Stereochemistry
1
Handedness

Some things have a “handedness,” that
is look at your right and left hand. They
look alike, but are not the same. They
are mirror images.
2
Nobel Prize - 2001
Their research
deals with the
fact that many
molecules
appear in two
forms that are
mirror images of
each other, just
like the left and
right hands.
3
Chirality
The mirror image
of a chiral object is
different and will not
superimpose on the
original object.
Objects which are chiral have a
sense of “handedness” and
exist in two forms.
4
Mirror Image
5
mirror
Cl Cl
H
H
Are these two
structures identical?
6
Stereoisomers
Cl Cl
H
H
7
Stereoisomers
8
Stereoisomers
9
Stereoisomers
10
Stereoisomers
11
Stereoisomers
12
Stereoisomers
enantiomers
Stereoisomers that are
nonidentical mirror
images are called
enantiomers.
13
Visualize, visualize ….
F
H
Br
Cl
C C
Cl
H H
Br Br
Br
C C
H
Cl
H
Br
F
F
C C
H
Br
14
Visualize, visualize …
F
H
Br
Cl
C C
Cl
H H
Br Br
Cl
H
Br
F
C C
H
Br
Cl
Br
H
F
Br
H
Br
H
F
15
Visualize, visualize …
CH3
CH3
C
C
Br
F
H
F
Br
H
enantiomer
ODD:
1..3..5…etc interchanges = enantiomer
EVEN:
2..4..6...etc interchanges = original compound
16
Are these identical or are they
enantiomers?
Br
1
Br
CH3
H
C
C
F
CH3
Br
C
C
F
H
CH3
CH3
H
F
2
H
ENANTIOMER
YOU CAN USE
INTERCHANGES
Br
F
H
H
C
C
CH3
SAME
F
Br
3
CH3
Br
F
ENANTIOMER17
Isomers



Isomers: different compounds with the
same molecular formula
Constitutional isomers: isomers with a
different connectivity
Stereoisomers: isomers with the same
molecular formula, the same connectivity
but a different orientation of their atoms in
space that cannot be interconverted by
rotation about a single bond
18
Chirality



Mirror image: the reflection of an object in a
mirror
Objects that are not superposable on their mirror
images are said to be chiral, that is, they show
handedness
Objects that are superposable on their mirror
images are said to be achiral, that is, they do not
show handedness. An achiral object has at least
one element of symmetry
19
Chirality

A molecule
cannot be chiral if
it has a plane of
symmetry.
20
Chirality


A plane of symmetry is a plane that
cuts through an object in such a way
that one half of the object is an exact
mirror image of the other half.
A molecule that has a plane of
symmetry must be identical to its mirror
image and therefore must be nonchiral,
or achiral.
21
Stereogenic Carbons
Cl
H
This is one type of ….
stereocenter
…. others are possible
F
Br
A stereogenic carbon is tetrahedral and
has four different groups attached.
22
Elements of Symmetry

Plane of symmetry: an imaginary plane
passing through an object dividing it
such that one half is the mirror image
of the other half
F
F
Cl
Cl
Br
Cl
Br
Cl
23
Elements of Symmetry

Center of symmetry: a point so situated
that identical components of the object are
located equidistant on opposite sides and
equidistant from the point along any axis
passing through the point
Br
H
Cl
Cl
H
Br
center of
symmetry
24
Achiral
F
Br
The plane of the paper
is a plane of symmetry
Cl
Cl
Cl
Cl
F
Br
Two identical groups renders a
tetrahedral carbon achiral.
25
Two Views of the Plane of
Symmetry
F
plane of
symmetry
F
Br
Cl
Cl
Cl
Br
Cl
side view
edge view
26
Symmetry Plane
Symmetry plane
No symmetry plane
COOH
H C H
CH3
H C OH
COOH
COOH
achiral
chiral
27
CONSTITUTIONAL
ISOMERS
ISOMERS
Different compounds
with the same
molecular formula
each isomer could
have stereoisomers
STEREOISOMERS
Isomers with the same order
of attachment, but a different
configuration (3D arrangement)
of groups on one or more of
the atoms
double bond
or ring
cis/trans
ISOMERS
(geometric)
with a ring
both can apply
Isomers with a different
order of attachment of
the atoms in their
molecules
ENANTIOMERS
Stereoisomers whose
molecules are nonsuperimposible mirror
images of each other
DIASTEREOMERS
Stereoisomers whose
molecules are not mirror
images of each other
TYPES OF ISOMERISM 28
Enantiomers

