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Stereochemistry23-1.pptx
1. Stereochemistry
1
William W
28/01/2024
Wilson N. William, PhD
Text Book: Organic Chemistry by Robert T. Morrison &
Robert N Boyd 6th Edition (1992)
John McMurry (2008) Organic Chemistry 7th
EdBelmont, CA.
William, W N. (2022) Fundamentals Of Organic
Chemistry reaction Mechanism and Spectroscopy For
University Students, Dar es salaam Tanzania.
2. STEREOCHEMISTRY
• Introduction
• STEREOCHEMISTRY derived from the word STEREO or
SOLID in Greek. This where we look at molecules in a
three dimension or 3-D. A good example, is the
molecular models of Methane and carbon
tetrachloride molecules.
• Before we proceed think of that, hold up your right hand to a
mirror, the image you see looks like a left hand. Such
handedness plays a great role in organic chemistry as a direct
consequence of the tetrahedral stereochemistry of sp3-
hybridized carbon.
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3. Continues
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In 1848 at the Ecole normale in Paris
the chemist Louis Pasteur through his
experimental observations he was the
first to propose stereochemistry
concept.
Pasteur, after he graduated with PhD
in chemistry, he tried to repeat
another chemist’s earlier work on salts
of tartaric acid (2,3-
dihydroxybutanedioc acid).
4. Cont…….
• Then he saw something no one had noticed
before: optically inactive sodium ammonium
tartrate existed as a mixture of two different
kinds of crystals.
• They appeared to be mirror images of each other.
• Using a hand lens and a pair of tweezers, he
carefully separated the mixture into two piles.
• One pile was of left-handed crystals while the
other was right-handed, much as one might
separate right handed from left handed gloves.
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5. Cont….
• Now, although the original mixture was optically
inactive, each set of separated crystals dissolved in
water was found to be optically active!
• Furthermore, the specific rotations of the two
solutions were exactly equal but of opposite signs.
• That is to say, one solution rotated plane-polarized
light the right and the other to the left (an equal
number of degrees).
• In all other properties the two solutions were identical.
• Pasteur concluded that the molecules making up the
crystals were mirror images of each other. Example,
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6. Continues
• Mirror-image molecules
example
• Mirror-image molecules that
are not superimposable are
called enentiomers (Greek,
enantio, means ‘opposite’)’
• Enantiomers are related to
each other as a right hand is
related to a left hand. We will
see its discovery on slide 37
• This results whenever a
tetrahedral carbon is bonded
to four different substituents
(one need not to be hydrogen)
example, next slide
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C
H O
C l
B r
H
C
H
B r
O H
C l
m i r r o r
s t e r e o g e n i c c e n t e r
T e t r a h e d r a l c a r b o n
w i t h 4 d i f f e r e n t g r o u p s
m o l e c u l e i s C h i r a l
7. Cont…
• Short summary of chirality
and enentiomerism.
• The cis isomer is achiral
because its mirror image is
superimposable on original
molecule. Let look at two
compounds( chiral and
achiral)
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C
C H 3
H O
H
C O O H
C
H O O C
H
C H 3
O H
m i r r o r
( + ) - L a c t i c a c i d ( - ) - L a c t i c a c i d
Cl
H
Cl
H
Cl
H
Cl
H
mirror
same compound (achiral)
H
C l
C l
H
C l
H
H
C l
m irro r
d ifferen t co m p o u n d (c h iral)
8. Cont……
• Some definition for
terminologies
• Enantiomers: these are mirro-
image isomers; pair of compounds
that are nonsuperimposable
• Chiral: e.g., left hand is different
from right hand in the mirror.
• Achiral: (not handed) it is identical
with its mirror-image e.g., a chair, a
spoon and a glass of water look the
same in a mirror.
• A molecule is not chiral if it
contains a plane of
symmetry. A plane of
symmetry is a plane that
cuts through the middle of
an object (or molecule) in
such a way that one half of
the object is a mirror image
of the other half.
• This kind of symmetry is
called internal mirror plane
(i.e., right-hand is a
reflection of left-hand) see
slide 8.
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9. Cont…..
• Enantiomers are optically
active, non superimposable
mirror image chiral
molecules.
• Enantiomers have chiral or
stereogenic center.
