Chapter Six

Chirality: The Handedness of Molecules

Isomers
In this chapter, we concentrate on enantiomers and diastereomers.
Enantiomers
• Enantiomers: Nonsuperposable mirror images
• As an example of a molecule that exists as a pair of
enantiomers, consider 2-butanol.

OH HO

H3 C
C H H C CH
3
CH2 CH3 CH3 CH2
Original molecule 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.
rotate the
mirror image
OH 180° OH by 180° about OH
C H the C-OH bond
H3 C H C CH H3 C
C CH CH
2 3
CH2 CH3 3
CH3 CH2 H
Original molecule Mirror image 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
turned by 180° C CH CH
H3 C 2 3
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. Allene (Propadiene) BINOL

I s this always true??

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 OH
C H H C CH
H3 C CH3 3
H3 C
Original molecule Mirror image
Enantiomers
• To see the relationship between the original and its mirror
image, rotate the mirror image by 120°.
120° OH rotate by 120°
OH about the OH
C H H C CH C-OH bond C H
H3 C 3 H3 C
CH3 H3 C CH3
Original molecule Mirror image The mirror image
rotated by 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.
(R)-2-Butanol (R-2-丁醇) (S)-2-Butanol (S-2-丁醇)

HO H
H OH

CH3 CH3
H OH (1) (2)

H H Newman projection? (3) (4)

Newman projection?
CH3
CH3

CH3
CH2CH3

Fischer projection? A' B'

A B
Fischer projection?
OH
CH3
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 H OH
H OH OH
C H C
H3 C H3 C
CH2 CH3 CH2 CH3
(1) (2) (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 OH OH

One enantiomer Alternative representations

of 2-butanol for its mirror image
OH

OH
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 H3 C H

COOH HOOC

The inactive enantiomer The active enantiomer

of ibuprofen

• 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).
The R,S System
• Problem: Assign an R or S configuration to each stereocenter.

H Cl H
(a) OH
S (b)

R
O
(c) -
O
+
NH3
S
Amino acids
The R,S System
• Problem: Assign an R or S configuration to the enantiomers of
ibuprofen.
• Remember to add the H at the stereocenter.

R CH3 CH3 S
COOH HOOC

The inactive enantiomer The active enantiomer

of ibuprofen

CH3
Nomenclature ??
(including configuration)
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 plane-
polarized 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 COOH
C H H C
H3 C CH3
OH HO
(S)-(+ )-Lactic acid (R)-(-)-Lactatic acid
21 21
[] D = +2.6° [] 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 the Biological World
• Figure 6.7 Schematic diagram of the surface of an enzyme
capable of distinguishing between enantiomers.
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)-Ibuprofen (S)-Naproxen
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.
The separation of a racemic mixture into its
• Resolution:
enantiomers.
Resolution
• Enzymes as resolving agents.
H CH3 H3 C H
OEt Et O
C C
O + O
H3 CO OCH3
Ethyl ester of (S)-naproxen Ethyl ester of (R)-naproxen
(not affected by the esterase)
1. esterase NaOH, H2O
2. HCl, H2 O
H CH3

C OH

H3 CO O
(S)-Naproxen
Enantiomers & Diastereomers
• 2,3,4-Trihydroxybutanal
O
* *
HOCH2 -CH-CH-CH
OH OH

• Two stereocenters; 22 = 4 stereoisomers are possible.

CHO CHO CHO CHO
H C OH HO C H H C OH HO C H

H C OH HO C H HO C H H C OH
CH2 OH CH2 OH CH2 OH CH2 OH
A pair of enantiomers A pair of enantiomers
(Erythrose) (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 COOH COOH
H H H C OH HO C H H C OH HO C H
HOOC C C COOH
H C OH HO C H HO C H H C OH
OH OH
COOH COOH COOH COOH
A meso compound A pair of enantiomers
(plane of symmetry)
 (2R,3R)-Tartaric acid (2S,3S)-Tartaric acid
操作重點提示
HO H
1. 觀察兩個立體中心的鏡 H OH

COOH
像異構物的結構與 R/S
命名 COOH
HOOC
2. 了解結構表徵法之間的 HOOC

H
轉換
HO OH
H

COOH OH
H H
A B A' B'
HOOC C C COOH
C D OH OH C' D'

COOH COOH
 (2R,3S) or (2S,3R)-Tartaric acid
操作重點提示
H OH 1. 觀察兩個立體中心的非
HO H
鏡像異構物的結構與
COOH R/S 命名
COOH
HOOC 2. 了解結構表徵法之間的
HOOC
轉換
HO H
H OH

COOH
COOH
1 2 A B

4 3 C D
COOH
COOH
Cyclic Molecules
• 4-Methylcyclohexanol
• How many stereoisomers are possible?
• Answer: two. The cis isomer (achiral) and the trans isomer
(also achiral).

H3 C OH H3 C OH

cis-4-Methylcyclohexanol trans-4-Methylcyclohexanol

H3C CH3 H3 C CH3

Cyclic Molecules
• 3-Methylcyclohexanol
• 2 stereocenters = a maximum of 4 stereoisomers
• How many exist? Answer: four, two pairs of enantiomers.

OH HO OH HO

CH3 H3 C CH3 H3 C
cis-3-Methylcyclohexanol trans-3-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

OH HO OH HO
cis-1,3-Cyclohexanediol trans-1,3-Cyclohexanediol
Cyclic Molecules
• 2-Methylcyclohexanol
• 2 stereocenters = a maximum of 4 stereoisomers
• how many exist? Answer: four, two pairs of enantiomers.

OH HO OH HO

CH3 H3 C CH3 H3 C
cis-2-Methylcyclohexanol trans-2-Methylcyclohexanol

CH3 H3C CH3 H3C

CH3 H3C CH3 H3C

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.

R
R
OH S OH

2-Isopropyl-5-methyl- Menthol
cyclohexanol
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 HO
The carbon skeleton of This is the stereoisomer found in
cholesterol human metabolism