Organic synthesis

The single subtopic here is printed under "A Level subject content" in the 9701 syllabus and all three of its objectives carry the tier "A Level". None of it is AS, and it is a separate topic from the AS topic 21 of the same name. It is examined on Paper 4. Paper 1 is the AS multiple-choice paper and the whole 9701 bank on this site comes from it, so no practice here is tagged to this topic.

This topic introduces no new chemistry at all. Every reaction it uses has already appeared in topics 13 to 21 and 29 to 35. What it asks is that you can move around that chemistry in both directions: forwards, to predict what a molecule will do, and backwards, to work out how to make one. It is the topic most worth practising rather than reading, so use the reaction summary below as a map and then work through routes.

Syllabus points

36.1 Organic synthesis

• For an organic molecule containing several functional groups: identify organic functional groups using the reactions in the syllabus; predict properties and reactions.
• Devise multi-step synthetic routes for preparing organic molecules using the reactions in the syllabus.
• Analyse a given synthetic route in terms of type of reaction and reagents used for each step of it, and possible by-products.

Identifying functional groups by their reactions

Given an unknown compound, the reactions of the syllabus are also the tests. The most useful:

The pairs that need a second test to separate them are the point. Tollens' distinguishes an aldehyde from a ketone; sodium carbonate distinguishes a carboxylic acid from a phenol; whether a precipitate forms with bromine water distinguishes a phenol from an alcohol.

Predicting the reactions of a molecule with several groups

A molecule with more than one functional group reacts at each group independently, unless the groups interact. So the method is:

1. List every functional group in the structure.
2. Write down what each one does with the reagent offered.
3. Check for interaction: is one group attached directly to a benzene ring, which changes its behaviour? Is a halogen on the ring or on a side-chain? Is an OH on the ring, making it a phenol rather than an alcohol?

Step 3 is where most marks are lost. The same atoms behave completely differently depending on attachment:

• OH on a ring is a phenol: acidic, dissolves in NaOH, brominates three times in cold water. OH on a chain is an alcohol: neutral, oxidisable, esterifiable.
• Cl on a ring is inert to nucleophiles. Cl on a side-chain is an ordinary halogenoalkane.
• NH₂ on a ring is very weakly basic. NH₂ on a chain is a reasonably strong base.
• A COOH on a ring directs a further substituent to position 3; an NH₂ or OH directs to 2, 4 and 6.

The reaction map

Learn these as conversions, since that is how a synthesis question is posed.

Chain length unchanged, aliphatic:

Chain length changed:

Those four rows are the most valuable in the whole map, because only the nitrile routes lengthen a carbon chain. If a synthesis question asks you to go from a three-carbon compound to a four-carbon one, the answer must pass through a nitrile.

Aromatic:

Devising a route

Work backwards from the target, which is far more reliable than guessing forwards.

1. Compare the target with the starting material. Note the change in carbon skeleton first and the change in functional group second. If the number of carbons has changed, the route must include a step that changes it, and there are only the two.
2. Ask what the target can be made from, using the map. Usually two or three answers.
3. Repeat on each of those until you reach the starting material.
4. Check every step has reagents and conditions written out, since a route without conditions earns little.
5. Check the order. On an aromatic ring, the directing effects mean the order decides the product.

Worked route, propan-1-ol to butanoic acid. The chain grows from three carbons to four, so a nitrile is required.

1. Propan-1-ol to 1-bromopropane: HBr, or NaBr with concentrated H₂SO₄, reflux.
2. 1-bromopropane to butanenitrile: KCN in ethanol, reflux. The chain now has four carbons.
3. Butanenitrile to butanoic acid: dilute hydrochloric acid, reflux.

Worked route, benzene to 3-nitrobenzoic acid. Two groups must go onto the ring, and the order matters.

1. Benzene to methylbenzene: CH₃Cl with AlCl₃, heat.
2. Methylbenzene to benzoic acid: hot alkaline KMnO₄, then dilute acid.
3. Benzoic acid to 3-nitrobenzoic acid: concentrated HNO₃ with concentrated H₂SO₄, 25 to 60 °C.

The oxidation must come before the nitration. The methyl group is 2,4-directing, so nitrating first would give 4-nitromethylbenzene and then 4-nitrobenzoic acid, which is the wrong isomer. Only once the COOH group is present, which is 3-directing, does the nitro group go to position 3.

Worked route, benzene to an azo dye. Four steps, each with a condition that carries a mark.

1. Nitration: conc. HNO₃ and conc. H₂SO₄, 25 to 60 °C, giving nitrobenzene.
2. Reduction: Sn and conc. HCl, heat, then NaOH(aq), giving phenylamine.
3. Diazotisation: NaNO₂ and dilute HCl, below 10 °C, giving benzenediazonium chloride.
4. Coupling: phenol in NaOH(aq), below 10 °C, giving the azo compound.

Analysing a given route

The third objective asks you to read someone else's route and comment. Three things to say about each step:

• The type of reaction: nucleophilic substitution, electrophilic addition, electrophilic substitution, elimination, oxidation, reduction, hydrolysis, condensation, addition-elimination, free-radical substitution.
• The reagents and conditions, in full.
• Possible by-products, which is the part usually left out.

By-products worth being ready to name:

• Halogenoalkane with NaOH: an alkene as well as the alcohol, from the competing elimination reaction, favoured by hot ethanolic conditions and by a tertiary halogenoalkane.
• Halogenoalkane with ammonia: secondary, tertiary and quaternary products from further substitution, which is why excess ammonia is used.
• Oxidation of a primary alcohol: the carboxylic acid contaminating the aldehyde if the product is not distilled off as it forms.
• Nitration of benzene: dinitrobenzene if the temperature exceeds about 60 °C.
• Friedel-Crafts alkylation: multiple alkylation, because the alkyl group added activates the ring towards further attack.
• Halogenation of a methylbenzene ring: a mixture of the 2- and 4-isomers, which must then be separated.
• A reaction at a planar intermediate, such as nucleophilic addition to a carbonyl or S_N1 substitution: a racemic mixture rather than a single enantiomer, as in topic 29.

Being able to say why a by-product forms, and what condition suppresses it, is what separates a full answer from a list.

Common mistakes

• Writing a route without reagents or conditions, which earns almost nothing however correct the sequence.
• Changing the number of carbon atoms without a nitrile step, or using KCN and forgetting that the chain has grown.
• Treating an OH on a benzene ring as an alcohol, so it is oxidised or esterified by the usual alcohol reactions.
• Treating a chlorine on a ring as a halogenoalkane, so a route hydrolyses chlorobenzene to phenol.
• Nitrating before oxidising when the target is a 3-substituted benzoic acid.
• Forgetting the NaOH step after reducing nitrobenzene.
• Letting a diazotisation run above 10 °C.
• Distilling when refluxing is needed, or refluxing when the aldehyde must be distilled off.
• Naming a reaction type wrongly, most often calling electrophilic substitution on a ring an addition.
• Listing no by-products at all when asked to analyse a route.