Synthesising Aspirin — The Reaction That Founded Modern Pharmaceuticals

Work in a fume hood or well-ventilated area. Put on chemical splash goggles, nitrile gloves, and a lab coat. Acetic anhydride vapour is acutely irritating to the eyes and respiratory tract — it hydrolyses to acetic acid on contact with moist mucous membranes. Have a beaker of water nearby for rinsing any spills immediately. Keep the acetic anhydride bottle capped when not in use.

Weigh 2.0 g of salicylic acid (2-hydroxybenzoic acid, C₇H₆O₃) into a dry 125 ml Erlenmeyer flask. Salicylic acid is a white crystalline powder with a slight phenolic odour. It was first synthesised by Hermann Kolbe in 1859 by treating sodium phenoxide with carbon dioxide under pressure — the Kolbe-Schmitt reaction, one of the earliest industrial organic syntheses. The hydroxyl group on the benzene ring is the target for acetylation.

Measure 3 ml of acetic anhydride (C₄H₆O₃) using a graduated cylinder and add to the salicylic acid in the flask. Acetic anhydride is a colourless liquid with a sharp, vinegar-like odour — it is the dehydrated form of two acetic acid molecules joined together. It is a more reactive acetylating agent than acetic acid itself because the reaction releases acetic acid (a good leaving group) rather than water. Work quickly and recap the bottle — the vapour is a powerful lacrimator.

Add 5 drops of concentrated phosphoric acid (H₃PO₄, 85%) to the mixture. The acid serves as a catalyst — it protonates the carbonyl oxygen of the acetic anhydride, making the carbonyl carbon more electrophilic and accelerating the nucleophilic attack by the hydroxyl group of salicylic acid. Swirl gently to mix. Sulfuric acid was used historically but phosphoric acid is preferred because it is less likely to cause charring or side reactions.

Place the flask in a water bath heated to 75–85 °C. Clamp the flask so it does not tip. Heat for 15 minutes, swirling occasionally. The salicylic acid dissolves as the reaction proceeds and the mixture becomes a clear solution. The esterification reaction is: C₇H₆O₃ + (CH₃CO)₂O → C₉H₈O₄ + CH₃COOH. The acetyl group from acetic anhydride replaces the hydrogen on the phenolic hydroxyl, forming the ester bond that defines aspirin. The acetic acid by-product evaporates partly as a vinegar smell.

Remove the flask from the water bath and carefully add 20 ml of cold distilled water. The water reacts with the excess acetic anhydride: (CH₃CO)₂O + H₂O → 2 CH₃COOH. This is exothermic — the flask warms noticeably. Stir until no more heat is produced. This step destroys the unreacted acetic anhydride so that it does not contaminate the product. The solution is now a mixture of dissolved aspirin, acetic acid, phosphoric acid, and water.

Place the flask in an ice bath and allow to cool for 10–15 minutes. As the solution cools, acetylsalicylic acid crystallises out as a mass of white, needle-like crystals — aspirin is much less soluble in cold water than in hot. If crystals do not appear, scratch the inside of the flask with a glass rod to provide nucleation sites. The crystals form rapidly once nucleation begins, often filling the flask with a dense white mass within minutes.

Set up a filtration apparatus with a funnel and filter paper. Pour the crystal suspension through the filter. The white crystals collect on the paper while the acetic acid, phosphoric acid, and water pass through. Wash the crystals twice with 10 ml of cold distilled water to remove residual acid. Press the crystals gently with a spatula to remove excess water. The crude aspirin should be a white, crystalline solid with a faint vinegar-like odour from traces of acetic acid.

Transfer the crystals to a clean watch glass or evaporating dish and allow to air-dry for 30 minutes. The dried product is pure white, crystalline acetylsalicylic acid — aspirin. Weigh the product: the theoretical yield from 2.0 g salicylic acid is 2.6 g aspirin (the acetyl group adds mass). Typical lab yields are 1.5–2.2 g (60–85%). The crystals have a characteristic needle-like habit and a melting point of 135 °C — testing the melting point is the standard purity check in teaching laboratories.

Dissolve a few crystals in 5 ml of water and add 1–2 drops of ferric chloride solution (FeCl₃). Pure aspirin gives no colour change or a very faint yellow. If a deep purple colour appears, unreacted salicylic acid is present — the free phenolic hydroxyl reacts with iron(III) to form a coloured complex. In pure aspirin, that hydroxyl is blocked by the acetyl group, preventing the colour reaction. This is one of the simplest and most elegant purity tests in organic chemistry.

Transfer the dried aspirin to a small glass vial and label: ACETYLSALICYLIC ACID (ASPIRIN) — LAB SYNTHESIS — NOT FOR CONSUMPTION. Store in a cool, dry place. Over time, aspirin slowly hydrolyses back to salicylic acid and acetic acid — old aspirin tablets have a vinegar smell for exactly this reason. Hoffmann's 1897 synthesis created not just a drug but an industry: Bayer's Aspirin was the first branded pharmaceutical, the first drug sold as tablets, and remains the most widely used medicine in history — over 100 billion tablets are consumed annually worldwide.