Stereochemistry

Stereochemistry refers to the

3-dimensional properties and reactions
of molecules. It has its language and
terms that need to be learned to fully
communicate and understand the
concepts.

1
 Definitions
• Stereoisomers – compounds with the same
connectivity, different arrangement in
space
• Enantiomers – stereoisomers that are non-
superimposible mirror images; only
properties that differ are direction (+ or -)
of optical rotation
• Diastereomers – stereoisomers that are not
mirror images; different compounds
with different physical properties
2
 More Definitions
• Asymmetric center – sp3 carbon with 4
different groups attached
• Optical activity – the ability to rotate the
plane of plane –polarized light
• Chiral compound – a compound that is
optically active (achiral compound will
not rotate light)
• Polarimeter – device that measures the
optical rotation of the chiral compound

3
 Chirality

• “Handedness”: Right-hand glove does

not fit the left hand.
• An object is chiral if its mirror image is
different from the original object.
4
Chapter 5 4
 Achiral
• Mirror images that can be superposed
are achiral (not chiral).

5
Chapter 5 5
 Stereoisomers
Enantiomers: Compounds that are
nonsuperimposable mirror images. Any
molecule that is chiral must have an enantiomer.

6
Chapter 5 6
 Chiral Carbon Atom
• Also called asymmetric carbon atom.
• Carbon atom that is bonded to four different
groups is chiral.
• Its mirror image will be a different compound
(enantiomer).

7
Chapter 5 7
 Stereocenters
• An asymmetric carbon atom is the most
common example of a chirality center.
• Chirality centers belong to an even broader
group called stereocenters. A stereocenter
(or stereogenic atom) is any atom at which
the interchange of two groups gives a
stereoisomer.
• Asymmetric carbons and the double-bonded
carbon atoms in cis-trans isomers are the
most common types of stereocenters.

8
Chapter 5 8
Examples of Chirality Centers

Asymmetric carbon atoms are examples of chirality

centers, which are examples of stereocenters.
9
Chapter 5 9
10
 Achiral Compounds

Take this mirror image and try to

superimpose it on the one to the
left matching all the atoms.
Everything will match.

When the images can be superposed, the

compound is achiral.
11
Chapter 5 11
 Planes of Symmetry

• A molecule that has a plane of symmetry is

achiral.
12
Chapter 5 12
 Cis Cyclic Compounds

• Cis-1,2-dichlorocyclohexane is achiral because

the molecule has an internal plane of symmetry.
Both structures above can be superimposed
(they are identical to their mirror images).

13
Chapter 5 13
 Trans Cyclic Compounds

• Trans-1,2-dichlorocyclohexane does not have a

plane of symmetry so the images are
nonsuperimposable and the molecule will have
two enantiomers.

14
Chapter 5 14
 (R) and (S) Configuration

• Both enantiomers of alanine receive the same name in the

IUPAC system: 2-aminopropanoic acid.
• Only one enantiomer is biologically active. In alanine only
the enantiomer on the left can be metabolized by the
enzyme.
• A way to distinguish between them is to use stereochemical
modifiers (R) and (S).

15
Chapter 5 15
 Cahn–Ingold–Prelog
Priority System
• Enantiomers have different spatial arrangements of
the four groups attached to the asymmetric carbon.
• The two possible spatial arrangements are called
configurations.
• Each asymmetric carbon atom is assigned a letter
(R) or (S) based on its three-dimensional
configuration.
• Cahn–Ingold–Prelog convention is the most widely
accepted system for naming the configurations of
chirality centers.

16
Chapter 5 16
(R) and (S) Configuration: Step 1
Assign Priority
• Assign a relative “priority” to each group
bonded to the asymmetric carbon.
Group 1 would have the highest priority,
group 2 second, etc.
• Atoms with higher atomic numbers
receive higher priorities.

I > Br > Cl > S > F > O > N > 13C > 12C > 2H > 1H
17
Chapter 5 17
 Assign Priorities

Atomic number: F > N > C > H

18
Chapter 5 18
(R) and (S) Configuration: Breaking
Ties

In case of ties, use the next atoms along

the chain of each group as tiebreakers.

19
Chapter 5 19
 (R) and (S) Configuration:
Multiple Bonds
Treat double and
triple bonds as if
each were a bond to
a separate atom.

