Chemistry • Year 12 • Module 8 • Lesson 13
Optical Isomerism & Chirality in Medicines
Apply enantiomer concepts to real pharmaceutical data, interpret an optical rotation graph, and reason about biological consequences of chirality.
1. Interpret enantiomer property data
The table below compares selected properties of the two enantiomers of ibuprofen and thalidomide. Study the data and answer the questions that follow. 8 marks
| Property | (S)-ibuprofen | (R)-ibuprofen | (R)-thalidomide | (S)-thalidomide |
|---|---|---|---|---|
| Molecular formula | C13H18O2 | C13H18O2 | C13H10N2O4 | C13H10N2O4 |
| Melting point (°C) | 52 | 52 | 270 | 270 |
| Solubility in water | Slightly soluble | Slightly soluble | Slightly soluble | Slightly soluble |
| Optical rotation (measured in ethanol) | +51° | −51° | +0.17° (DMSO) | −0.17° (DMSO) |
| COX-2 enzyme inhibition (analgesic activity) | Active (anti-inflammatory) | Largely inactive | Not applicable | Not applicable |
| Known clinical effect in humans | Pain relief | Slowly converts to S-form in body | Sedative effect | Teratogenic (causes birth defects) |
| Australian PBS availability | Prescription (S-form) | Racemic Nurofen (OTC) | TGA-monitored restricted use; Australian birth defect registry active | |
Data collated from NESA chemistry syllabus, TGA product information, and PBS schedule. Optical rotation values for ibuprofen adapted from Geisslinger et al. (1994) J Clin Pharmacol.
1.1 Identify two physical properties that are the same for both enantiomers of ibuprofen. 2 marks
1.2 Explain why the optical rotations of (S)-ibuprofen and (R)-ibuprofen are equal in magnitude but opposite in sign. 2 marks
1.3 Using the data, explain why Nurofen (racemic ibuprofen) still works as an analgesic even though only one enantiomer is initially active against COX-2. 2 marks
1.4 The TGA maintains an Australian birth defect registry linked to thalidomide use. What does the data in the table suggest about why such a registry is necessary, even for the R-enantiomer alone? 2 marks
2. Interpret optical rotation data — a pharmaceutical quality control test
A quality control laboratory is testing four ibuprofen samples. The graph below shows the measured optical rotation (α) in ethanol for each sample. Use the data to answer the questions. 7 marks
Hypothetical quality control data. Reference values: pure (S)-ibuprofen = +51°, pure (R)-ibuprofen = −51° (adapted from Geisslinger et al. 1994, J Clin Pharmacol).
2.1 Identify which sample is most likely a pure enantiopure preparation of the pharmacologically active form of ibuprofen. Justify your answer. 2 marks
2.2 Describe what Sample 3 most likely represents, and predict the result if Sample 3 were tested in a polarimeter. 2 marks
2.3 Sample 4 shows +26°. A scientist calculates the ‘enantiomeric excess’ (ee%) as approximately 51%. Explain in chemical terms what this means about the composition of Sample 4. 3 marks
3. Cause-and-effect chain — the thalidomide tragedy
Each cause box below is given. Write the matching effect in the empty box. An overall outcome line closes the chain. 5 marks
Overall outcome (so…): In light of the thalidomide case, drug regulators and pharmaceutical companies now…
4. Apply to a new scenario — L-amino acids and D-glucose
Living organisms almost universally use only L-amino acids in proteins and only D-glucose in metabolic pathways. Both amino acids and glucose contain chiral centres. 4 marks
4.1 Explain why a cell's enzymes would not be able to process D-amino acids into proteins, even though D-amino acids have identical molecular formulas to their L-counterparts. 2 marks
4.2 A synthetic chemist in a CSIRO laboratory makes an amino acid from scratch without using biological enzymes. The product contains equal amounts of the L- and D-forms. Identify what type of mixture this is, and predict the optical rotation result. 2 marks
Q1.1
Molecular formula (C13H18O2) and melting point (52°C) are identical for both ibuprofen enantiomers. Solubility is also the same. [1 mark each, any two of these three]
Q1.2
(S)- and (R)-ibuprofen are non-superimposable mirror images (enantiomers) [1]. They rotate plane-polarised light by the same amount because they have the same strength of interaction with polarised light, but in opposite directions because their spatial arrangements are mirror images of each other [1].
Q1.3
The table shows that R-ibuprofen slowly converts to S-ibuprofen inside the body [1]. Therefore, even though only the S-form is initially active, the R-form acts as a reservoir that is metabolically converted to the active enantiomer, so the racemic drug still delivers analgesic effect over time [1].
Q1.4
The table shows the R-enantiomer is associated with sedative effects, not teratogenic effects. However, thalidomide enantiomers interconvert (racemise) in the body under physiological conditions [1]. So even if only the R-form were administered, it would convert to the S-form inside the patient, meaning the teratogenic form would still be present. A registry is needed to monitor this ongoing risk in women of child-bearing age [1].
Q2.1
Sample 1 (+51°) is the enantiopure pharmacologically active form. The lesson states (S)-ibuprofen is the active anti-inflammatory enantiomer [1], and the reference value for pure (S)-ibuprofen is +51°, matching Sample 1 [1].
Q2.2
Sample 3 (~0°) is most likely a racemic mixture (50:50 R and S) [1]. A polarimeter would show zero net optical rotation because the equal and opposite rotations of the two enantiomers cancel [1].
Q2.3
+26° is approximately half of +51°, so Sample 4 is not a pure enantiomer [1]. An ee% of ~51% means there is 51% more (S)-ibuprofen than (R)-ibuprofen in the sample [1]. In a 100 g sample there would be approximately 75.5 g of S-form and 24.5 g of R-form — the sample contains both enantiomers but is enriched in the S-form [1].
Q3 — Cause-and-effect chain
Effect 1: Patients received a racemic mixture containing both the R- and S-enantiomers of thalidomide.
Effect 2: Both enantiomers entered the pregnant women's bodies, including the S-enantiomer.
Effect 3: The S-enantiomer interacted with chiral biological targets in the developing foetus differently from the R-enantiomer, producing teratogenic effects that caused birth defects.
Overall outcome: Drug regulators now require investigation of each enantiomer separately, and modern drug development prefers enantiopure drugs where possible to avoid administering a potentially harmful enantiomer.
Q4.1
Enzymes have chiral active sites shaped to bind only the L-configuration of amino acids [1]. D-amino acids, being non-superimposable mirror images of the L-form, do not fit the enzyme's active site correctly, so the enzyme cannot catalyse their incorporation into a peptide chain [1].
Q4.2
This is a racemic mixture (50:50 L- and D-amino acid) [1]. The optical rotation would be zero (no net rotation) because the equal amounts of L- and D-forms rotate plane-polarised light in opposite directions and cancel out [1].