Enantiomers: stereoisomers that are
nonsuperposable mirror images; refers
to the relationship between pairs of
objects
29
Enantiomers
Cl
H
F
Br
F
Br
rotate
H
Cl
this molecule
is chiral
H
do interchanges in class
Cl
Br
F
note that the fluorine
and bromine have been
interchanged in the
enantiomer
30
Enantiomers

Lactic acid
HO
HO
O
O
OH
C
C
C
C
H
CH3
H
H3 C
OH
31
Enantiomers
OH
CH3 CHCH2 OH

1,2-propanediol
OH
H3 C
C
H
OH
CH2 OH
HOH2 C
C
CH3
H
32
Enantiomers

Cl
3-Chlorocyclohexene
Cl
H
Cl
H
33
Br
CH3CH2CH2CH2CH2 C CH2CH2CH2CH3
H
34
HO
H
CH3
H
CH3
CH3
35
O
CH3
O
carvone
spearment oil
nootkatone
grapefruit oil
36
Carvone
CH3
O
H 3C C
(R)-carvone
caraway and dill seed oils
H
CH2
CH2
H 3C C
H
(S)-carvone
spearmint oil
O
CH3
37
Limonene
CH3
(R)-limonene
odor of oranges
H 3C C
H
CH 2
CH 2
H 3C C
H
(S)-limonene
odor of lemons
CH3
38
Chiral Drugs


Most pharmaceutical drugs are chiral
thalidomide
O
O
H
N
H
O
O
N
H
N
O
O
N
H
O
O
39
Optically Active

Refers to molecules that interact with
plane-polarized light
Jean Baptiste Biot
French Physicist - 1815
He discovered that some natural substances
(glucose, nicotine, sucrose) rotate the plane
of plane-polarized light and that others did not.
40
Optical Activity
angle of
rotation, a
a
incident
polarized
light
sample cell
(usually quartz)
transmitted
light (rotated)
a solution of the substance to be
examined is placed inside the cell
41
Plane Polarized Light



Ordinary light: consists of waves vibrating in
all planes perpendicular to its direction of
propagation
Plane polarized light: consists of waves
vibrating only in one plane
Plane polarized light is an equal mixture of
left and right-circularly polarized light. These
two forms are nonsuperposable mirror
images and, therefore, enantiomers.
42
Plane-Polarized Light Beam
l
wavelength
SIDE
VIEW
.
END
VIEW
polarized beam
frequency ( n )
n = c
l
NOT PLANE-POLARIZED
Sine waves
are not aligned
in the same
plane.
c = speed of light
unpolarized
beam
43
Plane Polarized Light



Because of its handedness, circularly
polarized light reacts one way with a
stereocenter with R-handedness, and
differently with its enantiomer
The net effect of the interaction of plane
polarized light with a chiral compound is that
the plane of polarization is rotated
Polarimeter: a device for measuring the
extent of rotation of plane polarized light
44
Optical Activity


optical activity - ability of certain
molecules to rotate plane polarized light
detected using a polarimeter
45
Polarimeter
46
Polarimeter
a
Na vapor lamp
sample cell
polarizer
analyzer
l
(dam)
47
Optical Activity



Observed rotation: the number of
degrees, a, through which a compound
rotates the plane of polarized light
Dextrorotatory (+): rotation of the
plane of polarized light to the right
Levorotatory (-): rotation of the plane
of polarized light to the left
48
Optical Activity

Specific rotation:
Observed rotation
of the plane of
polarized light
when a sample is
placed in a tube
1.0 dam in length
and at a
concentration of
1g/mL.
a 
T
D
a
a

cl
= observed rotation
c = concentration ( g/mL )
l = length of cell ( dm )
D = yellow light from sodium lamp
T = temperature ( Celsius )
49
Optical Activity

For a pair of enantiomers, the value of
the specific rotation of each is the
same, but opposite in sign
OH
HO
C
H
CH3 CH2
C
CH3
(S)-(+)-2-Butanol
25
[ a] D
+13.52
H3 C
H
CH2 CH3
(R)-(-)-2-Butanol
25
[ a] D
-13.52
50
Discovery of Enantiomers
Louis Pasteur
 Recrystallized
tartaric acid
 Two different kinds
of crystals that were
mirror images.
 Each type of crystal
rotated light in
opposite directions.
51
Discovery of Enantiomers
“There is no doubt
that in dextro
tartaric acid there
exists an
assymetric
arrangement
having a
nonsuperimposible
image.”
-
COO Na
+
H C OH
HO C H
-
COO Na
+
52
OH OH
HOOC
meso
COOH
H
HAcid
Tartaric
OH OH
HOOC
H
OH OH
H
COOH
(+)-tartaric acid
H
HOOC
enantiomers
OH OH
HOOC
H
H
meso
COOH
meso -tartaric acid
OH OH
H
COOH
(-)-tartaric acid
ALSO FOUND
(as a minor component)
[a]D = 0
more about this
compound later
OH OH
53
R,S Convention