20
Chapter 5 20
 (R) and (S) Configuration: Step 2

• Working in 3-D, rotate the

molecule so that the
lowest priority group is in
back.
• Draw an arrow from
highest (1) to second
highest (2) to lowest (3)
priority group.
• Clockwise = (R),
Counterclockwise = (S)

21
Chapter 5 21
 Assign Priorities

Counterclockwise
(S)

Draw an arrow from Group 1 to Group 2 to Group 3 and

back to Group 1. Ignore Group 4.

Clockwise = (R) and Counterclockwise = (S)

22
Chapter 5 22
 Example
3
1 CH2CH3
OH
rotate
C 3 2
C 4
2 CH2CH3 CH3CH2CH2 H
CH3CH2CH2
H OH
4 1

Clockwise
(R)

When rotating to put the lowest priority group in the back,

keep one group in place and rotate the other three.

23
Chapter 5 23
Example (Continued)

3
CH3

1
CH3CH2CH=CH H4
CH2CH2CH2CH3
2

Counterclockwise
(S)

24
Chapter 5 24
Configuration in Cyclic
Compounds

25
Chapter 5 25
 Properties of Enantiomers
• Same boiling point, melting point, and density.
• Same refractive index.
• Rotate the plane of polarized light in the same
magnitude, but in opposite directions.
• Different interaction with other chiral molecules:
– Active site of enzymes is selective for a specific
enantiomer.
– Taste buds and scent receptors are also chiral.
Enantiomers may have different smells.

26
Chapter 5 26
 Polarized Light

Plane-polarized light is composed of

waves that vibrate in only one plane.

27
Chapter 5 27
 Optical Activity
• Enantiomers rotate the plane of polarized
light in opposite directions, but same
number of degrees.

28
Chapter 5 28
 Polarimeter

Clockwise Counterclockwise
Dextrorotatory (+) Levorotatory (-)

Not related to (R) and (S)

29
Chapter 5 29
 Specific Rotation
Observed rotation depends on the length
of the cell and concentration, as well as the
strength of optical activity, temperature,
and wavelength of light.

[] =  (observed)
c•l

Where  (observed) is the rotation observed in the

polarimeter, c is concentration in g/mL, and l is
length of sample cell in decimeters.
30
Chapter 5 30
 Solved Problem 2
When one of the enantiomers of 2-butanol is placed in a polarimeter, the observed rotation is 4.05°
counterclockwise. The solution was made by diluting 6 g of 2-butanol to a total of 40 mL, and the
solution was placed into a 200-mm polarimeter tube for the measurement. Determine the specific
rotation for this enantiomer of 2-butanol.

Solution
Since it is levorotatory, this must be (–)-2-butanol The concentration is 6 g per 40 mL = 0.15 g/mL,
and the path length is 200 mm = 2 dm. The specific rotation is

– 4.05°
[] 25 = = –13.5°
D (0.15)(2)

31
Chapter 5 31
 Chirality of Conformational Isomers

The two chair conformations of cis-1,2-dibromocyclohexane

are nonsuperimposable, but the interconversion is fast and
the molecules are in equilibrium. Any sample would be
racemic and, as such, optically inactive.
32
Chapter 5 32
 Nonmobile Conformers

• The planar conformation of the biphenyl derivative is too

sterically crowded. The compound has no rotation around
the central C—C bond and thus it is conformationally
locked.
• The staggered conformations are chiral: They are
nonsuperimposable mirror images.
33
Chapter 5 33
 Allenes can be Chiral

H H
H H
C C C C C C
Cl Cl
CH3 CH3

34
Penta-2,3-diene Is Chiral

35
Chapter 5 35
Fischer Projections (Continued)

36
Chapter 5 36
 Fischer Rules

• Carbon chain is on the vertical line.

• Highest oxidized carbon is at top.
• Rotation of 180 in plane doesn’t
change molecule.
• Rotation of 90 is NOT allowed.

37
Chapter 5 37
 180° Rotation

• A rotation of 180° is allowed because it will

not change the configuration.

38
Chapter 5 38
 90° Rotation

• A 90° rotation will change the orientation of

the horizontal and vertical groups.
• Do not rotate a Fischer projection 90°.

