate within ±2 °C of the product boiling point.

Steam distillation

• Steam distillation separates an insoluble liquid below its normal boiling point and reduces thermal decomposition.

Reflux

• Reflux keeps reactants and products in the flask while the reaction goes to completion, with the condenser clamped vertically.
• Used for oxidising to carboxylic acids and for esters such as ethyl ethanoate (about 15 minutes).

Section 7 of 23Purifying organic products

Solvent extraction

• Solvent extraction use a separating funnel, identify the aqueous layer by adding water, wash with sodium carbonate to neutralise, release pressure and run off the lower layer.

Drying agents

• Drying agents anhydrous CaCl₂ for hydrocarbons and MgSO₄ or CaSO₄ generally.
• Add until some stays free-flowing, since clumping means water remains.

Recrystallisation

• Recrystallisation dissolve in the minimum hot solvent, filter hot if needed, cool slowly, filter (Buchner), wash with cold solvent and dry.
• Repeating gives a purer product but a lower yield.

Section 8 of 23Testing purity

Melting point

• Melting point a pure solid melts sharply at the data book value and impurities lower the melting point and broaden the range.
• The sample must be dry and finely powdered, heated slowly, repeated three times and quoted as a range.
• Methods are an oil bath, Thiele tube or melting-point station.

Boiling point

• Boiling point found by distillation; impurities raise the boiling point or make it boil over a range.

Section 9 of 23Aliphatic reaction pathways

From	To	Reagents and conditions	Reaction type
Alkene	haloalkane	X2 or HX	electrophilic addition
Alkene	alcohol	steam + H2SO4, heat	hydration
Alkene	alkane	H2, Ni, 150 °C	hydrogenation
Alcohol	alkene	Al2O3 or concentrated H2SO4, heat	elimination (dehydration)
Alcohol	haloalkane	NaX + H2SO4, reflux	nucleophilic substitution
Haloalkane	alcohol	NaOH(aq), reflux	nucleophilic substitution
Alkane	haloalkane	halogen, UV light	free radical substitution
Primary alcohol	aldehyde	K2Cr2O7 / H2SO4, distil	oxidation
Secondary alcohol	ketone	K2Cr2O7 / H2SO4, heat	oxidation
Primary alcohol	carboxylic acid	K2Cr2O7 / H2SO4, reflux	oxidation
Aldehyde	primary alcohol	NaBH4 / H2O	reduction
Ketone	secondary alcohol	NaBH4 / H2O	reduction
Haloalkane	nitrile	KCN in aqueous ethanol, heat	nucleophilic substitution
Haloalkane	amine	NH3 in ethanol	nucleophilic substitution
Nitrile	carboxylic acid	H2O / HCl	hydrolysis
Aldehyde	hydroxynitrile	NaCN / H+	nucleophilic addition
Alcohol or carboxylic acid	ester	carboxylic acid or alcohol, H2SO4	esterification
Ester	carboxylate salt + alcohol	NaOH(aq)	alkaline hydrolysis
Ester	carboxylic acid	dilute acid	acid hydrolysis
Carboxylic acid	acyl chloride	SOCl2	chlorination
Acyl chloride	carboxylic acid	H2O	hydrolysis
Acyl chloride	primary amide	NH3	nucleophilic addition-elimination
Acyl chloride	secondary amide	primary amine	nucleophilic addition-elimination

Section 10 of 23Aromatic reaction pathways

From	To	Reagents	Reaction type
Benzene	methylbenzene	CH3Cl / AlCl3	Friedel-Crafts alkylation
Benzene	bromobenzene	Br2 / FeBr3	electrophilic substitution
Benzene	chlorobenzene	Cl2 / AlCl3	electrophilic substitution
Benzene	nitrobenzene	HNO3 / H2SO4	nitration
Nitrobenzene	phenylamine	Sn / HCl	reduction
Phenylamine	2,4,6-tribromophenylamine	bromine	electrophilic substitution
Benzene	phenylethanone	CH3COCl / AlCl3	Friedel-Crafts acylation
Phenylethanone	1-phenylethanol	NaBH4	reduction

Section 11 of 23Designing a reaction pathway

• Target molecule
  • the compound to be made, with the synthesis designed to be as efficient as possible.
    • (few steps, good yield)

1

Draw the structures of the target and the starting molecule.

2

Compare the numbers of carbon atoms.

3

List what can be made from the starting molecule and what can be converted into the target.

4

Match the functional groups in common and choose reagents and conditions for each step.

1Lengthening the chain

• Lengthening the chain add a nitrile group by nucleophilic substitution, which adds one carbon, or use a Grignard reagent.

2Step limit

• Step limit routes of up to four steps may be needed.

3Control measures

• Control measures identify measures to reduce risk based on hazard data.