Priority rules (Cahn, Ingold, Prelog)

1
H
Each atom bonded to the stereocenter is
assigned a priority, based on atomic
number. The higher the atomic number,
the higher the priority
6
CH3
7
NH2
8
16
17
35
53
OH
SH
Cl
Br
I
Increasing Priority
54
R,S Convention

If priority cannot be assigned on the basis
of the atoms bonded to the stereocenter,
look to the next set of atoms. Priority is
assigned at the first point of difference.
1
CH2
H
6
CH2 CH3
7
CH2 NH2
8
CH2 OH
Increasing Priority
55
R,S Convention

Atoms participating in a double or triple
bond are considered to be bonded to an
equivalent number of similar atoms by
single bonds
H
H
C O
C O
O C
56
Naming Enantiomers
1.
2.
3.
Locate the stereocenter
Assign a priority to each substituent
from 1 (highest) to 4 (lowest)
Orient the molecule so that the group
of lowest priority (4) is directed away
from you
57
Naming Enantiomers
4.
5.
Read the three groups projecting
toward you in order from highest (1)
to lowest priority (3)
If reading is clockwise, configuration is
R (from the Latin rectus). If it is
counterclockwise, configuration is S
(from the Latin sinister).
58
R, S Convention
clockwise
1
2
2
1
C
C
4
view with
substituent
of lowest
priority in
back
counter
clockwise
4
3
R
3
(rectus)
S
(sinister)
59
Bromochlorofluoroiodomethane
1
1
I
4
I
4
C
F
Cl
Br
2
C
F
3
Cl
Br
3
2
R
S
Enantiomers
60
Priorities
1.
2.
3.
4.
-OH
-COOH
-CH3
-H
HO
H
C
COOH
CH3
(R)-(-)-lactic acid
HOOC
H
C
OH
CH3
(S)-(+)-lactic acid
61
You try it!
1.
2.
3.
4.
Br
COOH
CH3
H
H
H3C
CH3
Br
COOH
COOH
H
Br
62
Diastereoisomer


Enantiomers: opposite configurations at
all stereogenic centers.
Diastereomers: Stereoisomers that are
not mirror images of each other.
Different configuration at some
locations.
63
Diastereoisomer

Stereoisomers
that are not
mirror images of
each other.
Different
configuration at
some locations.
COOH
NH2
H
C
H
C
OH
CH3
COOH
H 2N C H
H
C
OH
CH3
64
Two Stereocenters
Cl Br
H3C
H
H
Br Cl
CH3
H3C
H
H
CH3
entaiomers
Cl Br
H3C
H
Br Cl
H
CH3
H
H3C
H
CH3
d
i
a
s
t
e
r
o
m
e
r
s
entaiomers
65
Diastereomers

Threonine: 2 pairs
of enantiomers
COOH
NH2
H
C
H
2R,3R
2S,3S
2R,3S
2S,3R
2S,3S
2R,3R
2S,3R
2R,3S
2R,3S & 2S,3R
2R,3S & 2S,3R
2R,3R & 2S,3S
2R,3R & 2S,3S
C
OH
CH 3
2R, 3R
COOH
H C NH2
C
COOH
H
H 2N
C
C
HO
H
H 3C
2S, 3S
COOH
H 2N C H
C
HO
H
H 3C
H
OH
CH3
2R, 3S
2S, 3R
66
Enantiomers & Diastereomers




For a molecule with 1 stereocenter, 2
stereoisomers are possible
For a molecule with 2 stereocenters, a
maximum of 4 stereoisomers are
possible
For a molecule with n stereocenters, a
maximum of 2n stereoisomers are
possible
2n-1 pairs of enantiomers
67
Enantiomers & Diastereomers


For tartaric acid, the three possible
stereoisomers are one meso compound
and a pair of enantiomers.
Meso compound: an achiral compound
possessing two or more stereocenters.
68
Symmetry Plane


2R, 3S and 2S, 3R
are identical
Molecule has a plane
of symmetry
perpendicular to C-C
and is therefore
achira
COOH
H C OH
COOH
H
HO
C
C
HO
H
COOH
2R, 3R
COOH
H C OH
H
H
2R, 3S
OH
COOH
2S, 3S
COOH
H
HO
C
C
OH
COOH
C
HO
C
H
COOH
2S, 3R
69
Symmetry Plane