39
Chapter 5 39
 Fischer Mirror Images
• Fisher projections are easy to draw and make
it easier to find enantiomers and internal
mirror planes when the molecule has two or
more chiral centers.
CH3
H Cl
Cl H
CH3

40
Chapter 5 40
 Fischer (R) and (S)
• Lowest priority (usually H) comes forward, so
assignment rules are backward!
• Clockwise 1-2-3 is (S) and counterclockwise
1-2-3 is (R).
• Example:
(S)
CH3
H Cl
Cl H
CH3
(S)
41
Chapter 5 41
 Glyceraldehyde
• The arrow from group 1 to group 2 to group 3 appears
counterclockwise in the Fischer projection. If the
molecule is turned over so the hydrogen is in the back,
the arrow is clockwise, so this is the (R) enantiomer of
glyceraldehyde.

42
Chapter 5 42
43
 When naming (R) and (S) from
Fischer projections with the
hydrogen on a horizontal bond
(toward you instead of away
from you), just apply the normal
rules backward.

44
Chapter 5 44
 Racemic Mixtures

• Equal quantities of d- and l-enantiomers.

• Notation: (d,l) or ()
• No optical activity.
• The mixture may have different boiling point (b. p.) and melting
point (m. p.) from the enantiomers!

45
Chapter 5 45
 Racemic Products
If optically inactive reagents combine to
form a chiral molecule, a racemic mixture
is formed.

46
Chapter 5 46
 Racemic Mixture
R,R S,S
CO2H CO2H

H OH HO H

HO H H OH

CO2H CO2H
Racemic Mixture (Racemate): 50/50 mixture of enantiomers

(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid

o
m.p. C 168-170 168-170 210-212
[] (degrees) - 12 + 12 0
 (g/mL) 1.7598 1.7598 1.7723
47
Resolution of Enantiomers
Separation of a racemic mixture into its two
enantiomeric forms

48
Resolution of a racemic modification

1. Physical methods:
- Spontaneous resolution
- Inclusion compounds
- Chromatography
2. Chemical methods:
- Diastereomeric salt formation
3. Biochemical methods:
- Enzymatic decomposition

49
50
Strategy

enantiomers

C(+) C(-)

51
 Strategy

enantiomers

C(+) C(-)

2P(+)

C(+)P(+) C(-)P(+)

diastereomers
52
 Strategy

enantiomers

C(+) C(-)

2P(+) C(+)P(+)

C(-)P(+)

C(+)P(+) C(-)P(+)

diastereomers
53
 Strategy

enantiomers C(+)

C(+) C(-) P(+)

2P(+) C(+)P(+)

C(-)P(+)

C(+)P(+) C(-)P(+) P(+)

diastereomers
54 C(-)
 Resolution of a Racemic Mixture

(S)-base
(R)-acid (S)-acid (R,S)-salt (S,S)-salt
enantiomers diastereomers

(R,S)-salt (S,S)-salt
HCl HCl

(S)-baseH+ (S)-baseH+
+ +
(R)-acid (S)-acid
55
Lock and Key Model

CH2OH CHO

H C OH H C
OH
H CHO OH H CH2OH
OH
CHO CHO

56
Discrimination of Enantiomers by
Biological Molecules

57
 Optical Purity
• Optical purity (o.p.) is sometimes called
enantiomeric excess (e.e.).
• One enantiomer is present in greater
amounts.

observed rotation
o.p. = X 100
rotation of pure enantiomer

58
58
59
Physical Properties of Stereoisomers—Optical Purity
• Enantiomeric excess (optical purity) is a measurement of
how much one enantiomer is present more than the racemic
mixture. It is denoted by the symbol ee.

ee = % of one enantiomer - % of the other enantiomer.

• Consider the following example—If a mixture contains 75%
of one enantiomer and 25% of the other, the enantiomeric
excess is 75% - 25% = 50%. Thus, there is a 50% excess of
one enantiomer over the racemic mixture.
• The enantiomeric excess can also be calculated if the
specific rotation [] of a mixture and the specific rotation []
of a pure enantiomer are known.
ee = ([] mixture/[] pure enantiomer) x 100.
60
60
 Calculate % Composition
The specific rotation of (S)-2-iodobutane is +15.90.
Determine the % composition of a mixture of (R)- and
(S)-2-iodobutane if the specific rotation of the mixture is
-3.18.
The sign is from the enantiomer in excess: levorotatory.