• Enantiomers possess same
physical and chemical
properties, except properties
at the chiral center.
• Enantiomers show different
properties only in a chiral
medium, or with a chiral
reagent.
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10. Cont……
• Note that molecules with
internal mirror plane of
symmetry cannot be chiral,
even though it may contains
asymmetric carbon atom.
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C l
H
C l
H
I n t e r n a l m i r r o r p l a n e o f s y m m e t r y ( )
H
C O O H
C H 3
H
p la n e o f s y m m e tr y (a c h ira l)
P ro p a n o ic a c id
O H
C O O H
C H 3
H
n o p la n e o f s y m m e tr y ( c h ir a l)
L a c tic a c id
11. Cont……..
• Note that the reverse of
the above is not
necessarily true, when
you cannot find a mirror
plane of symmetry,
does not necessarily,
that the molecule must
be chiral for example,
below has no plane of
symmetry yet, its
mirror-image is
superimposable to the
• A carbon atom with two
identical substituents’
usually has an internal
mirror or plane of
symmetry. The
structure is not chiral.
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B
r
C
l
B
r
C
l
C
l
B
r B
r
C
l
12. Cont….
• Note that a carbon with
(only three different kind of
substituents’, usually has an
internal mirror plane of
symmetry. The structure is
not chiral as you can see
above.
• Q. For each compound determine
whether the molecule has an
internal mirror plane of
symmetry. If it does, draw the
mirror plane on a three-
dimensional drawing of the
molecule.
• If the molecule does not have n
internal mirror plane, determine
whether or not the structure is
chiral. (a) methane (b) 1,2-
dichloropropane (c) ci-1,2-
dibromocyclobutane.
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C
V
i
e
w
f
r
o
m
t
h
i
sa
n
g
l
e
C
1
2
3
3
3 3
2
1
=
13. Stereoisomers
• Isomers are compounds that
have the same chemical
formula, but different
structure.
• There are two basic types of
isomers; namely
constitutional isomer and
stereoisomers.
• Constitutional isomers are
compounds whose atoms are
connected differently e.g., skeletal,
functional and position isomers.
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C
H
H
3
C C
H
3
C
H
3
d
i
f
f
e
r
e
n
t
c
a
r
b
o
n
s
k
e
l
t
o
n
s
C
H
3
C
H
2
C
H
2
C
H
3
a
n
d
C
H
3
O
C
H
3
C
H
3
C
H
2
O
H
a
n
d
d
i
f
f
e
r
e
n
t
f
u
n
c
t
i
o
n
a
l
g
r
o
u
p
C
H
3
C
H
2
C
H
2
N
H
2
C
H
3
C a
n
d
d
i
f
f
e
r
e
n
t
p
o
s
i
t
i
o
n
o
f
f
u
n
c
t
i
o
n
a
l
g
r
o
u
p
H
N
H
2
C
H
3
14. Cont……
• Stereoisomers are
compounds whose atoms are
connected in the same order,
but with different geometry.
These include enantiomers,
diastereomers, and cis-trans
isomers. Note that cis-trans
isomers are really just
another kind of
diastereoisomers, because
they are non-mirror-image
stereoisomers. As you can
see in slide 17.
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C
CH3
HO
H
COOH
C
HOOC
H
CH3
OH
mirror
(+)-Lactic acid (-)-Lactic acid
example of enantiomer
15. Cont……
• Diastereoisomer (non-superimposable non-mirror-image
stereoisomers)
• Cis-trans diastereoisomer example,
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C
C
H
COOH
NH2
CH3
H OH
C
C
H
COOH
NH2
CH3
HO H
2R, 3R-2-Amino-3-hydroxobutanoic acid 2R, 3s-2-Amino-3-hydroxybutanoic acid
C
C
H
C
H
3
H
H
3
C
c
i
s
-
2
-
b
t
e
n
e
16. Diastereoisomers
• These are stereoisomers that are NOT mirror image of each
other and have multiple chiral centers.
• They have more than one chiral center. They also have some
configuration that are the same and some are opposite.
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17. Cont……
• In other word diastereoisomer have at least one different
chiral center
• If they have multiple configurations and they are all opposite,
these are called enantiomers.
