Stereoisomers
Stereoisomers have the same molecular formula and connectivity
but differ in their orientation in 3-dimensional space.
Chiral Carbon Atoms
An sp3 hybridized carbon atom with four different substituents is chiral
Chiral atoms are also referred to as sterogenic centers
Solid wedge – substituent projecting forward
Dashed wedge – substituent projecting backward
Chiral Molecules
If a molecule contains one or more chiral carbon atoms, and it does not have a plane
of symmetry, it is a chiral molecule.
Achiral molecule
Meso compound
Chiral molecule
Meso compounds contain chiral centers, but have a plane of symmetry so are achiral.
Enantiomers
Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
Molecules with one or more chiral carbon atoms can have enantiomers.
(R)-carvone
caraway scent
(S)-carvone
spearmint scent
Enantiomers have the same chemical properties (e.g. melting point, boiling point) but can
have different biological effects because the body has chiral biomolecules proteins, peptides, carbohydrates, nucleic acids, lipids.
Physical Properties of Enantiomers are Identical Except…
Identical
Enantiomers have identical NMR, IR and UV spectra, densities, melting points and boiling
points.
Different
Enantiomers rotate plane polarized light in opposite directions of each other.
(+): Rotation to the right
(-): Rotation to the left
You can not assign absolute configuration based on optical rotation alone.
(R)-enantiomers can be (+) or (-) and (S)-enantiomers can be (+) or (-).
Some Drugs Are Marketed as Racemic Mixtures
Ibuprofen
NSAID
Racemic mixture
A racemic mixture is a 50:50 mixture of two enantiomers.
(S)-Ibuprofen
active
(R)-Ibuprofen
inactive
Some Drugs Must be Administered as Single Enantiomers Due to
Toxicity of Enantiomer
L-Dopa
D-Dopa
Flip D-Dopa like a
pancake, can see it’s the
mirror image of L-Dopa
L-Dopa
Treatment of Parkinson’s disease
D-Dopa
Toxic
Single Enantiomers Are Marketed For Some
Drugs That Do Not Have a Toxic Enantiomer
Mixture of
enantiomers
Single
enantiomer
Celexa® (citalopram oxalate)
R- and S- enantiomers
antidepressant / antianxiety
selective serotonin reuptake inhibitor (SSRI)
Lexapro® (escitalopram oxalate)
S-enantiomer
Considerations of single-enantiomer drugs:
1) Lower dose (only active enantiomer)
2) Potentially fewer side effects
3) More expensive
Enantiomeric Compounds Can Have Drastically Different Biological Effects
(S)-methamphetamine
FDA approved for ADHD, obesity
CNS stimulant (euphoria at high doses)
(R)-methamphetamine
OTC decongestant - Vicks Vapor Inhaler
Little or no CNS activity
“Levmetamfetamine” listed as active ingredient
Enantiomeric Compounds Can Have Drastically Different Biological Effects
(R)-thalidomide
sedative, antiemetic prescribed
for morning sickness 1957-1961
Can not administer thalidomide as a single
enantiomer drug because it isomerizes in vivo.
(S)-thalidomide
potent teratogen
Thousands of children born with birth defects
As the Number of Chiral Carbons in a Molecule Increases, So Does the Number of
Possible Stereoisomers
If a molecule has n chiral carbon atoms, there are 2n possible steroisomers
* may be fewer due to symmetry
2 chiral carbons
22 = 4 steroisomers
* *
Diasteromers
Diastereomers are stereoisomers that are not enantiomers.
Molecules with two or more chiral carbon atoms can have diasteromers.
Ephedrine
Pseudoephedrine
Stimulant, appetite
suppressant,
decongestant
Decongestant,
stimulant
On a Side Note… Pseudoephedrine and Ephedrine Are No Longer OTC
Pseudoephedrine
Original formula
No longer OTC
(S)-methamphetamine
FDA approved for ADHD, obesity
CNS stimulant (euphoria at high doses)
Phenylephrine
“New formula”
Sudafed
Configuration and Conformation
Configuration: Changing the configuration of a molecule requires bonds to be broken
and reformed. A different configuration is a different molecule.
(R)-configuration
(S)-configuration
Conformation: Changing the conformation of a molecule means rotating about single
bonds. Conformations are interconvertible and are the same molecule.
(R)-configuration in different conformations