29.4 Optical isomerism
- Syllabus
- 9701–2028–2029
- Topic
- 29.4
- Level
- A2
Learning objectives
29.4.1Enantiomers have identical physical/chemical• Understand: enantiomers have identical physical/chemical properties apart from their ability to rotate plane polarised light and their potential biological activity29.4.2Terms: optically active and racemic mixture• Use terms: optically active and racemic mixture29.4.3Effect on plane polarised light of the two• Describe the effect on plane polarised light of the two optical isomers of a single substance29.4.4Relevance of chirality to the synthetic• Explain the relevance of chirality to the synthetic preparation of drug molecules including:- (a) the potential different biological activity of the two enantiomers- (b) the need to separate a racemic mixture into two pure enantiomers- (c) the use of chiral catalysts to produce a single pure optical isomer (Candidates should appreciate that compounds can contain more than one chiral centre, but knowledge- of meso compounds and nomenclature such as diastereoisomers is not required.)
Enantiomers usually share properties but differ in biological fit and optical rotation
Enantiomers are non-superimposable mirror images. In an achiral environment they have the same melting point, boiling point and many chemical properties, but they rotate plane-polarised light in opposite directions.
A chiral receptor or enzyme is itself asymmetric, so the two enantiomers can bind differently and produce different biological effects.
Two enantiomers may pass through an ordinary solvent identically yet one fit a biological active site better, like opposite hands fitting a glove.
R and S labels do not by themselves tell you clockwise optical rotation, and ‘same formula’ does not mean the molecules are superimposable.
Optically active samples rotate plane-polarised light; racemates cancel
An optically active sample rotates plane-polarised light. A racemic mixture contains equal amounts of both enantiomers, whose opposite rotations cancel, so the mixture shows no net rotation.
Optical activity describes the sample, not simply the presence of a chiral carbon. A sample enriched in one enantiomer can be active; a perfectly 1:1 mixture is racemic.
A pure (+) enantiomer and pure (−) enantiomer rotate light by equal magnitudes in opposite directions. Mixing equal amounts gives zero observed rotation.
No net rotation does not prove that no chiral molecules are present; it may indicate cancellation in a racemate.
Enantiomers rotate plane-polarised light in opposite directions
The two enantiomers of one substance rotate plane-polarised light by equal angles in opposite directions under the same conditions. One is dextrorotatory (+), the other laevorotatory (−).
The sign of rotation is measured experimentally; it is not predicted from the R/S descriptor or from the direction in which the structure is drawn on a page.
If one enantiomer rotates light +12°, its mirror image rotates it −12° at the same concentration, path length and temperature.
R/S nomenclature and +/− optical rotation are independent labels. Never replace one with the other.
Chiral drug synthesis must control which enantiomer reaches the patient
Drug targets such as receptors and enzymes are chiral. Two drug enantiomers can therefore fit them differently, so one may give the intended effect while the other is less active, inactive or produces a different effect; the outcome must be measured rather than assumed.
| Preparation route | What happens | Why it matters |
|---|---|---|
| achiral synthesis then resolution | a racemic 1:1 mixture is formed and separated into pure enantiomers | supplies the required enantiomer, but separation adds steps and the other enantiomer must be handled or recycled |
| synthesis with a chiral catalyst | the catalyst creates an asymmetric reaction environment that favours formation of one mirror-image pathway | produces predominantly the chosen enantiomer and reduces later separation demand |
| biological chiral catalyst | an enzyme active site binds reactants in one orientation | can provide high stereoselectivity toward one enantiomer |
A pharmaceutical route must identify which enantiomer has the desired biological activity, control or separate the product composition, and verify enantiomeric purity. A racemate cannot be assumed equivalent to the same dose of one pure enantiomer.
A molecule can contain more than one chiral centre, increasing the possible spatial arrangements. This syllabus does not require meso compounds or nomenclature such as diastereoisomers, so do not use those as required explanations here.