Section 12 of 23Grignard reagents and chain extension

1

Preparation

• Preparation a halogenoalkane in dry ether reacts with magnesium.
• CH₃CH₂I + Mg → CH₃CH₂MgI.
• Conditions must be dry because water destroys Grignard reagents.

2

Nucleophilic R group

• Nucleophilic R group the alkyl group carries a partial negative charge, R-[⁺MgI].

3

Two-step reaction

• Two-step reaction addition to a carbonyl compound or CO₂, then hydrolysis with dilute acid.
• Methanal gives a primary alcoholCH₃CH₂MgI + HCHO → CH₃CH₂CH₂OH.
• Other aldehydes give secondary alcoholsethanal gives butan-2-ol.
• Ketones give tertiary alcoholspropanone gives 2-methylbutan-2-ol.
• Carbon dioxide gives a carboxylic acidCH₃CH₂MgI + CO₂ → CH₃CH₂COOH.

Section 13 of 23Simple distillation

1Purpose

• Purpose separates compounds by boiling point, with the lowest boiling point distilling first.
• Used when a reaction does not go to completion or other chemicals form.

2Oxidising a primary alcohol to an aldehyde

• Oxidising a primary alcohol to an aldehyde the aldehyde has no hydrogen bonding,
  • so it boils below the alcohol and distils off as it forms, preventing oxidation to the acid.

1

Place the alcohol and acidified potassium dichromate(VI) in a round-bottomed flask with anti-bumping granules.

2

Fit a still head and a condenser, with lightly greased joints.

3

Place the thermometer bulb where vapour enters the condenser.

4

Pass water through the condenser jacket, entering at the bottom and leaving at the top.

5

Heat with an electric heating mantle, which allows temperature control and is safe with flammable chemicals.

6

Collect the distillate within ±2 °C of the product's boiling point and discard earlier fractions.

Section 14 of 23Combined techniques for deducing structures

• Data used
  • combustion analysis, elemental percentage composition, test-tube reactions, IR, mass spectra and NMR spectra.

1

Find the empirical formula.

2

Determine the molecular formula using Mr from mass spectrometry.

3

Identify the functional groups present.

4

Deduce the overall structure.

Section 15 of 23Combustion analysis

• Method
  • a known mass of the compound is burned in excess dry oxygen and the CO₂ and H₂O produced are weighed.
  • Sulfur and nitrogen can be included but are not required at this level.

1

Mass of C = (12.0 / 44.0) x mass of CO₂.

2

Percentage C = mass of C / mass of sample x 100.

3

Mass of H = (2.0 / 18.0) x mass of H₂O.

4

Percentage H = mass of H / mass of sample x 100.

5

Percentage O = 100 - percentage C - percentage H.

Hydrogen in water

• Hydrogen in water use 2.0 g for the two hydrogen atoms in a water molecule.

Empirical formula

• Empirical formula divide each percentage by its Ar and take the simplest whole-number ratio.

Section 16 of 23Functional group tests and spectra

Reagent or technique	Detects
Bromine	C=C bond
Acidified potassium dichromate(VI)	primary and secondary alcohols (and aldehydes)
Fehling's or Tollens' reagent	aldehydes, distinguishing them from ketones
2,4-dinitrophenylhydrazine (2,4-DNPH)	C=O bond
Sodium carbonate	carboxylic acids
Iodoform test	a methyl group next to C=O
Infrared spectroscopy	functional groups and certain bond types
Mass spectrometry	molecular formula and fragments
13C and 1H NMR	the structure of the compound

Section 17 of 23Preparation: steam distillation and reflux

Steam distillation

• Steam distillation separates an insoluble liquid from an aqueous mixture.
• Steam bubbled through the mixture mixes the layers so both evaporate.
• The insoluble liquid distils below its usual boiling point, reducing thermal decomposition.
• The distillate is cloudy when the product is immiscible with water.

Reflux

• Reflux heating so that reactants, products and solvent return to the flask, allowing the reaction to go as far as possible.
• Used for primary alcohol to carboxylic acid with acidified dichromate and for esterification.
• Ethyl ethanoate is prepared by reflux for about 15 minutes.

1

Put the mixture and anti-bumping granules in a round-bottomed flask.

2

Heat with a heating mantle or water bath rather than a Bunsen burner.

3

Clamp the condenser vertically with greased joints.

4

Run water in at the bottom of the condenser jacket and out at the top.

5

Stop heating and let the mixture cool to room temperature.

Section 18 of 23Purification by solvent extraction and drying

Separating funnel

• Separating funnel cleans and isolates the organic product from the aqueous layer.
• Add water to identify the aqueous layer, which is the layer that grows.
• Wash with sodium carbonate solution to neutralise acid impurities.
• Invert and open the stopcock to release pressure, repeating 15-20 times, and open slowly after neutralisation.
• Let the layers separate and drain off the lower layer.

