Functional groups in drug molecules
A functional group is a small group of atoms that decides how a molecule behaves. A drug works because its groups fit and react in the body. Four are important here:
- Hydroxyl, -OH on a ring (phenol): weakly acidic, turns purple with iron(III) chloride.
- Carboxylic acid, -COOH: acidic; it can form esters and amides.
- Ester, -COO-: made from an acid and an -OH. Esters are less acidic than acids.
- Amide, -CONH-: made from an acid and an amine (-NH2); very stable.
Salicylic acid has a phenol -OH and a -COOH. Aspirin (acetylsalicylic acid) has an ester and a -COOH. Paracetamol has a phenol -OH and an amide. Ibuprofen has a -COOH.
Simple retrosynthesis
Retrosynthesis means planning a synthesis backwards. You start from the target molecule, find the bond you can make easily, and break it on paper to see which simple starting molecules you need. We draw this with an open arrow pointing from target to starting materials.
Aspirin: the ester bond is the one we can make. Break it on paper and you get the alcohol-type piece (the -OH of salicylic acid) and an acetyl piece. A safe, cheap source of acetyl is acetic anhydride. Paracetamol: break the amide bond and you get 4-aminophenol and an acetyl source.
Ester and amide formation: the mechanism
Both reactions are nucleophilic acyl substitution. The mechanism has two parts: addition then elimination.
- The carbonyl carbon (C=O) of the acetyl group is slightly positive. The oxygen of the -OH (or the nitrogen of an -NH2) has a lone pair and attacks this carbon. This is the nucleophile.
- The C=O bond opens and a short-lived tetrahedral intermediate forms.
- The C=O bond reforms and the leaving group (here acetate, from the anhydride) leaves. A proton moves. The product is an ester (from -OH) or an amide (from -NH2), and acetic acid is the by-product.
A few drops of strong acid (phosphoric or sulfuric) act as a catalyst: they make the carbonyl carbon even more positive so the attack is faster. Amines are better nucleophiles than alcohols, so amide formation is easier.
Extracting and synthesising aspirin
Where it started: bark of the willow tree (Salix) contains salicin, which the body turns into salicylic acid. People used it for pain for centuries, but it irritates the stomach. Chemists changed the -OH into an ester, which gave the gentler aspirin.
Lab synthesis (typical school scale):
- Put 2.0 g salicylic acid in a dry flask. Add 4 mL acetic anhydride and 4-5 drops of concentrated phosphoric acid (in a fume cupboard, with goggles and gloves).
- Warm gently in a water bath at about 70 °C for 10-15 minutes.
- Add cold water carefully to destroy extra anhydride, then cool in ice so crystals form.
- Filter the crystals with suction, wash with cold water and dry.
- Recrystallise from an ethanol-water mixture to make it purer.
Yield. Molar masses: salicylic acid 138 g/mol, aspirin 180 g/mol, ratio 1:1. From 2.0 g: 2.0 / 138.1 = 0.0145 mol, so the theoretical mass is 0.0145 x 180.2 = 2.61 g. Percent yield = actual / theoretical x 100.
Purity checks: melting point, chromatography and Rf
Melting point. Pure aspirin melts sharply near 135 °C. Impure samples melt lower and over a range. Iron(III) chloride test. Left-over salicylic acid (a phenol) turns purple; pure aspirin stays yellow-brown.
Thin-layer chromatography (TLC). Put small spots of the samples on a pencil line on a silica plate. Stand the plate in a little solvent. The solvent climbs and carries each substance a different distance, because some stick to the silica more than others. When the solvent is near the top, mark the solvent front.
Rf = distance moved by the spot / distance moved by the solvent front. It is always between 0 and 1 and has no unit. Under the same conditions, the same substance gives the same Rf, so you can compare a sample spot with a known reference. One spot suggests a pure sample; two or more spots mean a mixture.
Try it
Safe version at home: draw a pencil line on a coffee filter strip, put a dot of black felt-tip ink on it, stand the strip in 1 cm of water and watch the colours separate. Measure the distance of one colour and of the water front, then divide to find its Rf. In the 3D, move the sliders and see how Rf changes.
Key formulas and definitions
- Rf = distance moved by spot / distance moved by solvent front (0 to 1, no unit)
- salicylic acid + acetic anhydride -> aspirin + acetic acid
- acid + alcohol -> ester; acid + amine -> amide
- percent yield = (actual mass / theoretical mass) x 100
- moles = mass / molar mass
Worked examples
1. A spot travels 3.3 cm and the solvent front travels 6.0 cm. Find Rf.
Rf = 3.3 / 6.0 = 0.55.
2. Name the functional groups in aspirin.
A benzene ring, an ester (-OCOCH3) and a carboxylic acid (-COOH).
3. How many moles of aspirin form from 2.0 g of salicylic acid (M = 138 g/mol), if the reaction is 1:1?
Moles of salicylic acid = 2.0 / 138 = 0.0145 mol, so 0.0145 mol of aspirin (at 100% yield).
4. Find the theoretical mass of aspirin (M = 180 g/mol) from 2.0 g salicylic acid.
0.0145 mol x 180 g/mol = 2.61 g.
5. A student gets 1.8 g of aspirin from a theoretical 2.61 g. Find the percent yield.
1.8 / 2.61 x 100 = 69%.
6. A TLC plate of crude aspirin shows spots at Rf 0.55 and 0.30. The pure reference gives one spot at 0.55. What does this tell you?
The 0.55 spot matches aspirin. The 0.30 spot is another substance (probably left-over salicylic acid), so the crude sample is impure.
Common mistakes
- Saying Rf can be more than 1. The spot cannot travel further than the solvent.
- Measuring the spot from the bottom edge of the plate instead of from the pencil start line.
- Using a pen instead of a pencil for the start line: ink runs with the solvent.
- Forgetting the by-product: the reaction with acetic anhydride also gives acetic acid.