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an introduction
For example:
H
H 2D drawing
H C Cl H C Cl Not appropriate for Stereochem
Br Br
H H
3D drawing
C
H Cl H Cl Appropriate for Stereochem
Br Br
2
Let’s consider some molecules……
First pair
H Br same molecular formula (CH2BrCl)
same atom connectivity
H H
Br
Cl H superposable
Cl
A B identical (same compound)
Second pair
H F same molecular formula (CHFBrCl)
same atom connectivity
F Cl H Cl nonsuperposable
Br Br
C D stereoisomers
(two different compounds)
3
Thus, we can define………
Stereoisomers:
Stereoisomers isomers that have
same formula and connectivity but
differ in the position of the atoms
in space
Stereochemistry:
Stereochemistry chemistry that
studies the properties of stereoisomers
4
Historical perspective
Christiaan Huygens
(1629-1695). Dutch astronomer,
mathematician, and physicist.
He discovers plane polarized
light:
Light
completely
blocked
Horizontal Vertical
Direction of filter filter
light 5
Historical perspective
Carl Wilhelm Scheele (1742-1786)
“Oh, how happy I am! No care for eating or
drinking or dwelling, no care for my
pharmaceutical business, for this is mere play
to me. But to watch new phenomena this is all
my care, and how glad is the enquirer when
discovery rewards his diligence; then his heart
rejoices"
In 1769, he discovers Tartaric HO CO2H
Acid from tartar (the potassium
salt of tartaric acid, deposited
HO CO2H
on barrels and corks during
fermentation of grape juice). Tartaric Acid
6
Historical perspective
Jean Baptiste Biot (1774-1862)
In 1815, he notes that certain
natural organic compounds (liquids
or solutions) rotate plane polarized
light (Optical Activity).
IN molecule OUT
l ec ule
m oleculele
mo moleculelecu
moleculemo
tube containing
plane plane
a liquid organic
polarized polarized
compound or
light light
solution
7
Definitions
Optically Active:
Active the ability of some
compounds to rotate plane polarized light.
Dextrorotatory (+):
(+) an optically active
compound that rotates plane polarized
light in a clockwise direction.
Levorotatory (-): an optically active
compound that rotates plane polarized
light in a counterclockwise direction.
H H
N
(-)-Nicotine N CH3
CH3 H3C H
N
(+)-Methamphetamine
8
Historical perspective
In 1819, Racemic Acid was HO CO2H
IN OUT
HO CO2H
HO CO2H HO CO2H
HO CO2H
HO CO2H
HO CO2H HO CO2H
HO CO2H
IN OUT
HO CO2H
HO CO2H HO CO2H
HO CO2H
HO CO2H
HO CO2H HO CO2H
HO CO2H
12
Historical perspective
Joseph A. Jacobus H.
LeBel van’t Hoff
(1847-1930)
In 1874, they propose: (1852-1930)
13
Therefore…..
Stereoisomers:
Stereoisomers isomers that differ only
in the position of atoms in space, and that
cannot be interconverted by rotation
around a single bond.
Stereocenter:
Stereocenter a carbon atom bearing 4
different atoms or group of atoms.
H F
C,D are a pair of stereoisomers
* *
F Cl H Cl Carbon * is a stereocenter
Br Br
C D
14
…..another example
Stereoisomers of 2-chlorobutane
A,B are stereoisomers
* * Carbons * are stereocenters
H Cl Cl H A,B are nonsuperposable
A mirror images
B
Enantiomers
Enantiomers: stereoisomers that are
nonsuperposable mirror images.
Chiral: any molecule that is nonsuperposable
with its mirror image (i.e. A and B are chiral).
Achiral: any molecule that is not chiral.
