Stereoisomerism
and Chirality
Chapter 3
1
Jean Baptiste Biot,1832 observed rotation of
tartaric acid.
Louis Pasteur continued this research in
1847 by investigating the shapes of
ammonium sodium tartrate crystals, which
he found to be chiral.
chiral. By manually sorting
the differently shaped crystals under
magnification, Pasteur was the first to
produce a pure sample of levotartaric acid.
2
O-Chem
rocks!
“In the field of observation,
chance favors only the prepared
mind.”
mind.”
HO
CO2H
HO
CO2H
levotartaric
3
Isomers
• Isomers: Different compounds with the
same molecular formula.
• Constitutional isomers: Isomers with a
different connectivity.
• Stereoisomers: Isomers with the same
connectivity but a different orientation of
their atoms in space.
4
Chirality
• Chiral: From the Greek, cheir, hand
– an object that is not superposable on its
mirror image.
• Achiral: An object that lacks chirality; one
that lacks handedness.
– An achiral object has at least one element of
symmetry.
5
Chirality
– An achiral object has at least one element of
symmetry:
– Plane of symmetry: An imaginary plane
passing through an object dividing it so that
one half is the mirror image of the other half.
– Center of symmetry: A point so situated that
identical components of the object are located
on opposite sides and equidistant from that
point along any axis passing through it.
6
Stereocenter
• The most common (but not the only) cause
of chirality in organic molecules is a
tetrahedral atom, most commonly carbon,
bonded to four different groups.
• A carbon with four different groups bonded to it
is called a chiral center.
– All chiral centers are stereocenters, but not all
stereocenters are chiral centers.
– Enantiomers: Stereoisomers that are
nonsuperposable mirror images.
– Refers to the relationship between pairs of objects.
7
Mirror
Plane
A compound with
4 different substitutents
Its stereoisomerstereoisomerNOT superimposable
These are called enantiomers
8
Elements of Symmetry
mirror
plane
OH
HO
9
Stereocenter & Chiral Centers
Stereocenters
H3 C
H
C
H
CH3
trans -2-Butene
swap
HO
CH3
swap
C
H
H3 C
H
(R)-2-Butanol
H
cis -2-Butene
Stereocenter as well
as a chiral center
H
OH
(S)-2-Butanol
10
Enantiomers
• 2-Butanol
– Has one stereocenter.
– Here are four representations for one
enantiomer.
OH
H
C H
H3 C
CH2 CH3
(1)
H3 C
OH
C
H OH
OH
(3)
(4)
CH2 CH3
(2)
– Here are two representations for the enantiomer
of (4).
OH
OH
OH
(4)
representations for th e
enan tiomer of (4)
11
Enantiomers
• 2-Chlorobutane
Cl
CH3 CHCH2 CH3
H Cl
Cl H
12
Enantiomers
• 3-Chlorocyclohexene
Cl
Cl
13
R & S Convention
• Priority rules
1. Each atom bonded to the chiral center is assigned a
priority based on atomic number; the higher the
atomic number, the higher the priority.
(1)
(6)
-H
-CH3
(7)
-N H2
(8)
(16)
- OH
- SH
(17)
(35)
(53)
- Cl
- Br
-I
Increasing priority
2. If priority cannot be assigned per the atoms bonded
to the chiral center, look to the next set of atoms;
priority is assigned at the first point of difference.
(1)
- CH 2 -H
(6)
- CH 2 -CH 3
(7)
- CH 2 -N H2
(8)
- CH 2 -OH
Increasing priority
14
R & S Convention
3. Atoms participating in a double or triple
bond are considered to be bonded to an
equivalent number of similar atoms by
C C
single bonds.
-CH=CH2
is treated as
O
-CH
is treated as
-CH-CH2
O C
C
O
H
C CH
is treated as
C C
C C H
C C
15
Naming Chiral Centers
1. Locate the chiral center and identify its four
substituents.
2. Assign priority from 1 (highest) to 4 (lowest) to each
substituent.
3. Orient the molecule so that the group of lowest
priority (4) is directed away from you.
(S)-2-Chlorobutane
1
H Cl
S
4
2
3
16
Naming Chiral Centers
4. Read the three groups projecting toward you in order
from highest (1) to lowest priority (3).