2R, 3S and 2S, 3R
are identical
Molecule has a plane
of symmetry
perpendicular to C-C
and is therefore
achira
One meso
compound and a
pair of enantiomers
COOH
H C OH
COOH
H
HO
C
C
HO
H
COOH
2R, 3R
COOH
H C OH
H
C
OH
COOH
2R, 3S
H
C
OH
COOH
2S, 3S
COOH
Mirror
H
HO
C is
image
C
identical
HO
H
COOH
2S, 3R
70
CH3CHCHCH3
Cl Br
2-Bromo-3-chlorobutane
mirror
Cl Br
S
CH3
H
R
H
S
CH3
CH3
H
R
H
CH3
enantiomers 1
diastereomers
CH3
Br Cl
Cl Br
Br Cl
S
S
H
H
CH3
R
H
CH3
R
H
CH3
enantiomers 2
71
CH3CHCHCH3
Cl Cl
2,3-Dichlorobutane
Cl Cl
S
CH3
H
Cl Cl
R
H
diastereomers
CH3
mirror image
CH3 is identical CH3
meso
H
Cl Cl
CH3
H
Cl Cl
S
S
H
H
CH3
R
H
CH3
R
H
CH3
enantiomers
72
Meso

Meso compounds are achiral by virtue of a
symmetry plane, but contain a stereogenic
center.
plane of symmmetry
mirror
Cl Cl
H3C
H
H
Cl Cl
CH3
H3C
H
H
CH3
73
Racemic Mixture

Racemic mixture (d,l;): an equimolar
mixture (50:50) of two enantiomers

because a racemic mixture contains equal
numbers of dextrorotatory and levorotatory
molecules, its specific activity is zero.
74
Properties of Stereoisomers



Enantiomers have identical physical
(except for a) and chemical properties.
Diastereomers are different compounds
and have different physical and
chemical properties
Meso-tartaric acid, for example, has
different physical and chemical
properties from its enantiomers
75
Tartaric Acid
(-) - tartaric acid
[a]D = -12.0o
mp 168 - 170o
solubility of 1 g
0.75 mL H2O
1.7 mL methanol
250 mL ether
insoluble CHCl3
d = 1.758 g/mL
(+) - tartaric acid
[a]D = +12.0o
mp 168 - 170o
solubility of 1 g
0.75 mL H2O
1.7 mL methanol
250 mL ether
insoluble CHCl3
d = 1.758 g/mL
meso - tartaric acid
[a ] D = 0o
mp 140o
d = 1.666 g/mL
solubility of 1 g
0.94 mL H2O
insoluble CHCl3
76
CH 3
H
Fischer Projections

OH
CH 2 CH 3
Fischer projection: a two-dimensional
representation showing the
configuration of a stereocenter



horizontal lines represent bonds projecting
forward
vertical lines represent bonds projecting to
the rear
the only atom in the plane of the paper is
the stereocenter
77
Fischer Projections
COOH
COOH
OH
H
C
H
CH3
OH CH3
How?
(R)-lactic acid
78
Fischer Projections
COOH
C
H
H
OH CH3
COOH
OH
CH3
79
Fischer Projections
COOH
COOH
OH
OH H
H
CH3
CH3
80
Fischer Projections
1.
2.
Orient the stereocenter so that bonds
projecting away from you are vertical and
bonds projecting toward you are horizontal
Flatten it to two dimensions
OH
H
CH 3 CH 2
CH 3
(1)
C
(S)-2-Butanol
(3-D formula)
H
C
CH 3
OH (2)
H
OH
CH 3
CH 2 CH 3
CH 2 CH 3
(S)-2-Butanol
(Fis cher projection)
81
Assigning R,S Configuration





Lowest priority group goes to the top.
View rest of projection.
A curved arrow from highest to lowest
priority groups.
Clockwise - R (rectus)
Counterclockwise - S (sinister)
82
Assigning R,S Configuration
4
H
2
3
H 3C
COOH
OH
1
s-lactic acid
83
Rules of Motion
 Can rotate 180°, but not 90° because
90° disobeys the Fischer projection.

COOH
H
OH
CH3
Same groups go in and out of plane
COOH
=H
OH
CH3
CH3
180
HO
H
COOH
=
CH3
HO
H
COOH
84
Rules of Motion
 Can rotate 180°, but not 90° because
90° disobeys the Fischer projection.


