Chapter Six
Chirality : The Handedness of molecules
Key words
 Chiral carbon, assymetric carbon
 Stereocenter
 R/S configuration
 Enantiomer
 Diastereomer
 Mecompound
Isomers
In this chapter, we concentrate on enantiomers and diastereomers.
CHIRALITY
Asymmetric Center/Stereocenter - A tetrahedral atom bonded to
four different groups.
A s y m m e tr ic c e n te r
R
a w a y fro m
y o u
R
1
R
4
2
R
3
to w a rd s y o u
H
B r
C O O H
H
H
2
N
H
O
Br
CHIRALITY
A chiral molecule does not contain a plane of symmetry or
inversion center.
Are these molecules chiral or achiral?
Enantiomers
• Enantiomers: Nonsuperposable mirror images
• As an example of a molecule that exists as a pair of
enantiomers, consider 2-butanol.
OH
C H
H3 C
CH 2 CH 3
Origin al molecu le
HO
H C CH
3
CH3 CH2
Mirror image
Enantiomers
• One way to see that the mirror image of 2-butanol is not
superposable on the original is to rotate the mirror image.
OH
C H
H3 C
CH2 CH3
Origin al molecu le
180° OH
H C CH
3
CH3 CH2
Mirror image
rotate th e
mirror image
by 180° about
the C-OH b on d
OH
C CH CH
2
3
H3 C
H
The mirror image
rotated by 180°
Enantiomers
• Now try to fit one molecule on top of the other so that
all groups and bonds match exactly.
OH
The mirror image
turn ed by 180°
C CH CH
2
3
H3 C
H
OH
The original molecule
C H
H3 C
CH2 CH3
• The original and mirror image are not superposable.
• They are different molecules with different properties.
• They are enantiomers (nonsuperposable mirror
images).
Enantiomers
• Objects that are not superposable on their mirror images are
chiral (from the Greek: cheir, hand)
• They show handedness.
• The most common cause of enantiomerism in organic molecules
is the presence of a carbon with four different groups bonded to
it.
• A carbon with four different groups bonded to it is called a
stereocenter.
Enantiomers
• If an object and its mirror image are superposable, they are
identical and there is no possibility of enantiomerism.
• We say that such an object is achiral (without chirality).
• As an example of an achiral molecule, consider 2-propanol.
• Notice that this molecule has no stereocenter.
OH
C H
H3 C
CH3
Origin al molecu le
OH
H C CH
3
H3 C
Mirror image
Enantiomers
• To see the relationship between the original and its mirror image,
rotate the mirror image by 120°.
OH
C H
H3 C
CH3
Origin al molecu le
120° OH
H C CH
3
H3 C
Mirror image
rotate by 120°
about th e
C-OH bond
OH
H3 C
C H
CH3
The mirror image
rotated b y 120°
• When we do this rotation, all atoms and bonds of the mirror image
fit exactly on the original.
• This means that the original and its mirror image are the same
molecule.
• They are just viewed from different perspectives.
Enantiomers
• To summarize
• An object that is nonsuperposable on its mirror image is chiral
(it shows handedness).
• The most common cause of chirality among organic molecules
is the presence of a carbon with four different groups bonded
to it.
• We call a carbon with four different groups bonded to it a
stereocenter.
• An object that is superposable on its mirror image is achiral
(without chirality).
• Nonsuperposable mirror images are called enantiomers.
• Enantiomers, like gloves, always come in pairs.
Drawing Enantiomers
• Following are four different representations for one of the
enantiomers of 2-butanol.
OH
C H
H3 C
CH2 CH3
(1)
H
H3 C
OH
C
CH2 CH3
(2)
H OH
OH
(3)
(4)
• 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 here, we do not normally show them in line-angle
formulas.
• (4) is the most abbreviated representation; you must
remember that there is an H present on the stereocenter.
Drawing Mirror Images
• On the left is one enantiomer of 2-butanol.
• On the right are two representations for its mirror image (in this
case, its enantiomer).
OH
One en antiomer
of 2-b utanol
OH
OH
Alternative rep res entations
for its mirror image
Naming Enantiomers - R,S
• Because enantiomers are different compounds, each must
have a different name.
• Here are the enantiomers of the over-the-counter drug ibuprofen.
