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Planning a chemical synthesis
Designing a route to a product: choosing reagents and conditions, limiting reagents and percentage yield, why yields multiply in multi-step syntheses, and how products are purified and their purity checked.
The active ingredient in a modern medicine may take ten or more steps to make. If each step gives a respectable 80% yield, more than 89% of the starting material is lost by the end. Chemists who design these routes spend as much time cutting out steps and improving yields as they do inventing new reactions, because each step that is saved can make a medicine cheaper and the process cleaner.
Designing a synthesis
A chemical synthesis makes a target compound from available starting materials. Products are made for many industries: pharmaceuticals (paracetamol, aspirin), cosmetics (esters for fragrances, emulsifiers), cleaning products (soaps and detergents) and fuels (ethanol, biodiesel). Whatever the product, the chemist asks the same questions:
- Availability of reagents. Are the starting materials cheap, available in quantity and reliable in supply? Petrochemicals such as ethene are cheap now but come from finite oil and gas; renewable feedstocks (sugar, starch, plant oils) depend on harvests.
- Reaction conditions. What temperature, pressure, catalyst and solvent are needed? High temperature and pressure cost energy and need expensive, strong equipment.
- Yield. How much product is obtained compared with the theoretical maximum, and how fast?
- Purity. How will the product be separated from by-products, unreacted reagents and the catalyst, and how pure must it be? A medicine must be over 99% pure; a fuel need not be.
- Safety, cost and environmental impact (page 8L).
A three-step route
Ethyl ethanoate can be made from ethene, using reactions from Module 7:
- Hydration: $\text{CH}_2{=}\text{CH}_2(g) + \text{H}_2\text{O}(g) \rightleftharpoons \text{CH}_3\text{CH}_2\text{OH}(g)$, with a phosphoric acid catalyst at about 300 °C and 60–70 atm. Only about 5% of the ethene reacts in each pass, so unreacted ethene is separated and recycled until about 95% has been converted.
- Oxidation: ethanol is oxidised to ethanoic acid (in the lab, with acidified dichromate under reflux).
- Esterification: $\text{CH}_3\text{COOH} + \text{CH}_3\text{CH}_2\text{OH} \rightleftharpoons \text{CH}_3\text{COOCH}_2\text{CH}_3 + \text{H}_2\text{O}$, with concentrated sulfuric acid as catalyst. This is an equilibrium with $K \approx 4$, so with equal amounts of acid and alcohol only about two-thirds converts.
Yield
The theoretical yield is the mass of product you would get if all of the limiting reagent reacted to form product. The percentage yield compares what you actually collect with this maximum:
$\text{percentage yield} = \dfrac{\text{actual yield}}{\text{theoretical yield}} \times 100$
Yields are below 100% because reactions may reach equilibrium, side reactions use some reactant, and product is lost on glassware, in filter paper and in each purification step. In a multi-step synthesis the yields multiply:
$\text{overall yield} = Y_1 \times Y_2 \times Y_3 \times \ldots$
So three steps of 95%, 80% and 67% give only $0.95 \times 0.80 \times 0.67 = 0.51$, or 51%, before any purification losses. This is why chemists prefer short routes, and why one low-yield step is often the target for improvement.
A student reacts 2.00 g of salicylic acid (C₇H₆O₃, M = 138.1 g/mol) with excess ethanoic anhydride and collects 1.95 g of pure, dry aspirin (C₉H₈O₄, M = 180.2 g/mol). The equation is C₇H₆O₃ + C₄H₆O₃ → C₉H₈O₄ + CH₃COOH. Calculate the percentage yield.
Improving the yield
For an equilibrium step, Le Chatelier's principle suggests ways to push the reaction forward. In esterification you can use an excess of the cheaper reactant (usually the alcohol) or remove a product as it forms (distilling off the ester or removing water). For a slow step, a catalyst or higher temperature increases the rate but, for an exothermic equilibrium, a higher temperature lowers the equilibrium yield, so the conditions are a compromise. The recycling of unreacted reagents (as in ethene hydration and the Haber process) turns a low conversion per pass into a high overall yield.