• Diastereoisomers can be chiral or achiral
• Diastereoisomers have different chemical and physical
properties.
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18. Cont….
• Diastereoisomers have:
– Different melting and
boiling points.
– Different solubilities in
a given solvent.
– Different densities.
– Different refractive
indices
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19. Diastereoisomers: Non-Identical Group at Chiral Center
• If carbon atoms at stereogenic unit or chiral center are NOT
bonded to identical sets of substituents, they are called NON
EQUIVALENT.
• The number of isomers derived from chiral center = 2n
where by n = number of chiral center.
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20. Diastereoisomer: Identical Group at Chiral Center
• If the carbon at stereogenic center has identical sets of
substituent's, the centers are EQUIVALENT. The number of
isomers = 2n-1
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21. Chemical properties of Diastereomers:
• Diastereomers have similar
chemical properties since
they are members of the
same family.
• However, these properties are
not identical.
• In the reaction of diastereomers
with a given reagent, neither the
two sets of reactants nor the
transition states are mirror
images and hence will not be of
equal energies.
• The Exact values will be
different and so will the
rates of reaction.
Physical properties of
Diastereomers:
– Diastereomers have different
physical properties.
– Different melting and boiling
points.
– Different solubilities’ in a
given solvent.
– Different densities.
– Different refractive indices
• As a result of their differences in
boiling points and solubilities
they can in principle be separated
from each other by fractional
distillation of fractional
crystallization.
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22. Cont…..
• As a result of differences in molecular shape and polarity, they
differ in adsorption and can be separated by chromatography.
• Given a mixture of four diastereomers we could separate it by
distillation into two fractions, but no further.
• One fraction would be a racemic modification of I and II and
the other a racemic modification of III and IV.
• Further separation would require resolution of the racemic
modification by use of optically active reagents.
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23. Cont…..
• Thus, the presence of two chiral centres can lead to the
existence of as many as four stereoisomers.
• For compounds containing three chirals centres there could
be as many as eight stereoisomers.
• For compounds containing four chirals centres there could be
as many as sixteen stereoisomers and so on.
• The maximum number of stereoisomers that can exist is equal
to 2n, where n = the number of chiral centres as we have seen
early.
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24. Stereoisomers
• Stereoisomers; are
isomers whose atoms are
bonded together in the same
order, but differ in how
atoms are directed in space.
• Stereoisomer tends to posses
stereogenic center.
• Stereoisomers exist in
different forms due to:
1. Presence of Chiral center
(Stereogenic center)
• 2. Presence of Chiral axis or
Axis of Symmetry.
3. Geometric Stereoisomers (
cis and trans isomers)
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25. Stereoisomers and originality
• Stereoisomers exist in
different forms due to:
1. Presence of Chiral center
(Stereogenic unit)
-Allow rotation of single
bond such as C-C or C-N or
C-O
2. . Presence of Chiral axis or
Axis of Symmetry
-Do NOT allow rotation of
single bond such as C-C or C-N
or C-O
• 3. Geometric
Stereoisomers ( cis and
trans isomers)
• -DO NOT allow rotation
of single bond such as C-C
or C-N or C-O
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26. • The particular kind of isomers that are different from
each other in the way the atoms are oriented in
space are called stereoisomers.
• Stereoisomers resemble each other in structure and
properties so much that most physical methods of
measurement are unable to distinguish them.
• Only one kind of measurement that employs light
interaction techniques is able to distinguish them.
• These isomers differ from one another in some very important
characteristics which may make only one of them function as a
food or medicine while the other is absolutely useless.
• We will see later a good example of chemical compound called
thalidomide drug, while R is useful and S is poisonous or cause
harm slide 129 and 130.
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27. • Optical activity:
• Light is defined as a wave phenomenon in which the vibrations
occur at right angles to the direction in which light travels;
(
a
)
o
r
d
i
n
a
r
y
l
i
g
h
t (
b
)
p
l
a
n
e
p
o
l
a
r
i
z
e
d
l
i
g
h
t
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28. • There is an infinite number of planes passing through
the line of propagation and ordinary light is vibrating
in all these planes.
• Plane-polarized light is light whose vibrations take
place in only one of these possible planes.
