Organic synthesis

· Organic synthesis = planning routes to make a target organic molecule using known functional group interconversions.
· For molecules with several functional groups, identify each reactive functional group first, then predict likely properties, reactions, and side reactions.
· Exam questions often ask for reagents, conditions, reaction type, intermediate structures, and possible by-products.
· Work backwards from the product using retrosynthesis: target → immediate precursor → earlier precursor → starting compound.
· Only use reactions from the CIE syllabus; avoid naming advanced reagents/routes not required.

This reaction map links common organic functional groups using labelled arrows for reagents and reaction types. It is useful for planning multi-step synthesis by seeing which conversions are possible directly and which require intermediates. Source

Functional group recognition

· C=C alkene: decolourises aqueous bromine; oxidised by cold dilute acidified KMnO₄ to a diol.
· Halogenoalkane, R–X: reacts by nucleophilic substitution with NaOH(aq), KCN/ethanol, or NH₃/ethanol under pressure.
· Alcohol, R–OH: forms halogenoalkanes, alkenes, carbonyls, carboxylic acids, or esters depending on conditions.
· Aldehyde, RCHO: positive with Tollens’ and Fehling’s; oxidised to carboxylic acid; reduced to primary alcohol.
· Ketone, RCOR: positive with 2,4-DNPH but negative with Tollens’/Fehling’s; reduced to secondary alcohol.
· Carboxylic acid, RCOOH: acidic; reacts with metals, alkalis, carbonates, alcohols, LiAlH₄, and chlorinating agents.
· Ester, RCOOR: made by esterification; hydrolysed by dilute acid or dilute alkali + heat.
· Nitrile, RCN: made from halogenoalkanes using KCN/ethanol + heat; hydrolysed to carboxylic acid or reduced to amine.
· Acyl chloride, RCOCl: very reactive; forms carboxylic acids, esters, and amides at room temperature.
· Phenol/arene: undergoes electrophilic substitution, with substituents affecting reactivity and positions of substitution.

Planning multi-step synthesis routes

· Start by comparing starting molecule vs target molecule: carbon chain length, functional groups, aromatic ring, and oxidation level.
· To increase carbon chain length by one, use halogenoalkane → nitrile with KCN/ethanol + heat, then convert the nitrile if needed.
· To move between alcohol ↔ halogenoalkane ↔ alkene, choose between substitution, elimination, addition, and dehydration.
· To move up oxidation levels: primary alcohol → aldehyde → carboxylic acid using acidified K₂Cr₂O₇/KMnO₄.
· To move down oxidation levels: use NaBH₄ for aldehydes/ketones → alcohols; use LiAlH₄ for stronger reductions such as carboxylic acid → primary alcohol, nitrile → amine, or amide → amine.
· For routes involving several groups, choose conditions that react with the intended functional group and do not destroy another group.
· In route-analysis questions, label every arrow with reaction type + reagent + condition + product/by-product.

Key aliphatic conversions to memorise

· Alkane → halogenoalkane: Cl₂/Br₂ + UV light, free-radical substitution; may produce mixtures.
· Alkene → alkane: H₂ + Ni/Pt + heat, hydrogenation/addition.
· Alkene → halogenoalkane: HX(g), room temperature or X₂, electrophilic addition.
· Alkene → alcohol: steam + H₃PO₄ catalyst; or via halogenoalkane → alcohol.
· Alkene → diol: cold dilute acidified KMnO₄.
· Halogenoalkane → alcohol: NaOH(aq) + heat, nucleophilic substitution.
· Halogenoalkane → alkene: NaOH in ethanol + heat, elimination.
· Halogenoalkane → nitrile: KCN in ethanol + heat, nucleophilic substitution; adds one carbon.
· Halogenoalkane → amine: NH₃ in ethanol, heated under pressure.
· Primary alcohol → aldehyde: acidified K₂Cr₂O₇/KMnO₄ + distillation.
· Primary alcohol → carboxylic acid: acidified K₂Cr₂O₇/KMnO₄ + reflux.
· Secondary alcohol → ketone: acidified K₂Cr₂O₇/KMnO₄ + distillation/reflux.
· Tertiary alcohol: not oxidised by acidified dichromate/manganate(VII).
· Alcohol → alkene: heated Al₂O₃ or concentrated H₂SO₄, dehydration/elimination.
· Alcohol → ester: carboxylic acid + concentrated H₂SO₄ catalyst.
· Aldehyde/ketone → alcohol: NaBH₄ or LiAlH₄, reduction.
· Aldehyde/ketone → hydroxynitrile: HCN + KCN catalyst + heat, nucleophilic addition.
· Carboxylic acid → acyl chloride: PCl₃ + heat, PCl₅, or SOCl₂.
· Acyl chloride → ester: alcohol or phenol, room temperature; by-product HCl.
· Acyl chloride → amide: NH₃ or primary/secondary amine, room temperature; by-product HCl.
· Ester → carboxylic acid + alcohol: dilute acid + heat, reversible hydrolysis.
· Ester → carboxylate salt + alcohol: dilute alkali + heat, followed by acidification to carboxylic acid if required.
· Nitrile → carboxylic acid: dilute acid or dilute alkali + heat, then acidification.
· Nitrile → amine: LiAlH₄ or H₂/Ni, reduction.

