Introduction: Making and Purifying Aspirin
Welcome to one of the most exciting and essential practical topics in CCEA A2 Organic Chemistry: the synthesis and purification of aspirin (also known chemically as 2-ethanoyloxybenzenecarboxylic acid or acetylsalicylic acid). In this chapter, you will learn how chemists build a widely used painkiller from simple starting materials, separate the crude product, purify it to pharmaceutical standards, and verify its purity using standard analytical techniques.
Don't worry if organic synthesis seems daunting at first! By breaking down the process into four logical stages—Reaction, Separation, Purification, and Testing—you will master both the practical steps and the theory needed for your exam.
Did you know? The active precursor of aspirin, salicylic acid, was originally extracted from willow bark and used for centuries to treat fever and pain. However, salicylic acid causes severe stomach irritation. By chemically converting its phenolic group into an ester (forming aspirin), chemists made it significantly gentler on the digestive tract!
---Section 1: The Chemistry of the Reaction
The Reactants and Products
Aspirin is prepared via an esterification or acylation reaction (nucleophilic addition–elimination) where the phenolic \(-\text{OH}\) group of 2-hydroxybenzoic acid is converted into an ester.
• 2-hydroxybenzoic acid (salicylic acid): \(\text{C}_7\text{H}_6\text{O}_3\) (Molar mass \(M_{\text{r}} = 138.12\text{ g mol}^{-1}\))
• Ethanoic anhydride (acetic anhydride): \((\text{CH}_3\text{CO})_2\text{O}\) (Molar mass \(M_{\text{r}} = 102.09\text{ g mol}^{-1}\))
• Catalyst: Concentrated sulfuric acid (\(\text{H}_2\text{SO}_4\)) or concentrated \(85\%\) phosphoric acid (\(\text{H}_3\text{PO}_4\))
• Main Product — Aspirin: \(\text{C}_9\text{H}_8\text{O}_4\) (Molar mass \(M_{\text{r}} = 180.16\text{ g mol}^{-1}\))
• By-product — Ethanoic acid: \(\text{CH}_3\text{COOH}\)
The Balanced Chemical Equation
\(\text{C}_7\text{H}_6\text{O}_3 + (\text{CH}_3\text{CO})_2\text{O} \xrightarrow{\text{acid catalyst}} \text{C}_9\text{H}_8\text{O}_4 + \text{CH}_3\text{COOH}\)
In this reaction, the lone pair of electrons on the phenolic oxygen atom attacks the carbonyl carbon of ethanoic anhydride. An acetyl group (\(-\text{COCH}_3\)) attaches to the oxygen, yielding aspirin and a molecule of ethanoic acid.
Why Use Ethanoic Anhydride Instead of Ethanoyl Chloride?
In organic synthesis, an acyl chloride (such as ethanoyl chloride, \(\text{CH}_3\text{COCl}\)) could technically react with 2-hydroxybenzoic acid to make aspirin. However, ethanoic anhydride is strongly preferred in school laboratories and industry for several critical reasons:
1. Safety and Corrosiveness: Ethanoic anhydride reacts less violently and does not release dangerous, corrosive, toxic white fumes of hydrogen chloride gas (\(\text{HCl}\)). Instead, it forms ethanoic acid (\(\text{CH}_3\text{COOH}\)).
2. Cost: Ethanoic anhydride is cheaper to purchase and manufacture.
3. Hydrolysis Rate: It hydrolyses much less rapidly in moist air, making it safer and easier to store and handle.
Key Takeaway for Section 1: Aspirin is made by reacting 2-hydroxybenzoic acid with excess ethanoic anhydride in the presence of an acid catalyst (\(\text{H}_2\text{SO}_4\) or \(\text{H}_3\text{PO}_4\)), producing aspirin and ethanoic acid.
---Section 2: Practical Synthesis and Purification
The laboratory preparation consists of three key practical phases: Synthesis, Filtration under reduced pressure, and Recrystallisation.
Phase 1: Synthesis (The Reaction Phase)
1. Accurately weigh a known mass of dry 2-hydroxybenzoic acid into a dry pear-shaped or conical flask.
2. Add an excess of ethanoic anhydride followed by a few drops of concentrated acid catalyst (\(\text{H}_2\text{SO}_4\) or \(\text{H}_3\text{PO}_4\)).
3. Heat the mixture gently in a water bath held at approximately \(70\text{--}85\text{ }^\circ\text{C}\) for around \(15\text{ minutes}\) to ensure the reaction goes to completion.
4. Allow the flask to cool, then add cold or iced distilled water. Why? The cold water hydrolyses (destroys) any unreacted excess ethanoic anhydride, converting it into soluble ethanoic acid.