• Ordinary light is turned into plane-polarized light by
passing it through a lens made of material known as
Polaroid (calcite- a crystalline form of CaCO3) so
arranged as to constitute what is called a Nicol prism.
• An optically active substance is one that rotates
plane-polarized light.
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29. • When polarized light, vibrating in a certain plane is
passed through an optically active substance, it
emerges vibrating in a different plane.
• The polarimeter:
• The plane-polarized light is detected and measured by
an instrument called the polarimeter.
• This consists of a light source, two lenses, (Polaroid
and NiCOl) and between the two lenses a tube to hold
the substance that is being examined for optical
activity.
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30. • These are arranged so that the light passes through
one of the lenses (polarizer) then the tube, then the
second lens (analyzer) and finally reaches the eye.
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31. • When the tube is empty, we find that the maximum
amount of light reaches the eye when the two lenses
are so arranged that they pass light vibrating in the
same plane.
• If the lens that is nearer the eye is rotated, the light
becomes dim and reaches a minimum when the lens
is at right angles to its previous position.
• Before the sample tube is placed in the polarimeter,
it is customary to adjust the lens to allow maximum
light to pass.
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32. • Then the tube is placed in the instrument.
• If the substance in the tube does not affect the
plane of polarization, light transmission is not
affected and no change is detected.
• The substance is said to be optically inactive.
• If on the other hand the substance rotates the
plane of polarization, then the lens nearer the
eye must be rotated to restore maximum light
transmission.
• The substance is then said to be optically active.
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33. • If rotation of the plane by the substance is to
the right, the substance is dextrorotatory
(Latin: dexter = right).
• If rotation of is to the left, the substance is
levorotatory (Latin: laevus = left).
• In this way it is possible to determine not only
that the substance has rotated the plane of
light and in which direction but also by how
much.
• The amount of rotation is simply the number
of degrees that the lens must be rotated to
conform to the original light. 33
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34. • The symbols (+) or (-) are used to indicate rotations to
the right and left, respectively.
• Lactic acid that is extracted from muscle tissue rotates
light to the right and hence is known as dextrorotatory
lactic acid, or (+) lactic acid.
• The 2-methyl-1-butanol that is obtained from fusel oil
( a by-product of fermentation of starch to ethyl
alcohol) rotates light to the left, and is known as
levorotatory 2-methyl-1-butanol or (-)-2-methyl-1-
butanol.
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35. • Specific rotation:
• Since optical rotation is caused by molecules of the
compound in question, the amount of rotation
depends upon how many molecules the light
encounters in passing through the tube.
• The light will encounter twice as many molecules in a
tube 20 cm as long as in a tube 10 cm long and the
rotation will be twice as large.
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36. • If the compound is in solution the number of
molecules encountered by the light will
depend on the concentration.
• For a given tube length, light will encounter
twice as many molecules in a solution of
2g/100ml as in a solution of 1g/ 100ml and the
rotation will be twice as large.
• Specific rotation is the number of degrees of
rotation observed if a 1-dm (10 cm) tube is
used and the compound is present to the
extent of 1 g/ml.
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37. • This is usually calculated from observations with
tubes of other lengths and at different
concentrations by means of the equation:
•
• [] =— i.e.
l x d
Where d= density of pure liquid or concentration of solution
• The specific optical rotation is as much a property
of a compound as its melting or boiling point.
s p e c i f i c r o t a t i o n =
o b s e r v e d r o t a t i o n ( o )
l e n g t h ( d m ) x g m / m l
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38. • Thus the specific rotation of 2-methyl-1-butanol
obtained from fusel oil is
• []20
D = -5.90o
• Here 20 is the temperature and D is the wavelength
of the light used in the measurement (D line of
sodium, 5893Å)
• Enatiomerism: the discovery
• Optical activity was discovered in 1815 at the College
de France by the physicist Jean-Baptiste Biot.
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39. • Now, although the original mixture was optically
inactive, each set of separated crystals dissolved in
water was found to be optically active!
• Furthermore, the specific rotations of the two
solutions were exactly equal, but of opposite
signs.
• That is to say, one solution rotated plane-polarized
light the right and the other to the left (an equal
number of degrees).
• In all other properties the two solutions were
identical.
• Pasteur concluded that the molecules making up
the crystals were mirror images of each other.