H CH3
COOH
The in active enantiomer
of ib uprofen
H3 C H
HOOC
The active enan tiomer
• The R,S system is a way to distinguish between enantiomers
without having to draw them and point to one or the other.
The R, S System
• To assign an R or S configuration:
• Assign a priority from 1 (highest) to 4 (lowest) to each group on
the stereocenter; for priority rules, see Section 4.3C.
• Orient the stereocenter so that the group of lowest priority is
facing away from you.
• Read the three groups projecting toward you in order from (1) to
(3).
• If reading the groups is clockwise, the configuration is R (Latin,
rectus, straight, correct).
• If reading the groups is counterclockwise, the configuration is S
(Latin: sinister, left).
Naming Enantiomers: The R,S System of Nomenclature
The R, S System
• Problem: Assign an R or S configuration to each stereocenter.
OH
C l
O
O
N
H
3
•Determine the chirality (R/S) of the asymmetric carbons?
The R, S System
• Problem: Assign an R or S configuration to the enantiomers of
ibuprofen.
• Remember to add the H atoms at the stereocenter.
C
O
O
H
I
n
a
c
t
i
v
e
e
n
a
n
t
i
o
m
e
r
o
f
i
b
u
p
r
o
f
e
n
HO O C
active enantiom er of ibuprofen
Definition Reminders!!!!!!
CHIRAL MOLECULES have an asymmetric center.
STEREOCENTER: an atom at which the interchange of two
groups produces a stereoisomer
STEREOISOMERS are isomeric molecules that have the same
molecular formula and sequence of bonded atoms
(constitution), but differ in the three-dimensional orientations of
their atoms in space.
ENANTIOMER is one of two stereoisomers that are mirror
images of each other that are non-superposable (not identical),
DIASTEREOMERS are stereoisomers that are not
enantiomers
Enantiomers & Diastereomers
• For a molecule with n stereocenters, a maximum of 2n
stereoisomers are possible.
• 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.
n = 4 stereocenters
maximum of 2n stereoisomers are possible.
maximum of 24 stereoisomers are possible
= 16 stereoisomers are possible
ENANTIOMERS
DIASTREOMERS
Enantiomers & Diastereomers
Enantiomers & Diastereomers
• 2,3,4-Trihydroxybutanal
O
* *
HOCH2 -CH-CH-CH
OH OH
• Two stereocenters; 22 = 4 stereoisomers are
possible.
CHO
CHO
H
C
OH HO
C
H
H
C
OH HO
C
H
CH2 OH
CH2 OH
A pair of enan tiomers
(Erythrose)
CHO
CHO
H
C
OH HO
C
H
HO
C
H
C
OH
CH2 OH
H
CH2 OH
A pair of enantiomers
(Threose)
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.
COOH
COOH
H
C
OH HO
C
H
H
C
OH HO
C
H
COOH
COOH
A meso compound
(plane of symmetry)
COOH
COOH
H
C
OH HO
C
H
HO
C
H
C
OH
COOH
H
COOH
A pair of enantiomers
Cyclic Molecules
• 2-Methylcyclopentanol
• 2 stereocenters; according to the 2n rule, a maximum of 4
stereoisomers are possible.
• How many actually exist? Answer 4, two pairs of enantiomers.
CH3
H3 C
OH
HO
cis-2-Meth ylcyclop en tanol
CH3
H3 C
OH
HO
t rans -2-Meth ylcyclopen tanol
Cyclic Molecules
• 1,2-Cyclopentanediol
• 2 stereocenters = a maximum of 4 stereoisomers.
• How many exist? Answer: three, one meso compound (the cis
isomer) and one pair of enantiomers (the trans isomer).
OH
HO
OH
HO
OH
HO
OH
HO
cis-1,2-Cyclop entanediol
t rans-1,2-Cyclopen tan ediol
Cyclic Molecules
• 4-Methylcyclohexanol
• How many stereoisomers are possible?
• Answer: two. The cis isomer (achiral) and the trans isomer
(also achiral).
H3 C
OH
cis-4-Methylcyclohexanol
H3 C
OH
t rans-4-Methylcycloh exanol
Cyclic Molecules
• 3-Methylcyclohexanol
• 2 stereocenters = a maximum of 4 stereoisomers
• How many exist? Answer: four, two pairs of enantiomers.