5. If the groups are read clockwise, the configuration is
R; if they are read counterclockwise, the configuration
is S.
(S)-2-Chlorobutane
H Cl
1
S
4
3
2
17
1
2
3
Counter clockwise movementmovementi.e to the “left”
left” is the S configuration
18
Clockwise movementmovementi.e to the “right”
right” is the R configuration
19
Enantiomers & Diastereomers
• For a molecule with 1 chiral center, 21 = 2
stereoisomers are possible.
• For a molecule with 2 chiral centers, a
maximum of 22 = 4 stereoisomers are
possible.
• For a molecule with n chiral centers, a
maximum of 2n stereoisomers are
possible.
20
Fischer Projections
• The use of two-dimensional representations
to show the configuration of molecules with
multiple chiral centers are called Fischer
projections.
CHO
CHO
H
C
HO
OH
C
H
CH2OH
CH2OH
Mirror
21
Fischer Projections
The horizontal segments represent bonds toward you.
The vertical segments represent bonds directed away from you.
22
Enantiomers & Diastereomers
• 2,3,4-Trihydroxybutanal
– two chiral centers.
– 22 = 4 stereoisomers exist; two pairs of
enantiomers.
CHO
CHO
CHO
CHO
H
C
OH
HO
C
H
H
C
OH
H
C
OH
HO
C
H
HO
C
H
CH2 OH
CH2 OH
A pair of enantiomers
(Erythrose)
HO
C
H
H
C
OH
CH2 OH
CH2 OH
A pair of enantiomers
(Threose)
23
Enantiomers & Diastereomers
• Diastereomers:
– Stereoisomers that are not mirror images.
– Refers to the relationship among two or more objects.
CHO
CHO
CHO
CHO
H
C
OH
HO
C
H
H
C
OH
H
C
OH
HO
C
H
HO
C
H
CH2 OH
CH2 OH
A pair of enantiomers
(Erythrose)
CH2 OH
HO
C
H
H
C
OH
CH2 OH
A pair of enantiomers
(Threose)
24
Enantiomers & Diastereomers
• Another e.g.--2,3-Dihydroxybutanedioic
acid (tartaric acid)
– two chiral centers; 2n = 4, but only three
stereoisomers exist
COOH
COOH
COOH
COOH
H
C
OH
HO
C
H
H
C
OH
H
C
OH
HO
C
H
HO
C
H
COOH
HO
C
H
H
C
OH
COOH
COOH
One meso compound
(plane of symmetry)
COOH
A pair of enantiomers
25
Enantiomers & Diastereomers
Meso compound: An achiral compound
possessing two or more chiral centers that
also has chiral isomers.
COOH
COOH
H
C
OH
HO
C
H
H
C
OH
HO
C
H
COOH
COOH
One meso compound
(plane of symmetry)
26
Enantiomers & Diastereomers
• 2-Methylcyclopentanol
HO H 3 C
CH3 OH
H
H
H
H
cis- 2-Methylcyclopentanol
(a pair of enantiomers)
diastereomers
H H3 C
CH 3 H
H
OH
H
HO
trans- 2-Methylcyclopentanol
(a pair of enantiomers)
27
ciscis-2-Methylcyclopentanol
CH3
H3C
OH
OH
HO
CH3
Mirror
28
transtrans-2-Methylcyclopentanol
CH3
H3C
OH
OH
HO
CH3
Mirror
29
CH3
H3C
Enantiomers
HO
rs
me
o
e
ter
as
i
D
CH3
Diastereomers
Diastereomers
OH
H3C
Enantiomers
OH
HO
30
Enantiomers & Diastereomers
• cis-3-Methylcyclohexanol (a pair of
enantiomers)
H3 C
OH HO
CH 3
31
Enantiomers & Diastereomers
• trans-3-Methylcyclohexanol (a pair of
enantiomers)
H3 C
CH 3
OH
HO
32
Isomers
rotation about
single bonds
Compounds with the
same molecular formula
Conformations
same
connectivity
different
connectivity
Constitutional
Isomers
Stereoisomers
stereocenters
but no chiral centers
rotation
restricted
Conformational
Isomers
with chiral centers
Atropisomers
m ore than
one chiral center
Cis,Trans
(E,Z ) Isomers
(can be called
diastereomers)
achiral
one chiral center
chiral
not mirror
images
Meso
Compounds
Diastereomers
Enantiomers
mirror
images
Enantiomers
33
Properties of Stereoisomers
• Enantiomers have identical physical and
chemical properties in achiral environments.
