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

*

* chiral carbon atom

OH

O

OH

Lactic acid

*+H3N

O-

O

* chiral carbon atomPhenylalanine

HO

HO

NHMe

OH

*

* chiral carbon atomEpinephrine

Solid wedge – substituent projecting forwardDashed 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.

HO OH HO OH

Achiral moleculeMeso 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.

O O

(R)-carvonecaraway scent

(S)-carvonespearmint 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

CO2H

IbuprofenNSAID

Racemic mixture

A racemic mixture is a 50:50 mixture of two enantiomers.

CO2H CO2H

(S)-Ibuprofenactive

(R)-Ibuprofeninactive

HO

HONH3

O

O

HO

HONH3

O

O

L-DopaTreatment of Parkinson’s disease

D-DopaToxic

OH

OHNH3

O

O

D-Dopa

Flip D-Dopa like a pancake, can see it’s the mirror image of L-Dopa

HO

HONH3

O

O

L-Dopa

Some Drugs Must be Administered as Single Enantiomers Due to Toxicity of Enantiomer

Celexa® (citalopram oxalate)R- and S- enantiomers

antidepressant / antianxietyselective serotonin reuptake inhibitor (SSRI)

Lexapro® (escitalopram oxalate)S-enantiomer

Mixture of enantiomers

Single enantiomer

Considerations of single-enantiomer drugs:

1)Lower dose (only active enantiomer)2)Potentially fewer side effects3)More expensive

Single Enantiomers Are Marketed For Some Drugs That Do Not Have a Toxic Enantiomer

NC

O

NMe2

F

CN

O

Me2N

F

NC

O

NMe2

F

Enantiomeric Compounds Can Have Drastically Different Biological Effects

HN

HN

(S)-methamphetamineFDA approved for ADHD, obesity

CNS stimulant (euphoria at high doses)

(R)-methamphetamineOTC decongestant - Vicks Vapor Inhaler

Little or no CNS activity“Levmetamfetamine” listed as active ingredient

Enantiomeric Compounds Can Have Drastically Different Biological Effects

N

O

O

NHO

O N

O

O

HNO

O

in vivoisomerization

(R)-thalidomidesedative, antiemetic prescribedfor morning sickness 1957-1961

(S)-thalidomidepotent teratogen

Thousands of children born with birth defects

Can not administer thalidomide as a single enantiomer drug because it isomerizes in vivo.

2 chiral carbons22 = 4 steroisomers

As the Number of Chiral Carbons in a Molecule Increases, So Does the Number of Possible Stereoisomers

O

OH

OH

O

OH

OH

O

OH

OH

**

O

OH

OH

O

OH

OH

If a molecule has n chiral carbon atoms, there are 2n possible steroisomers

* may be fewer due to symmetry

Diastereomers are stereoisomers that are not enantiomers.

Molecules with two or more chiral carbon atoms can have diasteromers.

Diasteromers

Ephedrine

Stimulant, appetite suppressant, decongestant

Pseudoephedrine

Decongestant, stimulant

OHHN

* *

OHHN

* *

On a Side Note… Pseudoephedrine and Ephedrine Are No Longer OTC

(S)-methamphetamineFDA approved for ADHD, obesity

CNS stimulant (euphoria at high doses)

HN

OHHN

PseudoephedrineOriginal formulaNo longer OTC

HOHN

OH

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.

Conformation: Changing the conformation of a molecule means rotating about single bonds. Conformations are interconvertible and are the same molecule.

(R)-configuration (S)-configurationMe H

HO CN

Me H

NC OH

(R)-configuration in different conformations

Me H

HO CN

Me CN

H OH

Me OH

NC H