Racemic mixture: a 1:1 (equimolar) mixture of
two enantiomers. 15
Unsolved Issues
HO CO2H
HO CO2H
Mesotartaric Acid
could not be separated
Joseph A. Jacobus H. into (+) crystals and
LeBel van’t Hoff (-) crystals
(1847-1930) (1852-1930)
R enantiomer S enantiomer
22
Molecules with multiple stereocenters
Molecules with 1 stereocenter 2 possible
can be R or S stereoisomers
23
Tartaric Acid
HO CO2H
*
4 possible
2 stereocenters
stereoisomers
HO * CO2H
Mirror
H H
D HO CO2H
i Enantiomers HO2C OH D
S R i
a
s
S R a
t HO CO2H t s
D ia as
HO2C OH
e
H st D i H t
r H e
H r
o HO CO2H
HO2C OH
m R o
e S ? S m
r
R e
HO CO2H
s H
HO2C OH r
H s
24
Remember
Enantiomers:
Enantiomers stereoisomers that are non
superposable mirror images.
Diastereomers: stereoisomers that are not
mirror images.
For example:
H
not mirror H
HO CO2H HO2C OH
S image S
S R
mirror
HO CO2H HO2C OH
H image H
(S, S)-Tartaric acid (S, R)-Tartaric acid
DIASTEREOMERS
25
H H
HO CO2H
mirror HO2C OH
R image S
S R
mirror
HO CO2H HO2C OH
H image H
Enantiomers
?
26
Why not Enantiomers?
H H
HO CO2H HO2C OH
R S
S R
HO CO2H
Same HO2C OH
H compound!!!! H
Enantiomers:
Meso compound
A compound with at least 2 stereocenters
that is achiral due to the presence of a plane
of symmetry
28
Properties of Stereoisomers
Enantiomers:
Enantiomers have same chemical and
physical properties in an achiral
environment but they differ on the sign
of rotation of plane polarized light.
For example: Enantiomers of Epinephrine (Adrenaline)
CH3 CH3
H N N H
H H
R
S
HO OH
H H
α]D= + 53.3o
[α α]D= - 53.3o
[α
OH HO
OH OH
(+)-carvone (-)-carvone
smells like caraway smells like spearmint
α]D = + 62.5
[α] [α]D= − 62.5
Note:
•No relationship exists between the S/R configuration
and the sign or the magnitude of rotation of plane
polarized light.
•A 1:1 mixture of enantiomers (racemic mixture) has
always no optical activity (rotation equal to zero)
because the rotation of 50% of one enantiomer is
cancelled out by the rotation (equal but opposite) of
50% of the other enantiomer. 30
Properties of Stereoisomers
Diastereomers:
Diastereomers have different chemical
and physical properties in any type of
environment.
H H
HO CO2H HO2C OH
S S
S R
HO CO2H HO2C OH
H H
(S,S)-Tartaric Acid Mesotartaric Acid
α]D
[α - 12.7 0 (achiral)
Melting p. (oC) 171-174 146-148
Density (g/cm3) 1.7598 1.660
Solubility in H2O 139 125
31
Biological Significance of Chirality
Since most of the natural (biological) environment
consists of enantiomeric molecules (amino acids,
nucleosides, carbohydrates and phospholipids are
chiral molecules), then enantiomers will display
different properties. Then, in our body:
Enantiomers
Drug
Enzyme
Tight Binding Weak Binding
32
Biological Significance of Chirality
Enantiomers of Epinephrine
H3 C OH H3 C H
H N H N
OH OH
H R H S
H HO
OH OH
Enzyme
(+)-Epinephrine (-)-Epinephrine
Poorer Fit Less Active Better Fit More Active
33
The case of Thalidomide
O
N O
N
O H
O
N O
N
O H
O
N O
*
N
O H
O
1 stereocenter = 2 stereoisomers
O O
H H
N O N O
S N R N
O H O H
O O
S-thalidomide R-thalidomide
Sedative Teratogen
(to calm nervousness) (to cause birth defects)
36
Why did the two enantiomers display
different biological activity?
O O
H H
+
N O N O
N N
O H H
O O O
S R
1 : 1
Chemical synthesis (racemic mixture)
of Thalidomide
from achiral
starting materials Separate enantiomers
(Resolution)
38
Resolution of Enantiomers
Enantiomers are temporarily converted into a pair
of diastereomers by adding a chiral reagent…….
R-C* S-C*
Cleave off the
chiral reagent
Separated
R-Thalidomide S-Thalidomide
enantiomers
39
Conclusions
Some organic molecules possess one or more
(n) stereocenters,thus several (2n) stereoisomers
are possible.