• E.G. tartaric acid:
COOH
COOH
H
C
OH
HO
C
H
COOH
HO
C
H
H
C
OH
COOH
A pair of enantiomers
34
Properties of Stereoisomers
• Diastereomers are different compounds and
have different physical and chemical properties.
meso tartaric acid, for example, has different
physical and chemical properties from the R,R
and S,S enantiomers:
COOH
COOH
COOH
COOH
H
C
OH
HO
C
H
H
C
OH
H
C
OH
HO
C
H
HO
C
H
COOH
COOH
One meso compound
(plane of symmetry)
COOH
HO
C
H
H
C
OH
COOH
A pair of enantiomers
35
Plane-Polarized Light
• Ordinary light: Light oscillating in all
planes perpendicular to its direction of
propagation.
• Plane-polarized light: Light oscillating only
in parallel planes.
• Optically active: Refers to a compound
that rotates the plane of plane-polarized
light.
36
Plane-Polarized Light
– Plane-polarized light is the vector sum of left and right
circularly polarized light.
– Circularly polarized light interacts one way with an R
chiral center, and the opposite way with its
enantiomer.
– The result of interaction of plane-polarized light
with a chiral compound is rotation of the plane of
polarization.
37
Plane-Polarized Light
• Polarimeter: A device for measuring the extent of
rotation of plane-polarized light.
38
Optical Activity
– Observed rotation: The number of degrees, α,
through which a compound rotates the plane
of polarized light.
– Dextrorotatory (+): Refers to a compound
that rotates the plane of polarized light to the
right.
– Levorotatory (-): Refers to a compound that
rotates the plane of polarized light to the left.
COOH
C
H
OH
H3 C
(S)-(+)-Lactic acid
21
[ α] D = +2.6°
COOH
H C
HO
CH3
(R)-(-)-Lactic acid
21
[ α] D = -2.6°
39
Optical Activity
– Specific rotation: Observed rotation for a
sample in a tube 1.0 dm in length and at a
concentration of 1.0 g/mL; for a pure liquid,
concentration is expressed in g/mL (density).
COOH
C
H3 C
H
OH
(S)-(+)-Lactic acid
21
[ α] D = +2.6°
COOH
H C
HO
CH3
(R)-(-)-Lactic acid
21
[ α] D = -2.6°
40
Chirality in the Biological World
• Enzymes are like hands in a handshake.
– The substrate fits into a binding site on the
enzyme surface.
– A left-handed molecule, like hands in gloves,
will only fit into a left-handed binding site and
– a right-handed molecule will only fit into a
right-handed binding site.
– Because of the differences in their
interactions with other chiral molecules in
living systems, enantiomers have different
physiological properties.
41
Chirality in the Biological World
– A schematic diagram of an enzyme surface
capable of binding with (R)-glyceraldehyde
but not with (S)-glyceraldehyde.
42
Resolution
• Racemic mixture: An equimolar mixture of
two enantiomers.
– because a racemic mixture contains equal
numbers of dextrorotatory and levorotatory
molecules, its specific rotation is zero.
• Resolution: The separation of a racemic
mixture into its enantiomers.
43
Chirality in Medicinal Chemistry
Dissociative anesthesia
4X affinity for PCP site
More potent analgesic
Does not lower BP
Or respiration
hallucinogen
Dissociative anesthesia
analgesic
44
Amino Acids
– the 20 most common amino acids have a
central carbon, called an α-carbon, bonded to
an NH2 group and a COOH group.
– in 19 of the 20, the α-carbon is a chiral center.
O
sid e chain
H3 N
-
O
R
Ionized or zw itterion
form of an amino acid
45
Amino Acids
18 of the 19 α-carbons have the R
configuration, one has the S configuration.
– at neutral pH, an amino acid exists as an
internal salt.
– in this structural formula, the symbol R = a
side chain.
sid e chain
O
H3 N
-
O
R
Ionized or zw itterion
form of an amino acid
46