3.18
o.p. = X 100 = 20%
15.90

2l = 120% l = 60% d = 40%

61
Chapter 5 61
 Stereochemistry
Chemical Properties of Enantiomers
• Two enantiomers have exactly the same chemical properties except for
their reaction with chiral non-racemic reagents.
• Many drugs are chiral and often must react with a chiral receptor or chiral
enzyme to be effective. One enantiomer of a drug may effectively treat a
disease whereas its mirror image may be ineffective or toxic.

62
62
 Stereochemistry
Enantiomers and the Sense of Smell
• Research suggests that the odor of a particular molecule is
determined more by its shape than by the presence of a
particular functional group.
• Because enantiomers interact with chiral smell receptors,
some enantiomers have different odors.

63
63
 Two or More Chiral Carbons
• When compounds have two or more chiral
centers they have enantiomers,
diastereomers, or meso isomers.
• Enantiomers have opposite configurations at
each corresponding chiral carbon.
• Diastereomers have some matching, some
opposite configurations.
• Meso compounds have internal mirror planes.
• Maximum number of isomers is 2n, where n =
the number of chiral carbons.

64
Chapter 5 64
 Diastereomers
• Molecules with two or more chiral carbons.
• Stereoisomers that are not mirror images.

65
Chapter 5 65
 Stereochemistry
Physical Properties of Stereoisomers
• Since enantiomers have identical physical properties, they cannot be
separated by common physical techniques like distillation.
• Diastereomers and constitutional isomers have different physical
properties and therefore can be separated by common physical
techniques.
Figure 5.12
The physical properties of the
three stereoisomers of
tartaric acid

66
66
 Stereochemistry
Diastereomers
Figure 5.8
Summary: The four
stereoisomers of 2,3-
dibromopentane

67
67
 Diastereomers: Cis-trans
Isomerism on Rings
• Cis-trans isomers are not mirror images, so
these are diastereomers.

68
Chapter 5 68
 Diastereomers: Cis-trans
Isomerism on Double Bonds
• These stereoisomers are not mirror
images of each other, so they are not
enantiomers. They are diastereomers.

69
Chapter 5 69
 Properties of Diastereomers
• Diastereomers have different physical
properties, so they can be easily separated.
• Enantiomers differ only in reaction with other
chiral molecules and the direction in which
polarized light is rotated.
• Enantiomers are difficult to separate.
• Convert enantiomers into diastereomers to be
able to separate them.

70
Chapter 5 70
 Number of Stereoisomers

The 2n rule will not apply to compounds that may have a

plane of symmetry. 2,3-dibromobutane has only three
stereoisomers: (±) diastereomer and the meso
diastereomer.
71
Chapter 5 71
 Meso Compound Internal Plane of
Symmetry Optically Inactive
R,S S,R
CO2H CO2H

H OH HO H
mirror
plane
H OH HO H

CO2H CO2H
o
rotate 180
superimposible

72
2,3,4-trichlorohexane
How many stereoisomers?
Cl

* * *
Cl Cl
3 asymmetric centers
2n, n= # asymmetric centers (3)
8 stereoisomers
73
 n = 3; 2n =8
CH3 CH3 CH3 CH3
S H Cl Cl H R H Cl Cl H
S H Cl Cl H R H Cl Cl H
RH Cl Cl H S Cl H H Cl
CH2CH3 CH2CH3 CH2CH3 CH2CH3

CH3 CH3 CH3 CH3

H Cl Cl H Cl H H Cl
Cl H H Cl H Cl Cl H
H Cl Cl H H Cl Cl H
CH2CH3 CH2CH3 CH2CH3 CH2CH3
74
A Carbohydrate
CHO
H OH R

HO H S

H OH R
H OH R
CH2OH
(+) D-Glucose
75
 Meso Compounds

• Meso compounds have a plane of symmetry.

• If one image was rotated 180°, then it could be
superimposed on the other image.
• Meso compounds are achiral even though they have
chiral centers.

76
Chapter 5 76
 Chemical Resolution of
Enantiomers

React the racemic mixture with a pure chiral

compound, such as tartaric acid, to form
diastereomers, then separate them.

77
Chapter 5 77
 Meso Compound
Internal Plane of Symmetry
Optically Inactive

R,S S,R
CO2H CO2H

H OH HO H
mirror
plane
H OH HO H

CO2H CO2H
o
rotate 180
superimposible
78
Formation of (R)- and (S)-2-Butyl
Tartrate

79
Chapter 5 79
Biological Discrimination

80
Chapter 5 80