OH
HO
CH3 H3 C
cis-3-Methylcyclohexanol
OH
HO
CH3 H3 C
t rans-3-Methylcyclohexanol
Cyclic Molecules
• 2-Methylcyclohexanol
• 2 stereocenters = a maximum of 4 stereoisomers
• how many exist? Answer: four, two pairs of enantiomers.
OH
HO
CH3 H3 C
cis-2-Methylcyclohexanol
OH
HO
CH3 H3 C
t rans-2-Methylcyclohexanol
Cyclic Molecules
• 1,3-Cyclohexanediol
• 2 stereocenters = a maximum of 4 stereoisomers
• How many exist? Answer: three, the cis isomer (meso) and
the trans isomer (a pair of enantiomers).
OH
HO
OH
HO
cis-1,3-Cyclohexan ediol
OH
HO
OH
HO
trans -1,3-Cyclohexaned iol
•What is the relationship between the two pairs of compounds
below (enantiomers/distereomers/samecompound) ?
Three Or More Stereocenters
• How many stereocenters are present in the molecule on the
left?
• How many stereoisomers are possible?
• One of the possible stereoisomers is menthol.
• Assign an R or S configuration to each stereocenter in
menthol.
OH
2-Is op ropyl-5-meth ylcyclohexanol
OH
Menthol
Three Or More Stereocenters
• Cholesterol
• On the left is the carbon skeleton of cholesterol.
• How many stereocenters are present?
• How many stereoisomers are possible?
H
H
H
HO
H
HO
The carb on skeleton of
ch oles terol
Th is is th e stereoisomer found in
human metabolism
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: Showing that a compound rotates the plane of
plane-polarized light.
Polarimeter
• Figure 6.6 Schematic diagram of a polarimeter.
Optical Activity
• Dextrorotatory: Clockwise rotation of the plane of plane-polarized
light.
• Levorotatory: Counterclockwise rotation of the plane of planepolarized light.
• Specific rotation: The observed rotation of an optically active
substance at a concentration of 1 g/100 mL in a sample tube 10
cm long; for a pure liquid, concentration is in g/mL (density).
COOH
C
H
H3 C
OH
(S)-(+)-Lactic acid
21
[] D = +2.6°
COOH
H C
CH3
HO
(R)-(-)-Lactatic acid
21
[] D = -2.6°
Chirality in the Biological World
• Except for inorganic salts and a few low-molecular-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!
Chirality in Biomolecules
• Enzymes (protein bio-catalysts) all have many stereocenters.
• An example is chymotrypsin, an enzyme in the intestines of
animals that catalyzes the digestion of proteins.
• Chymotrypsin has 251 stereocenters.
• The maximum number of stereoisomers possible is 2251!
• Only one of these stereoisomers is produced and used by any
given organism.
• Because enzymes are chiral substances, most either produce
or react with only substances that match their stereochemical
requirements.
Chirality in Biomolecules
• Because interactions between molecules in living systems take
place in a chiral environment, a molecule and its enantiomer or
one of its diastereomers elicit different physiological responses.
• As we have seen, (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!
CH3
CH3
HOOC
HOOC
OCH3
(S)-Ib uprofen
(S)-N aproxen
Chirality in the Biological World
• Figure 6.7 Schematic diagram of the surface of an enzyme
capable of distinguishing between enantiomers.
Resolution
• Racemic mixture: An equimolar mixture of two enantiomers.
• Because a racemic mixture contains equal numbers of
dextrorotatory and levorotatory molecules, its specific activity is
zero.
• Resolution: The separation of a racemic mixture into its
enantiomers.
Resolution
• Enzymes as resolving agents.
H CH3
C
H3 C H
OEt
+
O
H 3 CO
Eth yl e ster of (S)-n aproxen
1. esteras e
N aOH, H 2O
2. HCl, H 2 O
H CH3
C
H3 CO
O
(S)-N ap roxe n
Et O
OH
C
O
OCH3
Eth yl es ter of (R)-n aproxen
(not affected by th e este ras e)
End of Chapter Six
Chirality : The Handedness of molecules
Key words
 Chiral carbon, assymetric carbon
 Stereocenter
 R/S configuration
 Enantiomer
 Diastereomer
 Mecompound