Stereochemistry
• Stereochemistry:
– The study of the three-dimensional structure of
molecules
• Structural (constitutional) isomers:
– same molecular formula but different bonding
sequence
• Stereoisomers:
– same molecular formula, same bonding sequence,
different spatial orientation
• The properties of many drugs depends on
their stereochemistry:
HN
HN
O
O
CH
CH3
NH3NH
O
NHCH3
Cl
Cl
Cl
O
CH3NH
Cl
(S)-ketamine
(R)-ketamine
anesthetic
hallucinogen
Optical Isomerism
Optical Activity
The property of the substance to rotate the plane of
the plane-polarized light is known as optical activity.
- Dextro-rotatory (+)
- Laevorotatory (- )
Necessary condition:
Molecule should be dissymmetric.
Example: Biphenyl 2, 2’ – disulphonic acid
Enantiomers
Enantiomers are defined as the isomers where molecular
Structures are mirror images of each other and which
rotate the plane of the polarized light equally but in
opposite directions.
Chirality is the necessary and sufficient condition
for the existence of enantiomers.
- Properties of enantiomers
H
Br
Chiral vs.BrAchiral
H
Example: Identify the following molecules as
CH3
chiral or achiral.
CH3 C CH2CH3
CH3
Cl
CH3CHCH2CH2CH3
H
Br
Br
H
CH3
CH2CH3
Cl CH CCH CH
3
2
3
Cl
Br
H
Br
H
CH3CH2
H
Br
H
C
C
Br
CH2CH3
Diastereomers
Pair of molecules with two or more different chiral
carbon atoms which are neither identical nor nonsuperimposable mirror images of each other.
Enantiomers
nonsuperimposible mirror images
mirror
plane
OH
H
HO2C
OH
CH3
(S)(+) lactic acid
from muscle tissue
o
[] = +13.5
CH3
H
CO2H
(R)(-) lactic acid
from milko
[] = -13.5
Meso Compound
A compound with two or more asymmetric carbon atoms
but also having a plane of symmetry (a mirror plane) is
called the Meso compound.
Meso Compound
Internal Plane of Symmetry
Optically Inactive
R,S
CO2H
mirror
plane
S,R
CO2H
H
OH
HO
H
H
OH
HO
H
CO2H
CO2H
o
rotate 180
superimposible
Absolute Configuration
Use Cahn, Ingold, Prelog priorities
Place the lowest priority group back
(focus down C - 4 bond)
draw arrow from 1-2-3
1
1
clockwise
counterclockwise
4
4
2
2
3
3
(R)
(S)
Assign Priority to each Group on
Asymmetric Center
I
Cl
H
I
rotate
F
4
H
F3
1
Cl
2
focus down C-4 bond
Example priorities:
I > Br > Cl > S > F > O > N > 13C > 12C > 3H > 2H > 1H
Lactic Acid
1
OH
1
OH
4
H
HO 2C
2
4
CH3
3
(S)
CH3
3
H
CO 2H
2
(R)
C.I.P. Priorities
Low
High
CH2CH2CH3
CH(CH 3)2
O
CH2CH2OH
CH2CH
CH2CH2CH3
CH=CH2
CO2H
CH 2Cl
CH2CH2Br
CH(CH3)2
(R) and (S) Nomenclature
• The two enantiomers of alanine are:
H3C
CO2H
CO2H
C
C
H
NH2
Natural alanine
(S)-alanine
H
H2N
CH3
Unnatural alanine
(R)-alanine
(R) and (S) Nomenclature
2 CH2CH2Br
C
3 CH3CH2
H4
CH(CH3)2
1
CH(CH3)2 > CH2CH2Br > CH3CH2
Fischer Projections
H
HO2C
OH
OH
OH
H
CH3
CO2H
CH3
H
CO2H
CH3
Horizontal bonds approach you (wedge bonds)
Vertical bonds move away (dashed bonds)
Assigning Absolute Configuration to
Fischer Projections
H
H
HO2C
CH3
(S)
OH
OH
OH
CO2H
CH3
rotate
(S)
H
CO2H
CH3
(S)
Fischer Projections with 2 Chiral
Centers
CO2H
H
Br
2
3
OH
H
CH3
(2S,3S)
CO2H
H
H
2
3
OH
Br
CH3
(2S,3R)
Tartaric Acids
R,R
CO 2H
H
HO
OH
H
S,S
CO 2H
HO
H
H
OH
CO 2H
CO 2H
R,S
CO 2H
S,R
CO 2H
H
OH
HO
H
H
OH
HO
H
CO 2H
CO 2H
2,3,4-trichlorohexane
How many stereoisomers?
Cl
* *
*
Cl
Cl
3 asymmetric centers
2n, n= # asymmetric centers (3)
8 stereoisomers
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
H
H
Cl
H
Cl
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
Cl
Cl
H
H
Cl
CH2CH3
Cl
H
Cl
H
H
H
Cl
H
Cl
Cl
H
H
H
Cl
Cl
H
Cl
CH2CH3
CH2CH3
Cl
CH2CH3
A Carbohydrate
CHO
OH
R
H
S
H
OH
R
H
OH
R
H
HO
CH2OH
(+) D-Glucose
Reactions that Generate Chirality
Centers
Hydrogenation, syn
CH3
CH2CH3
CH3
H
H2, Pt/C
CH3
CH2CH3
CH2CH3
H
CH3
CH2CH3
CH2CH3 product is meso
H
CH3
H
CH3
CH2CH3
Bromination
Trans is formed exclusively
No Meso is formed (cis)
Br2
Br
Br
R R
Br
Br
S S
racemic mixture