COOH
H
OH
CH3
Different groups go in and out of plane
This generates an enantiomeric structure
COOH
=H
OH
CH3
(R)-lactic acid
H
H
90
H 3C
COOH =
H 3C
OH
COOH
OH
(S)-lactic acid
85
Rules of Motion
 One group can be held steady and the
others rotated.
COOH
H
OH
CH3
COOH
same as
HO
CH3
H
86
Rules of Motion

To determine if two Fischer projections
represent the same enantiomer carry
out allowed motions.
C 2H5
H
H 3C
C2H5
OH
A
HO
H
CH3
B
OH
H
CH3
C2H5
C
87
C 2H5
H
H 3C
C2H5
HO
CH3
OH
Rules of Motion

H
CH3
B
A
H
CH3
C2H5
C
B
By performing two allowed movements
on B, we are able to generate
projection A. Therefore, they are
identical.
CH2CH3
HO
H
OH
CH3
HO
H
H
CH2CH3
CH3
CH3CH2
CH3
CH2CH3
HO
A
88
C 2H5
H
H 3C
C2H5
HO
H

C2H5
C
B
H
CH2CH3
CH3
CH2CH3
C
CH3
Perform one of the two allowed motions
to place the group with lowest priority
at the top of the Fischer projection.
OH
H
A
H
CH3
OH
Rules of Motion
OH
180
H
H3C
OH
OH
90
CH3
CH2CH
OH
not A
89
Priorities
1.
2.
3.
4.
NH2
COOH
CH3
H
HOOC
CH3
H 2N
H
HOOC
CH3
NH2
CH3
HOOC
H
NH2
HOOC
CH3
H
HOOC
H
NH2
CH3
H 2N
H
CH3
S - stereochemistry
90
Stereochemistry of Reactions
Br
CH3CH2CH CH2
achiral
H Br
ether
CH3CH2CHCH3
chiral
91
Addition of HBr
H
H Br
CH3CH2CH CH2
C
ether
-
Br
CH3
Br
C
H
CH3CH2
CH3CH2
CH3CH2 CH H
3
C
CH3
-
Br
CH3CH2 CH3 H
C
Br
92
Addition of Br2

Cis
a
H
H
C C
CH3
CH3


Br2
b
Br H
C C
CH3
CH3
b
a
Br
H
Racemic mixture
Achiral bromonium ion
Br H
H
a
C C
CH3 Br
CH3
b
CH3 Br
CH3
C C
H
Br H
93
Addition of Br2

Trans
a
H
CH3
C
C
CH3 Br2
H
b
H Br CH3
C C
CH3
H
a Br- b
a
H
Br
C
H3C
Br
b
H
C
H3C Br


C
CH3
H
BrCH
3
C
H
Symmetry plane, therefore meso
Models are superimposible
94
Addition of Br2
H
H3C
Br
C C
CH3
Br
H
BrCH
3
H
C C
H
H3C Br
Br Br
CH3
H3C
C C
H
H
95
Addition of HBr to a Chiral
Alkene
CH3
H
HBr
CH3
H H
-
Br
C CH3
CH3
H Br H
CH3
H H Br
CH3
CH3
2S,4R
2R,4R
96
Addition of HBr to a Chiral
Alkene

Chiral intermediate is not attacked
equally from top and bottom because of
steric reasons. Therefore, a mixture of
product is formed in unequal amounts.
97
Chirality in Substituted
Cyclohexanes




Symmetry plane
No stereogenic centers
1,4-disubstituted
Only cis & trans diastereomers
CH3
CH3
98
1,3-disubstituted



Cis
Symmetry plane
Meso compound
CH3
CH3
CH3
CH3
99
1,3-disubstituted



Trans
No symmetry plane
Therefore enantiomers
CH3
CH3
CH3
CH3
100
1,2-disubstituted


Trans
Enantiomers
CH3
CH3
CH3
CH3
101
1,2-disubstituted


Cis
Meso
CH3
CH3
CH3
CH3
102
1-Bromo-2-chlorocyclohexane
Br
Cl
Cl
Br
cis
Br
trans
enantiomers
diastereomers
Br
Cl
Cl
enantiomers
103
1-Bromo-2-chlorocyclopropane
Br R
S
Cl
Cl R
S
Br
cis
diastereomers
Br R
enantiomers
R
S
S
Br
trans
Cl
Cl
enantiomers
104
1,2-Dibromocyclopropane
mirror image identical
Br
Br
Br
Br
cis
diastereomers
meso
Br
Br
trans
Br
Br
enantiomers
105
(S)-ibuprofen
H
COOH
C
CH3
106