Organic synthesis

This topic pulls the organic chemistry of the course together. It shows how to plan a route from one compound to another, how to lengthen a carbon chain with Grignard reagents, and the practical techniques used to make, separate, purify and identify an organic product safely.

Planning a synthetic route

To plan a synthesis, identify the functional group you start with and the one you need, then work out a sequence of known reactions that connects them, often working backwards from the target. For each step you must be able to give the reagents, the conditions and the type of reaction. Fewer steps usually means a higher overall yield, because some product is lost at every stage.

Key aliphatic conversions

Aromatic routes

• Benzene → nitrobenzene → phenylamine: concentrated HNO₃ and H₂SO₄ below 55 °C; then tin and concentrated HCl, heat, followed by NaOH.
• Phenylamine → azo dye: NaNO₂ and HCl below 10 °C, then phenol in NaOH. Or phenylamine + an acyl chloride gives an N-phenyl amide.
• Benzene → phenylethanone (CH₃COCl with AlCl₃), which then reacts like any ketone: LiAlH₄ gives 1-phenylethanol, which can be esterified; HCN/KCN gives a hydroxynitrile, which hot HCl hydrolyses to a hydroxy acid.
• Other ring reactions: Br₂/FeBr₃, a chloroalkane with AlCl₃, SO₃ in fuming sulfuric acid, and H₂ over nickel (see Topic 18).

Grignard reagents

A Grignard reagent, RMgX, is made by warming a halogenoalkane with magnesium turnings in dry ether: CH₃CH₂Br + Mg → CH₃CH₂MgBr (ethylmagnesium bromide). The carbon bonded to magnesium carries a partial negative charge, so it acts as a nucleophilic carbon and forms new carbon–carbon bonds, lengthening the chain. Everything must be dry, because water destroys the reagent.

The Grignard reagent adds to the δ+ carbon of a C=O group; adding water (or dilute acid) afterwards gives the product.

The general equations, with the magnesium ending up as Mg(OH)X: RMgX + HCHO → RCH₂OH; RMgX + R′CHO → RCH(OH)R′; RMgX + R′COR″ → RR′C(OH)R″; RMgX + CO₂ → RCOOH (each after adding H₂O). Other ways to add a carbon are reacting a halogenoalkane with KCN, or a carbonyl with HCN.

Practical techniques

Heating under reflux and distillation

• Reflux heats a reaction mixture for a long time without losing volatile substances: a vertical condenser turns vapours back to liquid, which drips back into the flask. It is used, for example, to oxidise a primary alcohol fully to a carboxylic acid with excess dichromate. Never seal the top of the condenser: pressure would build up and the apparatus could explode.
• Distillation separates a liquid product from the mixture, collecting the fraction that boils near the product's boiling point; the thermometer bulb sits level with the side arm. Distilling the aldehyde off as it forms, with limited dichromate, stops it being oxidised further.
• Anti-bumping granules make small bubbles form, preventing violent uneven boiling. Organic liquids are heated with electric heaters or water baths, as they are usually flammable.
• When drawing apparatus: no lines across the joins between flask, still head and condenser; the condenser has an outer water jacket sealed at both ends, with water in at the bottom and out at the top.

Purifying an organic liquid

1. Put the impure product in a separating funnel and shake it with sodium hydrogencarbonate solution to neutralise acid impurities, releasing the pressure of CO₂ often. Shaking with saturated sodium chloride solution helps the layers separate.
2. Let the layers separate and run off the aqueous layer. The organic layer is usually the less dense, upper layer, but check densities.
3. Run the organic layer into a dry flask and add a drying agent, such as anhydrous calcium chloride or magnesium sulfate, until the liquid is clear. The drying agent must be insoluble in, and not react with, the product.
4. Decant or filter the liquid off the drying agent and distil, collecting the fraction at the product's boiling point.

Purifying an organic solid: recrystallisation

Steam distillation and solvent extraction

• Steam distillation: steam is blown through the mixture and the product distils over with the water at below 100 °C, so a high-boiling compound that would decompose at its own boiling point can be separated. Phenylamine is purified this way.
• Solvent extraction: shake the mixture with an organic solvent in which the product dissolves better than in water, separate the layers, dry the organic layer and distil off the solvent.

Checking purity

• Melting point: a pure solid melts sharply at the value in data books; impurities lower the melting point and make it melt over a range. Use a melting-point apparatus, or a capillary tube strapped to a thermometer in an oil bath (the oil must boil above the sample's melting point). Heat slowly so the thermometer and sample stay at the same temperature.
• Boiling point: measured with the thermometer bulb in the vapour just above the boiling liquid. It is less useful for identification, since different liquids can share a boiling point, and it changes with atmospheric pressure.

Hazards and risks

• A hazard is anything with the potential to cause harm: toxic, flammable, harmful, irritant, corrosive, oxidising, carcinogenic. A risk is the chance that harm actually results, which depends on the amount, the concentration and how the substance is used.
• Control measures match the hazard: eye protection for irritants and corrosives, gloves and a fume cupboard for toxic substances, no naked flames near flammable liquids, oxidising agents kept away from flammable materials.

Identifying the product

Combustion analysis

The spectroscopic methods (mass spectra, IR and NMR) are covered in Topics 10 and 15, including a full worked identification.

Chemical tests for functional groups

Quick checks

Interactive diagrams