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40. • Enantiomerism and tetrahedral carbon
• Consider a molecule made of five different atoms all
of different colours placed in front of a mirror:
C
O
P
Q
R
C
O
R
Q
P
m i r r o r
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41. • The wedge formula of this molecule will look
like this:
• The molecule and its mirror image are not
C
X
Z
W Y C
X
Z
Y W
m ir r o r
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42. • Similar models can be made for tartaric acid, lactic
acid, 2-methyl-1-butanol, chloroiodomethane
sulfonic acid and sec-butyl chloride.
• Most molecules, however are superimposable on
their mirror images, for example
bromochloromethane and do not show mirror image
isomerism.
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43. • Enatiomerism and optical activity
• When a beam of polarized light passes an
individual molecule, in nearly every instance its
plane is rotated a little by interaction with charged
particles of the molecule.
• The direction and extent of rotation varies with
the orientation of the particular molecules in the
beam.
• For most compounds, because of the random
distribution of the large number of molecules, for
every molecule that the light encounters, there is
another molecule oriented as the mirror image of
the first, which exactly cancels its effect.
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44. • The net result is no rotation, that is no optical
activity.
• Thus, optical inactivity is a property not of
individual molecules, but rather of the random
distribution of molecules that can serve as
mirror images of each other.
• In the special case of a molecule like CWXYZ,
the mirror image is not just another identical
molecule but a different molecule.
• In a pure sample of such a compound no
molecule can serve as the mirror image of
another.
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45. • There is therefore no cancelling-out of rotations and
the net result is optical activity.
• Thus the same non-superimposability of mirror
images that gave rise to enantiomerism also is
responsible for optical activity.
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46. • Prediction of enantiomerism: chirality
• Molecules that are not superimposable on their
images are chiral.
• Chirality is the necessary condition for the existence
of enantiomersim.
• In other words a compound whose molecules are
chiral can exist as enantiomers while a compound
whose molecules are not chiral (are achiral) cannot
exist as enantiomers.
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47. • In 1964 Cahn, Ingold and Prelog proposed that
chemists use the terms “chiral” and “chirality”based
on the Greek word for “hand” (Greek cheir = hand).
• Chirality means handedness.
• Before these terms the terms, “dissymetry”and
“dissymetric” were used.
• Still earlier the terms, “assymetry” and “assymetric”
were common.
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48. • The chiral centre:
• A chiral centre is defined as a carbon atom to which
four different groups are attached.
• A common way of representing a chiral centre is to
use wedge formulas.
• In such formulas the horizontal lines represent bonds
coming towards the viewer out of the plane of the
paper, whereas the vertical lines represent bonds
going away from the viewer behind the plane of the
paper.
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49. • For example:
• These isomers can simply be represented as:
C
2
H
5
C
H
3
C
H C
l
C
2
H
5
C
H
3
C
C
l H
C 2 H 5
H C l
C H 3
C 2 H 5
C l H
C H 3
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50. • In testing the superimposability of two of these flat,
two-dimensional representations of three
dimensional objects, certain procedures must be
followed.
1) These representations should only be used for
molecules containing a chiral centre
2) When one is drawn, the other is drawn as its mirror
image
3) In the mind of the person drawing these structures
they can be rotated or slided end to end, but they
should not be removed (lifted) from the plane of
the paper.
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51. • When used with caution this method of
representation is convenient.
• It is not foolproof and in doubtful cases,
models or wedge formulas should be used.
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52. • Problem:
• Using cross formulas, decide which of the following
compounds have a chiral centre:
• (a) 1-chloropentane (e) 2-chloro-2-methylpentane
• (b) 2-chloropentane (f) 3-chloro-2-methylpentane
• (c) 3-chloropentane (g) 4-chloro-2-methylpentane
• (d) 1-chloro-2-methylpentane (h) 2-bromo-1-chlorobutane
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53. • The racemic modification
• A mixture of equal parts (50:50) of enantiomers
is called a racemic modification.
• A racemic modification is optically inactive.
• When enantiomers are mixed together, the rotation
caused by a molecule of one isomer is exactly cancelled
by an equal and opposite rotation caused by a
molecule of its enantiomer.
