Chirality
• Stereoisomers: Isomers with the same
connectivity between atoms but have a
different arrangement of atoms.
• We have already examined a form of
stereoisomerism when we studied geometric
isomers, that is, cis-trans isomers in
disubstituted cycloalkanes and in alkenes.
• In this chapter, we study isomers where the
focus is the arrangement of atoms around one
carbon atom rather two neighboring atoms.
• Two stereoisomers, when compared to each
other, may be classified as enantiomers or
diastereomers.
Enantiomers
• Enantiomers: Two stereoisomers that are
nonsuperimposable mirror images of each other.
• As an example, consider 2-butanol, a molecule that exists
as a pair of enantiomers.
• One way to see that the mirror image of 2-butanol is
not superimposable on the original is to, first, rotate
the mirror image.
• Second, try to fit the mirror image on top of the mirror
image so that all groups and bonds match exactly.
• The original and mirror image are not superimposable.
• They are different molecules with different properties.
• They are enantiomers (nonsuperimposable mirror
images).
• Enantiomers: Stereoisomers that are
nonsuperimposable mirror images are chiral
(from the Greek: cheir, hand). The term refers to
relationship between pairs of objects.
• A person’s left hand is the same as his right hand,
except that they are mirror images of each other.
• In a similar way, when molecules are chiral, we say
that they show handedness.
• The most common cause of enantiomerism in
organic molecules is the presence of a
stereocenter, carbon with four different groups
bonded to it.
• Stereocenters are also known as chiral carbons.
• If an object and its mirror image are
superimposable, they are identical and there is
no possibility of enantiomerism.
• Such an object is achiral (without chirality).
• As an example, consider 2-propanol.
• Notice that this molecule has no stereocenter.
Drawing Chiral Molecules
• Below are four different representations for one
of the enantiomers of 2-butanol.
• Both (1) and (2) show all four groups bonded to the
stereocenter and show the tetrahedral geometry.
• (3) is a more abbreviated line-angle formula; although
we show the H atom on the stereocenter, we do not
normally show it in line-angle formulas.
• (4) is the most abbreviated representation; you must
remember that an H present on this stereocenter.
• On the left is one enantiomer of 2-butanol.
• On the right are two representations for its
mirror image.
Naming Enantiomers – The R,S System
• Because enantiomers are different compounds,
each must have a different name.
• Here are the enantiomers of the over-the-counter
drug ibuprofen.
• The R,S system is a way to distinguish between
enantiomers without having to draw them and point to
one or the other.
• Before we begin to assign an R or S
configuration to a stereocenter, we must assign
a priority to each of the atoms that are bonded to
the stereocenter.
• We will use the same prioritization rules we used
to assign an E or Z configuration to an alkene:
1. Priority is based on atomic number; the higher the
atomic number, the higher the priority.
2. If priority cannot be assigned on the basis of the
atoms bonded directly to the stereocenter, look to
the next set of atoms; priority is assigned at the first
point of difference.
3. Atoms participating in a double or triple bond are
considered to be bonded to an equivalent number of
similar atoms by single bonds.
• To assign an R or S configuration:
• Assign a priority from 1 (highest) to 4 (lowest) to each
group on the stereocenter.
• Orient the stereocenter so that the group of lowest
priority is projecting away from you.
• Read the priorities of the three groups projecting
toward you in order from (1) to (3).
• If reading these three groups is clockwise, the
configuration is R (Latin, rectus, straight, correct).
• If reading these three groups is counterclockwise, the
configuration is S (Latin: sinister, left).
Example: Assign an R or S configuration to the
stereocenter in 2-chlorobutane.
• Priorities of atoms attached to stereocenter
1.
2.
3.
4.
•
•
chlorine
“ethyl” branch
“methyl” branch
hydrogen
When the hydrogen is pointed away the other atoms are
arranged 1 – 2 – 3 in the counterclockwise direction.
Therefore, the pictured molecule is (S)–2–chlorobutane.
Example: Assign an R or S configuration to the
stereocenter in 3-cyclohexenol.
• Priorities of atoms attached to stereocenter
1.
2.
3.
4.
•
•
oxygen (hydroxyl)
carbon in a double bond
carbon in a single bond
hydrogen
When the hydrogen is pointed away the other atoms are
arranged 1 – 2 – 3 in the clockwise direction.
Therefore, the pictured molecule is (R)–3–cyclohexenol.
Example: Assign an R or S configuration to the
stereocenter in the amino acid, valine.
• Priorities of atoms attached to stereocenter
1.
2.
3.
4.
•
•
nitrogen (amine)
carboxylate carbon
“isopropyl” carbon
hydrogen
When the hydrogen is pointed away the other atoms are
arranged 1 – 2 – 3 in the counterclockwise direction.
Therefore, the pictured molecule is (S)–valine.
Example: Name the active enantiomer of
ibuprofen.
• Priorities of atoms attached to stereocenter
1.
2.
3.
4.
•
•
carbon in the carboxyl group
carbon in the benzene ring
“methyl” carbon
hydrogen
When the hydrogen is pointed away the other atoms are
arranged 1 – 2 – 3 in the counterclockwise direction.