5. Place the flask in an ice bath. As the temperature drops, crude aspirin crystals precipitate out because aspirin has very low solubility in cold water.
Phase 2: Separation of the Crude Product (Suction Filtration)
The crude solid is separated from the reaction solution using vacuum filtration (filtration under reduced pressure):
• A Büchner funnel fitted with flat filter paper is placed on a side-arm Büchner flask connected to a vacuum pump or water aspirator.
• The vacuum pulls air and liquid through rapidly, separating the solid crystals on the filter paper while pulling the liquid (the mother liquor or filtrate) into the flask.
• Rinsing: The crude crystals are washed on the funnel with a minimal volume of ice-cold distilled water to wash away soluble acids without dissolving the aspirin crystals.
Phase 3: Purification by Recrystallisation
The solid obtained in Phase 2 is "crude" because it still contains trapped impurities. Recrystallisation purifies the solid based on differences in solubility at different temperatures.
Step-by-step Recrystallisation Procedure:
1. Dissolution: Dissolve the crude aspirin crystals in the minimum volume of hot solvent (ethanol or a water-ethanol solvent mixture) in a conical flask.
Why "minimum volume"? If you use too much solvent, the solution will be too dilute, and the aspirin will remain dissolved instead of crystallising when cooled.
2. Hot Filtration (if required): If there are insoluble impurities present, the hot solution is filtered quickly through fluted filter paper.
3. Cooling and Crystallisation: Allow the clear, hot solution to cool slowly to room temperature undisturbed, and then chill it thoroughly in an ice bath. Pure aspirin crystals reform, while soluble impurities remain dissolved in the cold solvent.
4. Collecting the Pure Crystals: Filter the purified crystals under reduced pressure using a Büchner funnel.
5. Final Wash and Drying: Wash the collected pure crystals with a small amount of ice-cold solvent. Dry the crystals thoroughly in a desiccator, between filter papers, or in a low-temperature drying oven set well below the melting point of aspirin.
Analogy: Imagine cleaning a dirty sponge covered in salt and sand. You dissolve the sponge's trapped salt in hot water, filter out the sand, and cool the water so only clean crystals grow back!
Key Takeaway for Section 2: Recrystallisation requires the minimum volume of hot solvent, slow cooling, ice bath chilling, and washing with ice-cold solvent to maximise the recovery of pure crystals.
---Section 3: Testing Purity and Characterisation
Once your aspirin is dried, how do you prove that the synthesis worked and that the product is completely pure? There are three standard laboratory methods:
1. Melting Point Determination
Every pure crystalline organic compound has a characteristic, sharp melting point. For pure aspirin, the melting point is \(135\text{--}136\text{ }^\circ\text{C}\).
• A small, dry sample of aspirin is packed tightly into the sealed end of a glass capillary tube.
• The tube is placed in a melting point apparatus (e.g., an electrical melting point unit or a Thiele tube) and heated slowly near the expected melting temperature.
• Effect of Impurities: Impurities disrupt the regular crystalline lattice of the solid. Consequently, impurities lower the melting point and cause the solid to melt over a broad temperature range (e.g., \(126\text{--}132\text{ }^\circ\text{C}\)) rather than sharply at \(135\text{--}136\text{ }^\circ\text{C}\).
2. Iron(III) Chloride Test (\(\text{FeCl}_3\) Test)
This is a specific chemical test used to check whether any unreacted starting material (2-hydroxybenzoic acid) remains in your product.
• Aqueous neutral Iron(III) chloride (\(\text{FeCl}_3\)) is added to a sample dissolved in water/ethanol.
• Starting Material (2-hydroxybenzoic acid): Contains a free phenolic \(-\text{OH}\) group. It coordinates with \(\text{Fe}^{3+}\) ions to form an intense purple/violet complex.
• Pure Aspirin: The phenolic \(-\text{OH}\) group has been esterified and is no longer free. Therefore, pure aspirin produces no purple colouration / no colour change (the solution remains yellow/pale orange from the reagent).
3. Thin-Layer Chromatography (TLC)
TLC separates compounds based on their relative affinities for a stationary phase (silica plate) and a mobile phase (solvent):
• Samples of pure 2-hydroxybenzoic acid standard, authentic aspirin standard, crude aspirin, and purified aspirin are spotted onto the baseline of a TLC plate.
• After development, the spots are visualised under UV light.
• Pure Aspirin: Shows a single distinct spot with an identical Retention Factor (\(R_{\text{f}}\)) to the authentic aspirin standard.
• Impure Aspirin: Shows multiple spots (e.g., an extra spot corresponding to unreacted 2-hydroxybenzoic acid).