• The prefix is used to specify the racemic nature of the
particular sample, for
example -lactic acid
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54. • The identicalness of most physical properties of
enantiomers has one consequence of great practical
significance.
• The enantiomers in the mixture cannot be separated
by ordinary methods.
– Identical boiling points – no fractional distillation
-Identical solubility- no precipitation
-identical adherence to stationary phase – no
chromatographic separation
• The enantiomers can only be separated by optically
active solvents, stationary phases or reaction with
chiral reagents.
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55. • Configuration:
• The arrangement of atoms that characterizes a
particular stereoisomer is called its configuration.
• Supposing after carrying out the test of
superimposability it is concluded that there are two
stereoisomers of sec-butyl chloride with configuration I
and II:
C
C 2 H 5
C H 3
C l
H C
C 2 H 5
C H 3
H
C l
sec-b u ty l ch lo rid e
I II
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56. • Then polarimetric analysis reveals that one
isomer rotates plane polarized light to the right
and the other to the left.
• How can we tell which of the two has the
rotated left or right?
• In 1951 J.M. Bijvoet, then director of the van’t
Hoff laboratory at the Utrecht university
reported that using a special kind of X-ray
analysis he had determined the actual
arrangement of atoms of (+)-tartaric acid.
• This paved the way for the assignment of
configuration of other optically active compounds.
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57. • Specification of configuration: R and S.
• Now a further challenge arises. How can the
configuration of a particular compound be
specified in a simpler way without having to
draw its diagram?
• The solution to this was provided by R.S. Cahn
(Chemical Society of London), Sir Christopher
Ingold (University College, London) and V.
Prelog (Eidgenissiche Technische Hochschule,
Zurich).
57
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58. • They proposed two steps:
• Step1: A set of sequence rules is followed to assign
the four groups (ligands) of atoms attached to the
chiral centre.
• For example the four groups on bromochloro-
iodomethane are given the following priorities
depending on their atomic numbers:
C
Br
H
Cl
I C
Br
H
I
Cl
bromochloroiodomethane
I II
2
1 3
4
1
2
3
4
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59. • Step 2: The molecule is visualized as oriented so that
the ligand of lowest priority is directed away from the
viewer and the arrangement of the remaining ligands is
observed.
• If in proceeding from the ligand of highest priority to
the second and third the viewer’s eye travels in a
clockwise direction, the configuration is R (Latin,
rectus= right).
• If the eye travels counterclockwise the configuration is
S (Latin, sinister= left).
• Thus, configurations I and II are viewed like this:
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60. A complete name of an optically active compound
for which configuration and rotation have been
determined would be like: (S)-(+)-sec-butyl chloride.
B r
H
I C l
B r
H
C l I
R S
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61. • A racemic modification is specified as (RS)-sec-
butyl chloride.
• Note that the direction in which an optically
active compound rotates plane polarized light
(+) or (-) must be determined experimentally.
• It is not the same as R and S which are
assigned by the viewer.
61
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62. • Sequence Rules:
• If the four atoms (ligands) attached to the chiral centre are
at all different, priority depends on atomic number. The
higher the atomic number, the higher the priority. Higher
atomic number means higher priority.
I > Br > 37 Cl > 35.5Cl > F > O > N > C > 3H > 2 H > 1
H
• If two atoms are isotopes of the same element,
the isotope of higher mass gets higher priority.
• For example chloroiodosulfonic acid and -
deutero ethylbromide are arranged as follows:
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63. Sequence Rule 2
• Rule 2: If can’t find the difference in atomic number in
first atom, continues to the 2nd, 3rd, 4th and so on until
the difference is found.
C
C l
H S O 3 H
I
1
2
3
4
c h lo r o io d o s u lf o n ic a c id
C
H
H 3 C B r
D
1
2
3
4
a lp h a d e u te ro -
e th y lb r o m id e
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64. • Sequence Rule 3:
• Rule 3: Multiple bonds If a group contains a double
bond, both atoms are doubled. That is, a double bond
is counted as two single bonds to each of the atoms of
the double bond. The same principle is used for a
triple bond.
HC≡C- > CH2=CH- > CH3 CH2 -
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Priority Rule: Multiple Bonds
65. • The priority order for common functional groups containing
oxygen is
-CO2 H (carboxylic acid) > -CHO (aldehyde) > -CH2OH
(alcohol)
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Priority Rule: Multiple Bonds
66. Priority rules for Configuration Assignment
• The highest priority is 1st whereas lowest priority
is 4th .
