HookHow a cheap, nasty liquid turned salicylic acid into aspirin
In 1897 a chemist at Bayer named Felix Hoffmann took salicylic acid — a genuine painkiller, but one so harsh it left patients with burning, bleeding stomachs — and reacted it with a cheap, acrid liquid called ethanoic anhydride. The anhydride capped the one troublesome group on the molecule, and out came acetylsalicylic acid: aspirin, still one of the most-consumed drugs on the planet at roughly 40,000 tonnes a year. The reaction Hoffmann ran is called acylation, and the white crystals he filtered off, washed and recrystallised are exactly the kind of organic solid you will prepare and purify in Required Practical 10.
This section is really one story told through a family of related compounds. At its centre sits the carboxylic acid, with its \(-\text{COOH}\) group — the sharp taste of vinegar, the sting of an ant bite, the sourness of citrus. Carboxylic acids are weak acids, but they are acidic enough to give themselves away in a test tube. React one with an alcohol and you get an ester, the molecule behind the smell of pear drops and the flavour of countless sweets. Swap the acid for a more reactive relative — an acyl chloride or an acid anhydride — and the same ester forms in seconds instead of hours, which is why industry reaches for those reactive derivatives to build everything from aspirin to synthetic fibres. Underneath all of it is one repeating move: a nucleophile attacking the electron-poor carbon of a carbonyl.
ModelWhy vinegar is a weak acid — and how weakness gives it away
A carboxylic acid has the \(-\text{COOH}\) group and is named with the ending -oic acid (ethanoic acid, \(\text{CH}_3\text{COOH}\), is the acid in vinegar at about 5% by volume). It is a weak acid: in water it only partially ionises, sitting at an equilibrium that lies well over to the left, \(\text{CH}_3\text{COOH} \rightleftharpoons \text{CH}_3\text{COO}^- + \text{H}^+\). Only a small fraction of the molecules donate their proton at any instant — ethanoic acid has a \(K_a\) of about \(1.7 \times 10^{-5}\ \text{mol dm}^{-3}\) (\(\text{p}K_a \approx 4.76\)), which is why a typical vinegar sits around pH 2.4 rather than the pH 1 a strong acid of the same concentration would give.
Weak though it is, a carboxylic acid is a real acid and behaves like one. It reacts with reactive metals to give a salt (a carboxylate) and hydrogen; with bases and alkalis it is neutralised to a carboxylate and water. Its most useful reaction for identification is with carbonates and hydrogencarbonates: it fizzes, releasing carbon dioxide, \(2\text{CH}_3\text{COOH} + \text{Na}_2\text{CO}_3 \rightarrow 2\text{CH}_3\text{COONa} + \text{H}_2\text{O} + \text{CO}_2\).
That effervescence is a genuinely useful diagnostic, because it distinguishes carboxylic acids from phenols. Phenol is also weakly acidic, but far too weak to displace carbon dioxide from a carbonate — so 'add sodium carbonate; does it fizz?' cleanly separates a carboxylic acid (fizzes) from a phenol (does not). Small carboxylic acids also dissolve readily in water because the \(-\text{COOH}\) group hydrogen-bonds to it, though that solubility falls away as the hydrocarbon chain lengthens.
MechanismEsterification — the reversible route and the one-way route
Warm a carboxylic acid with an alcohol and a few drops of concentrated sulfuric acid catalyst, and they combine to form an ester plus water. This is esterification, and the crucial feature is that it is reversible: \(\text{CH}_3\text{COOH} + \text{C}_2\text{H}_5\text{OH} \rightleftharpoons \text{CH}_3\text{COOC}_2\text{H}_5 + \text{H}_2\text{O}\). Because it reaches an equilibrium rather than going to completion, the yield is limited; the concentrated sulfuric acid acts as both catalyst and dehydrating agent, and using an excess of one reactant or removing the water helps push the equilibrium towards the ester. The mixture is heated under reflux so that volatile reactants condense and return to the flask instead of escaping.
Esters are named the other way round from how they are written: the alcohol-derived part first, the acid-derived part second, ending in -oate. Ethanoic acid and ethanol give ethyl ethanoate. Esters are prized for their smells and are used as solvents, plasticisers, perfumes and food flavourings — ethyl ethanoate is the pear-drop note in many sweets and the solvent in nail-varnish remover.
There is a faster, one-way route to the same esters, and it is the reason the next block matters: reacting an alcohol with an acyl chloride or an acid anhydride forms the ester rapidly and essentially irreversibly, in high yield, without the equilibrium ceiling that limits the acid-plus-alcohol method.
Name the ester formed from propan-1-ol and ethanoic acid, and write the equation.
Take the acid-derived part from ethanoic acid: 'ethanoate'. Take the alcohol-derived part from propan-1-ol: 'propyl'. The alcohol part is written first, so the ester is propyl ethanoate — a common slip is to reverse the two and write 'ethyl propanoate', which is a different molecule entirely. The equation, catalysed by concentrated sulfuric acid and heated under reflux, is reversible:
\[\text{CH}_3\text{COOH} + \text{C}_3\text{H}_7\text{OH} \rightleftharpoons \text{CH}_3\text{COOC}_3\text{H}_7 + \text{H}_2\text{O}\]
The check: the ester oxygen bridge comes from the alcohol, and the \(\text{C=O}\) comes from the acid — trace which atoms end up where and the naming order stops being arbitrary.