Key Takeaway for Section 3: Pure aspirin melts sharply at \(135\text{--}136\text{ }^\circ\text{C}\), gives a negative (no purple colour) result with \(\text{FeCl}_3\) solution, and shows a single spot on a TLC plate.
---Section 4: Quantitative Calculations & Percentage Yield
Step 1: Calculating Moles of Limiting Reactant
Usually, 2-hydroxybenzoic acid is the limiting reactant because ethanoic anhydride is added in excess.
\(\text{Moles of 2-hydroxybenzoic acid} = \frac{\text{Mass used (g)}}{M_{\text{r}} \text{ (}138.12\text{ g mol}^{-1}\text{)}}\)
Step 2: Calculating Theoretical Yield
From the balanced equation, \(1\text{ mole}\) of 2-hydroxybenzoic acid produces \(1\text{ mole}\) of aspirin (\(1:1\) stoichiometric ratio):
\(\text{Theoretical moles of aspirin} = \text{Moles of 2-hydroxybenzoic acid}\)
\(\text{Theoretical mass of aspirin (g)} = \text{Theoretical moles} \times 180.16\text{ g mol}^{-1}\)
Step 3: Calculating Percentage Yield
\(\text{Percentage Yield} = \left(\frac{\text{Actual Mass Obtained (g)}}{\text{Theoretical Mass (g)}}\right) \times 100\%\)
Worked Example:
A student reacts \(2.76\text{ g}\) of 2-hydroxybenzoic acid with excess ethanoic anhydride. After purification, \(2.52\text{ g}\) of pure dry aspirin is collected. Calculate the percentage yield.
1. \(\text{Moles of 2-hydroxybenzoic acid} = \frac{2.76\text{ g}}{138.12\text{ g mol}^{-1}} = 0.0200\text{ mol}\)
2. \(\text{Theoretical mass of aspirin} = 0.0200\text{ mol} \times 180.16\text{ g mol}^{-1} = 3.603\text{ g}\)
3. \(\text{Percentage Yield} = \left(\frac{2.52\text{ g}}{3.603\text{ g}}\right) \times 100\% = 69.9\%\)
Why is the Percentage Yield Never 100%?
In organic syntheses, the actual yield is always lower than the theoretical yield due to:
• Incomplete reaction or equilibrium limits.
• Side-reactions producing unwanted by-products.
• Loss of product during transfers: Crystals sticking to the sides of beakers, flasks, and filter paper.
• Solubility losses: Some aspirin remains dissolved in the solvent during recrystallisation and washing, being discarded in the filtrate (mother liquor).
Section 5: Common Exam Pitfalls to Avoid
• Mistake 1: Using too much solvent during recrystallisation.
Correction: Always state that the minimum volume of hot solvent is used. Excess solvent prevents crystallisation when cooled, drastically reducing yield.
• Mistake 2: Washing crystals with warm or excess room-temperature solvent.
Correction: Always specify washing with a minimum volume of ice-cold solvent to prevent dissolving the purified aspirin crystals.
• Mistake 3: Thinking impurities raise the melting point.
Correction: In organic chemistry, impurities weaken the crystal lattice, which lowers the melting point and broadens the melting range.
• Mistake 4: Misinterpreting the \(\text{FeCl}_3\) test.
Correction: \(\text{FeCl}_3\) tests specifically for the phenolic \(-\text{OH}\) group on unreacted salicylic acid. Pure aspirin still contains a carboxylic acid (\(-\text{COOH}\)) group, but does not turn purple because its phenolic \(-\text{OH}\) has been converted to an ester.
• Mistake 5: Saying ethanoic anhydride is used because it produces a higher yield.
Correction: Ethanoic anhydride is chosen primarily because it is safer (no toxic/corrosive \(\text{HCl}\) fumes produced), cheaper, and reacts less violently than ethanoyl chloride.
Chapter Quick Review
• Reaction: 2-hydroxybenzoic acid + ethanoic anhydride \(\rightarrow\) Aspirin + ethanoic acid (catalysed by conc. \(\text{H}_2\text{SO}_4\) or \(\text{H}_3\text{PO}_4\)).
• Filtration: Büchner funnel under reduced pressure (suction filtration) allows fast separation.
• Recrystallisation: Dissolve in minimum hot solvent \(\rightarrow\) cool slowly \(\rightarrow\) place in ice bath \(\rightarrow\) filter and wash with ice-cold solvent \(\rightarrow\) dry.
• Purity Checks: Sharp melting point at \(135\text{--}136\text{ }^\circ\text{C}\), negative \(\text{FeCl}_3\) test (no purple colour), and a single spot on TLC.