- With the default settings (recycling on, 80% oxidation, 1 : 1 ratio, 10% purification loss), the overall yield is 45.6% and you need 0.70 kg of ethene for each 1.00 kg of ester.
- Turn off recycling. The overall yield falls to 2.4% and you'd need 13.26 kg of ethene. Explain why recycling matters so much.
- Change the ethanol : acid ratio to 2 : 1 and then 4 : 1. The ester step rises from 67% to 85% and 93%. Which principle explains this?
- Find settings that give the highest overall yield. Which single change improves the yield most from the default settings?
Purification and checking purity
| Technique | Separates | Example |
|---|---|---|
| Filtration | a solid product from a liquid | collecting aspirin crystals |
| Recrystallisation | a solid from small amounts of impurities, by dissolving in a minimum of hot solvent and cooling | purifying aspirin |
| Separating funnel | immiscible liquids; washing out acid or water-soluble impurities | washing a crude ester with sodium carbonate solution |
| Distillation / fractional distillation | liquids with different boiling points | ethanol from water; ester from the reaction mixture |
| Drying agent | traces of water from an organic liquid | anhydrous MgSO₄ in a crude ester |
Purity is then checked. A pure solid has a sharp melting point matching the literature value (aspirin melts at about 136 °C); impurities lower it and spread it over a range. A pure liquid boils at a constant temperature. Spectroscopy (IR, NMR) shows whether any starting material remains, and chromatography shows how many substances are present.
Test yourself
A synthesis has four steps with yields of 90%, 80%, 70% and 90%. The overall yield is closest to
0.90 × 0.80 × 0.70 × 0.90 = 0.454.
Which change would increase the equilibrium yield of ethyl ethanoate from ethanoic acid and ethanol?
Excess reactant shifts the equilibrium to the right. A catalyst only increases the rate, and adding water shifts it left.
A student's aspirin melts over the range 125–131 °C. The literature value is 136 °C. The best conclusion is that the product
Impurities lower the melting point and spread it over a range.
5.00 g of ethanol (M = 46.07) reacts with excess ethanoic acid and 5.20 g of ethyl ethanoate (M = 88.11) is collected. The percentage yield is
n(ethanol) = 0.1085 mol; theoretical = 0.1085 × 88.11 = 9.56 g; 5.20 ÷ 9.56 × 100 = 54.4%.
Name each step of the synthesis.
How does each change affect the synthesis of an ester by an equilibrium reaction?
The theoretical yield is calculated from the reagent. In a multi-step synthesis, the overall yield is the of the step yields. A solid is purified by . A pure solid has a melting point.
Ethyl ethanoate is made in three steps from ethene: hydration (95% after recycling), oxidation (80%) and esterification (67%). (a) Calculate the overall yield and the theoretical mass of ethyl ethanoate from 1.00 tonne of ethene. (b) Evaluate two ways the overall yield could be improved.
(a) Overall yield = 0.95 × 0.80 × 0.67 = 0.51, or 51%. One mole of ethene can give at most one mole of ethyl ethanoate (following the carbon that ends up in the acid half), so the theoretical mass from 1.00 t of ethene is $1.00 \times \dfrac{88.11}{28.05} = 3.14$ t, and the expected mass is about 0.51 × 3.14 = 1.6 t.
(b) The esterification is the lowest-yield step because it is an equilibrium with K ≈ 4. Using excess ethanol shifts the equilibrium to the right (Le Chatelier) and raises the step yield to about 85% with a 2 : 1 ratio. This is effective and the excess ethanol can be recovered by distillation, though that uses energy. Removing water (or distilling off the ester) as it forms also shifts the equilibrium right and can push the step above 90%; it adds equipment cost but is used industrially. Improving the 80% oxidation step, for example with a more selective catalyst, would also help. Overall, raising the yield of the esterification step gives the largest gain for the least cost.