Drying agents

• Drying agents anhydrous inorganic salts that readily hydrate and remove traces of water.
• Anhydrous calcium chloride dries hydrocarbons.
• Anhydrous calcium sulfate or magnesium sulfate are general-purpose agents.
• Potassium hydroxide is a less common cheap drying agent.

Using a drying agent

• Using a drying agent add a spatula, swirl, and use a stopper for low-boiling products.
• Clumping shows water remains, so add more until some stays as a free-flowing powder.
• Decant or filter, and the dry liquid appears clear.

Section 19 of 23Purification by recrystallisation

• Principle
  • a hot solvent dissolves the solid and impurities, and on cooling the solid crystallises and leaves the impurities in solution.

1

Dissolve the solid in the minimum amount of hot solvent to avoid loss of product.

2

Filter hot if solid impurities remain.

3

Cool slowly to room temperature, which gives larger, well defined crystals that are easier to filter and dry.

4

Filter off the crystals, using Buchner apparatus under reduced pressure for speed.

5

Wash with fresh cold solvent and dry on filter paper.

• Repeating
  • gives a purer product but the yield falls each time.

Section 20 of 23Testing purity: melting point

Melting point

• Melting point indicates the purity and identity of a solid.
• It can be matched to a known substance to confirm the product.
• A pure substance has a sharp melting point close to the data book value.
• Impurities lower the melting point and broaden the range.

Technique

• Technique the sample must be dry and finely powdered.
• Prepare the melting point tubes correctly.
• Use the first tube to find the approximate range, then repeat with slow heating.
• Repeat, normally three times.

Apparatus

• Apparatus an oil bath, a Thiele tube or an electronic melting-point station.

Reporting

• Reporting quote the melting point as a range (±) and compare with a data book value.

Section 21 of 23Testing purity: boiling point

Boiling point

• Boiling point indicates the purity and identity of a liquid and is found by gently heating it by distillation until it boils.

Comparison

• Comparison the value is compared with literature or database values.

Impurities

• Impurities the boiling point may be higher than the literature value.
• The sample may boil over a range of temperatures instead of at a single temperature.

Section 22 of 23Key terms

Term	Meaning
Target molecule	The compound a synthesis is designed to make.
Grignard reagent	An alkyl magnesium halide, RMgX, used to lengthen carbon chains.
Steam distillation	Distillation with steam to separate an immiscible liquid.
Reflux	Heating with a vertical condenser so that nothing is lost from the flask.
Drying agent	An anhydrous salt that removes traces of water.
Recrystallisation	Purification of a solid by dissolving in hot solvent and cooling.
Melting point range	The temperature interval over which a solid melts, indicating purity.

Term	Meaning
Target molecule	The compound a synthesis is designed to make.
Grignard reagent	An alkyl magnesium halide, RMgX, used to lengthen carbon chains.
Simple distillation	Separation of liquids by boiling point.
Nucleophilic addition-elimination	The mechanism type for reactions of acyl chlorides.
Empirical formula	The simplest whole-number ratio of atoms of each element in a compound.
Combustion analysis	Burning a known mass of compound in excess oxygen and weighing the CO2 and H2O formed.

Term	Meaning
Target molecule	The compound a synthesis is designed to make.
Grignard reagent	An alkyl magnesium halide, RMgX, used to lengthen carbon chains.
Simple distillation	Separation of liquids by boiling point.
Steam distillation	Distillation with steam to separate an immiscible liquid below its normal boiling point.
Drying agent	An anhydrous salt that removes traces of water.
Recrystallisation	Purification of a solid by dissolving in hot solvent and cooling.
Melting point range	The temperature interval over which a solid melts, indicating purity.

Section 23 of 23Exam technique

1

Using water as a solvent for Grignard reagents — dry ether is needed.

2

Choosing a route with unnecessary extra steps.

3

Collecting distillate outside ±2 °C of the boiling point of the product.

4

Using a large volume of solvent for recrystallisation.

5

Quoting a single melting point instead of a range.

1

Using water as a solvent for Grignard reagents — they are destroyed by water, so dry ether is needed.

2

Omitting the second mole of amine or ammonia when an acyl chloride reacts — it neutralises the HCl formed.

3

Choosing a route with unnecessary extra steps — design the synthesis with the fewest steps and the best yield.

4

Using 1.0 instead of 2.0 g for hydrogen in water in combustion analysis calculations.

1

Using water as a solvent for Grignard reagents — they are destroyed by water, so dry ether is needed.

2

Collecting distillate outside ±2 °C of the product boiling point.

3

Using a large volume of solvent for recrystallisation — use the minimum hot solvent.

4

Heating the melting point apparatus too quickly near the melting point.

5

Quoting a single value for a melting point instead of a range.