Therefore, the active enantiomer is (S)–ibuprofen.
Enantiomers and Diastereomers
• For a molecule with 1 stereocenter, 21 = 2
stereoisomers are possible.
• For a molecule with 2 stereocenters, a maximum
of 22 = 4 stereoisomers are possible.
• For a molecule with n stereocenters, a maximum
of 2n stereoisomers are possible.
• Diastereomers are stereoisomers that are not
enantiomers.
• A stereoisomer has one enantiomer and 2n – 2
possible diastereoisomers.
• Consider 2,3,4-trihydroxybutanal as an example.
• Two stereocenters; 22 = 4 stereoisomers (two pairs of
enantiomers) are possible.
• Erythrose and threose are diastereomers.
Meso Compounds
• Meso compound: an achiral compound
possessing two or more stereocenters.
• Tartaric acid contains two stereocenters.
• Two stereocenters; 2n = 4, but only three
stereoisomers exist, one meso compound and one
pair of enantiomers.
• Meso compounds can be identified because
they have a plane of symmetry.
• Plane of Symmetry: An imaginary plane
passing through an object and dividing it such
that one half is the mirror image of the other half.
• Molecules with a plane of symmetry are achiral.
• Thus a meso compound is it’s own mirror image.
Chirality in Cyclic Molecules
• 2-Methylcyclopentanol
• 2 stereocenters; according to the 2n rule, a maximum
of 22 = 4 stereoisomers are possible.
• Neither molecule has a plane of symmetry; therefore,
no meso stereoisomer exists.
• 2-methylcyclopentanol has a total of 4 stereoisomers,
two pairs of enantiomers.
• 1,2-Cyclopentanediol
• 2 stereocenters = a maximum of 4 potential
stereoisomers.
• However, the cis isomer has a plane of symmetry;
therefore, it is meso compound.
• Thus 1,2-cyclopentanediol has only 3 stereoisomers:
one meso compound (the cis isomer) and one pair of
enantiomers (the trans isomer).
• The cis and the trans isomers are diastereoisomers of each other.
• 4-Methylcyclohexanol
• Note the molecule has 2 stereocenters.
• However, both the cis isomer and the trans isomer
have a plane of symmetry.
• That is, both the cis and trans isomers are meso
compounds.
• Therefore, 4-methylcyclohexanol has two
stereoisomers and yet is not chiral.
• 3-Methylcyclohexanol
• The molecule has 2 stereocenters.
• Neither the cis isomer nor the trans isomer have a
plane of symmetry.
• Therefore, 4-methylcyclohexanol has four
stereoisomers.
Molecules with Three Or More Stereocenters
• We need to be able to identify the stereocenters
in larger molecules so that we can be aware of
the different stereoisomers.
• Menthol
• 3 stereocenters
• 23 = 8 potential stereoisomers.
• Only one of the stereoisomers is the flavoring.
• Cholesterol
• 8 stereocenters
• 28 = 256 potential stereoisomers.
• Only one of the stereoisomers is made by the human
body.
• Cholesterol has one enantiomer and 254 diastereoisomers.
Optical Activity
• Ordinary light: Light waves vibrating in all
planes perpendicular to its direction of
propagation.
• Plane-polarized light: Light waves vibrating
only in parallel planes.
• Polarimeter: An instrument for measuring the
ability of a compound to rotate the plane of
plane-polarized light.
• Optically active: A compound that rotates the
plane of plane-polarized light.
Schematic diagram of a polarimeter
• The angle of rotation for plane-polarized light
is measured from the perspective of the light
coming toward you rather than going away.
• Dextrorotatory (D): Clockwise rotation of the
plane of plane-polarized light.
• Levorotatory (L): Counterclockwise rotation of the
plane of plane-polarized light.
• Often chiral molecules are distinguished from
each other based on their optical activity, that
is, (L or D) is used rather than (R or S).
• Biological amino acids have the (S) configuration;
however, they are almost always refer to by their
optical activity (L) as in L-valine rather than (S)valine.
• The angle of rotation depends on
concentration and the wavelength of light;
therefore, a specific standard has been
created to be able to compare the angle of
rotation for different molecules to each other.
• Specific rotation: The observed rotation of planepolarized light at 589 nm of an optically active
substance at a concentration of 1 g/100 mL in a
sample tube 10 cm long.
Chirality in Biochemicals
• Except for inorganic salts and a few lowmolecular-weight organic substances, the
molecules in living systems, both plant and
animal, are chiral.
• Although these molecules can exist as a number of
stereoisomers, almost invariably only one
stereoisomer is found in nature.
• Instances do occur in which more than one
stereoisomer is found, but these rarely exist together
in the same biological system.
• It's a chiral world!
• Enzymes have gazillions  of potential
stereoisomers.
• Only one will have biological activity.
• Because living systems depend on chiral
environments, a molecule and its enantiomer or
one of its diastereomers elicit different
physiological responses.
• (S)-ibuprofen is active as a pain and fever
reliever, whereas its R enantiomer is inactive.
• The S enantiomer of naproxen is the active pain
reliever, whereas its R enantiomer is a liver toxin!