Evaluating an aspirin synthesis by limiting reagent, yield and titration
A student prepares aspirin (acetylsalicylic acid, Mr = 180.16) by reacting salicylic acid (Mr = 138.12) with acetic anhydride (Mr = 102.09, density = 1.08 g cm−3). The student uses 2.00 g of salicylic acid, 5.0 cm3 of acetic anhydride and a few drops of concentrated sulfuric acid. After heating, cooling, adding water and recrystallising, the crude product weighs 2.10 g. A 0.100 g sample of the recrystallised product is dissolved in ethanol and titrated with 0.100 mol dm−3 sodium hydroxide; 5.40 cm3 are required to reach the phenolphthalein end-point. Aspirin has one carboxylic acid group. The student claims the synthesis is a failure because the yield is below 100% and because the titration volume is not exactly the theoretical value. The teacher asks for a quantitative evaluation of limiting reagent, yield and purity, and for an explanation of why the reaction is carried out with acetic anhydride rather than acetic acid.
1. Identify the limiting reagent and calculate the theoretical yield, the percentage yield of crude aspirin and the percentage yield of pure aspirin.
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Moles of reactants
n(salicylic acid) = 2.00 / 138.12 = 1.448 × 10−2 mol
mass(acetic anhydride) = 5.0 cm3 × 1.08 g cm−3 = 5.40 g n(acetic anhydride) = 5.40 / 102.09 = 5.29 × 10−2 mol
The reaction is 1:1. Salicylic acid is present in the smaller amount, so it is the limiting reagent.
Theoretical yield
n(aspirin) = n(salicylic acid) = 1.448 × 10−2 mol mass(theoretical) = 1.448 × 10−2 × 180.16 = 2.61 g
Crude yield
percentage yield = (2.10 / 2.61) × 100 = 80.5%
Purity from titration
n(NaOH) = 0.100 × 5.40 × 10−3 = 5.40 × 10−4 mol n(aspirin) in 0.100 g = 5.40 × 10−4 mol mass of pure aspirin in 0.100 g = 5.40 × 10−4 × 180.16 = 9.73 × 10−2 g purity = (0.0973 / 0.100) × 100 = 97.3%
mass of pure aspirin obtained = 2.10 × 0.973 = 2.04 g percentage yield of pure aspirin = (2.04 / 2.61) × 100 = 78.2%
The synthesis is not a failure: a 78% pure yield is a reasonable laboratory result.
2. Explain why the yield is below 100% and why acetic anhydride is used instead of acetic acid.
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A yield below 100% is normal in a preparative reaction. Possible reasons include: the reaction may not go to completion; some product is lost during filtration, washing and recrystallisation; the crude product contains impurities; and some aspirin may hydrolyse back to salicylic acid when water is added. The recrystallisation step always sacrifices some pure product to obtain a higher purity.
Acetic anhydride is used rather than acetic acid because it is a much more reactive acylating agent. The carbonyl carbon of the anhydride is more electrophilic than that of acetic acid, so the phenolic oxygen of salicylic acid attacks it more readily. The by-product is acetic acid, not water. Using acetic acid would produce water as a by-product, and the esterification would be an equilibrium that is less favourable. Water could also hydrolyse the product. The anhydride therefore drives the reaction further towards aspirin and gives a better yield under mild conditions.
3. Outline the mechanism for the formation of aspirin from salicylic acid and acetic anhydride, identifying the nucleophile and the leaving group.
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The reaction is an acid-catalysed nucleophilic acyl substitution.
The sulfuric acid protonates one carbonyl oxygen of acetic anhydride, making that carbonyl carbon more electrophilic.
The phenolic –OH group of salicylic acid acts as the nucleophile. Its oxygen lone pair attacks the electrophilic carbonyl carbon, forming a tetrahedral intermediate.
The tetrahedral intermediate collapses. One acetate group is expelled as a leaving group, reforming the carbonyl group and forming the new ester link between the phenolic oxygen and the acetyl group.
Deprotonation gives aspirin and acetic acid as the by-product.
Nucleophile: the phenolic oxygen of salicylic acid, not the carboxylic acid oxygen. Leaving group: acetate ion, CH3COO−, which is stabilised by resonance. The carboxylic acid group of salicylic acid remains unchanged; it is the phenolic –OH that is acetylated.