• Lowest priority atom is placed toward the back of
the molecule
• If count 1..2..3 is CLOKWISE then chiral center
is R or Rectus
• If count 1..2…3 is COUNTERCLOKWISE then
chiral center is S or Sinister
• **If hydrogen is at the FRONT then assign the
opposite configuration:
If the final configuration is R then change to S
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67. Priority rules for Configuration Assignment
• The highest priority is 1st whereas
lowest priority is 4th .
• Lowest priority atom is placed
toward the back of the molecule
• If count 1..2..3 is CLOKWISE
then chiral center is R or Rectus
• If count 1..2…3 is
COUNTERCLOKWISE then
chiral center is S or Sinister
• If hydrogen is at the FRONT then
assign the opposite configuration:
If the final configuration is R then
change to S
28/01/2024 William W 67
68. R & S configuration vs Laevus (-) and Dextra (+)
Rotation
• We recall that the direction or magnitude of the optical rotation
of a stereoisomer does not determine its absolute
configuration.
That is, a (+) optical rotation does not mean that a molecule
has an R configuration.
For example, the optical rotation of (S)-2-butanol is clockwise
(+). This isomer is (S)-(+)-2-butanol.
28/01/2024 Chambuso 2019 68
69. • Problem Set 1:
• Assign S or R configurations to all the chiral
compounds among the following:
• (a) 2-chloropentane S
• (b) 1-chloro-2-methylpentane R
• (c) 3-chloro-2-methylpentane R
• (d) 4-chloro-2-methylpentane. R
• (e) 2-bromo-1-chlorobutane. R
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70. • Problem 2
• (a) Draw all isomers of formula C3H6DCl.
Decide which of these are chiral. (2)
• (b) Specify each of them as R or S.
• (c) Distinguish constitutional isomer from
stereoisomer.
• (d) A molecule with four (4) chiral centre has
how many stereoisomer? (16)
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71. • Problem Set 3
• Are the molecules shown below chiral or
achiral? Give them R, S labels.
• 1. chiral
• 2. S Chiral
• 3. S Chiral
• 4. chiral
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72. • Problem 4: Label each chiral carbon in the
compounds below as S or R
• 2 R
• 4.R
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73. • Problem Set 5: Assign the following
compounds R or S configurations
• 1. S
• 2. S
• 3. R
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74. • Meso structures:
• Consider the compound 2,3-dichlorobutane,
which also contains 2 chiral centres:
• The following cross formulas can be drawn:
CH3
Cl H
Cl
H
CH3
II
CH3
H Cl
H
Cl
CH3
I
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C
Cl
H3C C
Cl
CH3
H H
75. • I and II are not superimposable and are thus
mirror images and enantiomers.
• Next we draw structure III and its mirror image:
CH3
Cl H
H
Cl
CH3
IV
CH3
H Cl
Cl
H
CH3
III
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76. • This time the pair of III and IV can be
superimposed if rotated end to end.
• III and IV are therefore not mirror images, and
not enantiomers inspite of their chiral centres.
• The molecule and its mirror image cannot
exhibit optical activity and is therefore not
chiral.
• It is called a meso compound.
• Meso compounds are compounds whose
molecules are superimposable on their mirror
images even though they contain chiral
centres. 76
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77. • A meso compound is optically inactive.
• Very often a meso compound can be
recognized by having one half of its structure
existing as a mirror image of the other half.
• Such compounds have a plane of symmetry
and cannot be chiral
C H 3
C l H
H
C l
C H 3
C H 3
H C l
C l
H
C H 3
p la n e o f sy m m e try
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79. Cont…
• C-3 contains two enantiomorphic groups (H and OH) and two
achiral groups
• Compound I and II both contain plane of symmetry running through C-3
28/01/2024 Chambuso 2019
No plane of symmetry found in Compound III and IV
79
80. The Chiral Centre: Fischer Projection
• A chiral centre is defined as a carbon atom to which four
different groups are attached.
• A common way of representing a chiral centre is to use wedge
formulas.