The diagram shows backside attack by a nucleophile and simultaneous leaving-group departure in an SN2 mechanism. This supports synthesis routes where primary halogenoalkanes are converted into alcohols, nitriles, or amines. Source

Aromatic synthesis routes

· Benzene → halogenoarene: Cl₂/AlCl₃ or Br₂/AlBr₃, electrophilic substitution.
· Benzene → nitrobenzene: concentrated HNO₃ + concentrated H₂SO₄, 25–60°C, electrophilic substitution.
· Benzene → methylbenzene: CH₃Cl + AlCl₃ + heat, Friedel–Crafts alkylation.
· Benzene → acylbenzene: CH₃COCl + AlCl₃ + heat, Friedel–Crafts acylation.
· Methylbenzene → benzoic acid: hot alkaline KMnO₄, then dilute acid; side-chain oxidation.
· Nitrobenzene → phenylamine: hot Sn/concentrated HCl, then NaOH(aq).
· Phenylamine → diazonium salt: NaNO₂ + dilute acid below 10°C.
· Diazonium salt → phenol: warm with H₂O.
· Phenol → 2,4,6-tribromophenol: Br₂(aq), room temperature.
· Phenol → nitrophenol mixture: dilute HNO₃(aq), room temperature; gives mainly 2- and 4-nitrophenol.
· Phenol + diazonium salt in NaOH(aq): forms an azo compound used as a dye.
· Directing effects: –NH₂, –OH, –R direct mainly to 2-/4-positions; –NO₂, –COOH, –COR direct mainly to 3-position.

Choosing reagents and conditions carefully

· Distillation vs reflux matters: distil a primary alcohol to stop at an aldehyde; reflux to form the carboxylic acid.
· NaOH(aq) + heat gives substitution of halogenoalkanes to alcohols; NaOH/ethanol + heat gives elimination to alkenes.
· NaBH₄ is selective for aldehydes and ketones; LiAlH₄ is stronger and reduces carboxylic acids, nitriles, amides, and carbonyls.
· KCN/ethanol forms a nitrile and increases the chain length; HCN/KCN adds to a carbonyl to form a hydroxynitrile.
· Acyl chlorides react faster than carboxylic acids and usually form HCl as a by-product.
· Phenols are more reactive than benzene in electrophilic substitution, so they use milder conditions.
· Halogenoarenes are much less reactive than halogenoalkanes in nucleophilic substitution because the C–X bond has partial double-bond character.

Mechanisms linked to synthesis

· Free-radical substitution: alkane + halogen under UV light; stages = initiation, propagation, termination.
· Electrophilic addition: alkene reacts with H₂, HX, X₂, or steam; watch for Markovnikov addition via more stable carbocation.
· Nucleophilic substitution: halogenoalkane reacts with OH⁻, CN⁻, NH₃; primary tends to SN2, tertiary tends to SN1.
· Nucleophilic addition: aldehydes/ketones react with HCN/KCN; CN⁻ attacks the δ⁺ carbonyl carbon.
· Electrophilic substitution: arenes react by substitution, not addition, because substitution preserves aromatic stability.
· Addition–elimination: acyl chlorides react with water, alcohols, phenols, ammonia, or amines.
· Mechanism questions require correct curly arrows starting from a bond or lone pair, not from atoms or charges randomly.

The diagram shows how an aromatic ring reacts with an electrophile, forms a resonance-stabilised intermediate, then loses H⁺ to restore aromaticity. This explains why benzene usually undergoes substitution rather than addition. Source

Analysing a given synthetic route

· For each step, state the reaction type: addition, substitution, elimination, hydrolysis, condensation, oxidation, or reduction.
· Identify the functional group changed and the functional group formed.
· Give exact reagents and conditions, e.g. acidified K₂Cr₂O₇ + reflux, not just “oxidation”.
· Predict by-products, especially HCl from acyl chloride reactions, water from esterification/condensation, and salts from neutralisation.
· Check if the route changes the carbon skeleton: most reactions keep carbon number the same, but KCN substitution increases chain length by one.
· Consider possible mixtures: free-radical substitution and some aromatic substitution reactions can produce multiple products.
· Explain why a route works using functional group reactivity, not just memorised arrows.

Common exam traps

· Do not confuse KCN/ethanol with halogenoalkanes and HCN/KCN with carbonyls.
· Do not oxidise a ketone or tertiary alcohol under normal syllabus conditions.
· Do not use reflux when the question wants an aldehyde from a primary alcohol; use distillation.
· Do not forget acidification after alkaline hydrolysis of a nitrile or ester if the final product must be a carboxylic acid.
· Do not write NaBH₄ for reducing carboxylic acids, nitriles, or amides; use LiAlH₄ where required.
· Do not assume halogenoarenes react like halogenoalkanes; aryl C–X bonds resist nucleophilic substitution.
· Do not miss by-products: acyl chloride + alcohol/phenol/ammonia/amine forms HCl.
· Do not ignore directing effects in aromatic substitution.