MechanismAcylation — acyl transfer by addition–elimination
The reactive derivatives of carboxylic acids are the acyl chlorides, \(\text{RCOCl}\) (ethanoyl chloride is \(\text{CH}_3\text{COCl}\)), and the acid anhydrides, \((\text{RCO})_2\text{O}\) (ethanoic anhydride is \((\text{CH}_3\text{CO})_2\text{O}\)). Both transfer an acyl group, \(\text{RCO}-\), to a nucleophile, a reaction called acylation. The mechanism is nucleophilic addition–elimination: the nucleophile attacks the \(\delta+\) carbonyl carbon and the \(\text{C=O}\) bond breaks onto oxygen (the addition), then the \(\text{C=O}\) re-forms and pushes out a leaving group — chloride from an acyl chloride, or a carboxylate from an anhydride (the elimination).
The same four nucleophiles give four predictable products. With water an acyl chloride gives a carboxylic acid; with an alcohol it gives an ester; with ammonia it gives a primary amide; with a primary amine it gives an N-substituted (secondary) amide. Acyl chlorides react violently — ethanoyl chloride fumes in moist air, releasing steamy, misty \(\text{HCl}\) gas — while anhydrides react more gently and release a carboxylic acid rather than corrosive hydrogen chloride.
That gentleness is why industry prefers the anhydride. To make aspirin, salicylic acid is acylated with ethanoic anhydride rather than ethanoyl chloride because the anhydride is cheaper, is not corroded or destroyed by moisture in the air, does not produce dangerous \(\text{HCl}\) fumes, and is generally safer to handle on a large scale — a comparison AQA asks for almost every year.
DataRequired Practical 10 — making and purifying aspirin, and an ester
RP10 is preparing and purifying an organic solid and an organic liquid, and aspirin is the classic solid. Method: mix salicylic acid with an excess of ethanoic anhydride and a few drops of concentrated sulfuric acid (the catalyst) in a conical flask, and warm in a water bath to react. Add water to hydrolyse the leftover anhydride, then cool in ice so the aspirin crystallises out. Collect the crystals by filtration under reduced pressure (a Büchner funnel and side-arm flask), which pulls the crystals dry far faster than gravity filtration.
A solid is purified by recrystallisation: dissolve the crude solid in the minimum volume of hot solvent, filter the hot solution to remove insoluble impurities, then cool slowly so the pure product crystallises while soluble impurities stay behind in solution; filter under reduced pressure, wash with a little cold solvent, and dry. Purity is checked with a melting point — a pure sample melts sharply at, and matching, the data-book value, whereas an impure one melts lower and over a wider range.
A liquid product, such as an ester, is purified differently. Wash it in a separating funnel to remove impurities (for example, shaking with sodium carbonate solution to remove acid — remember to release the built-up carbon dioxide by venting the tap), run off and discard the aqueous layer, dry the organic layer with an anhydrous drying agent such as \(\text{CaCl}_2\) or \(\text{MgSO}_4\), then purify by distillation, collecting only the fraction that boils at the product's known boiling point. Typical sources of a low yield are losses on transfer between vessels, product left dissolved in the filtrate, and incomplete reaction — all of which you quantify in the yield calculation.
A student makes aspirin from 2.00 g of salicylic acid (\(M_r = 138.0\)) with an excess of ethanoic anhydride, so salicylic acid is the limiting reagent. After recrystallisation they obtain 1.90 g of pure aspirin (\(M_r = 180.0\)). Calculate the percentage yield.
Step 1 — moles of salicylic acid: \(n = \dfrac{2.00}{138.0} = 0.01449\ \text{mol}\).
Step 2 — the equation is 1:1, so the maximum (theoretical) moles of aspirin is also \(0.01449\ \text{mol}\). Theoretical mass \(= 0.01449 \times 180.0 = 2.61\ \text{g}\).
Step 3 — percentage yield \(= \dfrac{\text{actual}}{\text{theoretical}} \times 100 = \dfrac{1.90}{2.61} \times 100 = 72.8\%\).
Quote it to three significant figures. The 27% shortfall is realistic for a school prep: aspirin lost dissolved in the filtrate during recrystallisation, crystals left clinging to the glassware, and any unreacted salicylic acid all pull the figure below 100%. Naming the losses, not just stating the number, is what the marks reward.
VocabularyKey terms the mark scheme pays for
TrapsMisconceptions that cost marks
ExamWhat examiners want
Show acidity through reactions, not adjectives. Write the dissociation with a reversible arrow, \(\rightleftharpoons\), to signal a weak acid, and reach for the sodium carbonate effervescence test whenever a question asks you to distinguish a carboxylic acid from a phenol or an alcohol. Both the observation (fizzing, gas produced) and the balanced equation earn marks.
Name esters in the right order — alkyl group from the alcohol first, alkanoate from the acid second — because reversing them names a different compound and is one of the most common lost marks in this topic. State the conditions for esterification (concentrated sulfuric acid catalyst, heat under reflux) and show the equilibrium arrow.
For acylation, name the mechanism as nucleophilic addition–elimination and be ready to draw the curly arrows through to the loss of the leaving group. A standard six-mark question asks why ethanoic anhydride, not ethanoyl chloride, is used industrially to make aspirin: give the reasons in full — cheaper, not hydrolysed by atmospheric moisture, does not release corrosive HCl fumes, and safer to handle.
On Required Practical 10, quote the purification steps precisely. For the solid: recrystallise from the minimum volume of hot solvent, filter under reduced pressure, and measure the melting point, comparing it with the data book (sharp and correct means pure; low and broad means impure). For the liquid: wash in a separating funnel, dry with an anhydrous salt, then distil and collect at the boiling point. In yield calculations, identify the limiting reagent, use the correct \(M_r\), work to three significant figures, and explain the shortfall in terms of real losses.