RPA 1 – Sterioisomerism

Levels of formula from least to most detailed

  1. General formula e.g. CnH2n
  2. Empirical formula e.g. CH2
  3. Skeletal formula e.g. 
  4. Structural formula e.g. CH3CHO
  5. Displayed formula e.g. 
  6. 3D Displayed formula
Isomers are molecules with the same molecular formula but different arrangements of atoms, e.g. methylpropane and butane.
  1. Structural isomers are molecules with the same molecular formula but different structural formula, e.g. propanone CH3COCH3 and propanal CH3CH2CHO.
  2. Sterioisomers are molecules that have the same structural formula but different spatial arrangements:
  • E/Z or cis/trans isomerism – E/Z involves compounds that have a non-rotating bond between two carbon atoms ( C=C due to the π-bond), and each carbon is bonded to 2 different groups.
    Cis/trans involves E/Z isomerism when one of the two groups on each carbon is a hydrogen (H). 
  • Optical isomerism – are molecules with exactly the same formula but different arrangements of 4 different groups of atoms around a chiral carbon. The compounds are non-superimposable mirror images of each other.

    Each enantiomer is chemically identical. However, each enantiomer rotates plane-polarised waves in different directions; right (+ clockwise, dextra), or left (- anti-clockwise, levra). They also only vibrate in one direction only.
    In the human body, only one enantiomer is biologically active because enzymes are specific to only one of the two optical isomers. For amino acids, it is the ‘L’ enantiomer, and for sugars it is ‘D’. 

Chirality – asymmetric carbon with 4 different groups/atoms covalently bonded to it (see enantiomers 1&2 above).

Compound with x chiral carbons – the mixture has 2x different optical isomers because each chiral carbon has 2 possibilities; left or right.

Racemic mixture – is an equimolar mixture of optical isomers, and will normally not show any activity as the opposite optical effects of each enantiomer cancel each other out.

Disadvantages of racemic mixtures in drugs:

  • side effects of ‘other’ enantiomer could be dangerous
  • larger or double doses of drug will have to be taken if drug contains a mix of enantiomers
  • laboratory reactions  are more likely to make mixtures than those occuring in body
Thalidomide example
The thalidomide drug is optically active, but only one of the optical isomers is effective (reduces morning sickness during pregnancy). The ‘other’ enantiomer causes restriction of blood flow to developing baby limbs. Thalidomide racemises in the body so pure drug would not work.
Naproxen example
Naproxen treats pain caused by arthritis, and the drug is optically active. One enantiomer eases pain caused by arthritis, the other causes liver damage.
Ethambutol example
Drug is optically active; used to treat tuberculosis. The other enantiomer causes blindness.

Preparing pure enantiomers are beneficial:

  • reduces patients dosage by half as pure is more potent
  • cuts cost
  • minimises risk of side effects
  • protects drug companies from litigation
Methods to prepare Pure enantiomers
  1. separate products of reaction (optical resolution) – use traditional synthetic route to make compound, then separate by using pure enantiomer of another optically active compound to react with the racemate. Two products will form and will have different physical properties, so can be separated physically e.g. crystallisation and filtration. 
  2. optically active starting materials – starting materials are in the desired orientation (using naturally occurring compounds; carbohydrates, L-amino acids). No separation techniques required. Chemists are developing chiral catalysts to ensure one enantiomer is formed, e.g. ruthenium catalyst used in the production of naproxen.
  3. using enzymes – this promotes stereo-selectivity, and produces single enantiomers. The specific nature of the active site of enzymes means that only one enantiomer is formed. Immobilised enzymes on inert supports are used, and enzymes lower activation energies and temperature therefore costs.

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