• Horizontal lines represent bonds coming towards the viewer
(out of the plane of the paper),
• Vertical lines represent bonds going away from the viewer
(behind the plane of the paper.)
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82. Fischer Projection
• Chiral Tetrahedral carbon is
represented by two
perpendicular lines
• Vertical lines are bonds
going into the page
• Horizontal lines are bonds
coming out of the page
• 180o rotation lowest priority
H atom is at the top. Now
Assign the Configuration.
• Clockwise means R
configuration,
• If rotation happens
28/01/2024 Chambuso 2019 82
83. • Problem: Draw stereochemical formulas for all the
possible stereoisomers of the following compounds.
Label pairs of enantiomers and meso compounds. Tell
which if separated will show optical activity. Pick out
examples of diastereomers:
• (a) 1,2-dibromopropane (e) 1,2,3,4-tetrabromobutane
• (b) 3,4-dibromo-3,4-dimethylhexane (f) 2-bromo-3-chloro butane
• (c) 2,4-dibromopentane (g) 1-chloro-2-methylbutane
• (d) 2,3,4-tribromohexane (h) 1,3-dichloro-2-methylbutane
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84. Problem
• Determine if the following pairs of compounds
are identical, enantiomers, or diastereomers.
• 1.ident
• 2.Diast
• 3. Id, D
28/01/2024 Chambuso 2019 84
85. • Erythro, threo isomers and epimers
• Two common prefixes used to distinguish
diastereomers are erythro and threo (which
correspond to the syn and anti labels,
respectively).
• When drawn in the Fischer projection the
erythro isomer has two identical substituents’
on the same side and the threo isomer has
them on opposite sides.
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86. • Erythro, threo isomers and epimers
threo erythro
• Epimers are diastereomers that differ in
configuration of only one chiral center. or
• Epimers are diastereomers that differ in
configuration at only one of the several stereogenic
centers.
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89. • Other terms used to describe stereochemical
concepts
• Eutomer refers to the enantiomer having
higher pharmacological activity.
• Distomer is the enantiomer with the lesser
activity at or affinity for a given receptor.
• One receptor's distomer can be another
receptor's eutomer.
• Homochirality is the biological chirality in
which all biologic compounds have the same
chirality such as all amino acids are
levorotatory isomers.
28/01/2024 Chambuso 2019 89
90. • Specification of configuration – more than one
chiral centre:
• For compounds having more than one chiral
centre we simply specify the configuration of
each of the chiral centres and by use of numbers
tell which specification refers to which carbon.
• Consider for example, 2,3-dichloropentane:
90
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H3C
C
Cl
C
CH2CH3
Cl
H
H
91. • For the chiral centre C2, the order of priority of
ligands is:
• Configuration is therefore S
C2 C
H
(C
l)C
H
2C
H
3
H
3C
C
l
H
1
2
3
91
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92. • For C3 the order of priority of ligands is:
• The configuration is therefore R.
• The configuration of the whole molecule is
therefore 2(S), 3(R)
C
2
H
3
C
(C
l)H
C
C
l
H
1
2 3
C
H
3
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93. • Conformational isomers:
• In ethane we saw that the carbon-carbon
single bond rotates freely.
• The different arrangements of atoms that can
be converted into one another by rotation
about single bonds are called conformations.
• We can understand these wedge hatched, saw
horse or Newman projection formulas.
93
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94. Extreme Conformations of Ethane
Name Wedge Hatch Saw Horse Newman Projection
94
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96. • Consequently, the potential energy
associated with the various conformations
of ethane varies with the dihedral angle of
the bonds, as shown below. Although the
conformers of ethane are in rapid
equilibrium with each other, the 3 kcal/mol
energy difference leads to a substantial
preponderance of staggered conformers (>
99.9%) at any given time.
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98. • When the substituents are large as in butane
there is substantial repulsion in the eclipsed
conformation.
• The molecule thus prefers to assume the
staggered conformation.
• There are several staggered conformations:
• i. The anti conformation in which the methyl
groups are as far apart as they can be (180o
– dihedral angle)
• ii Gauche conformation I in which the methyl
groups are only 60o apart.
• iii. Gauche conformation II which is a mirror
98
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99. • Reactions involving stereoisomers:
• In the chlorination of n-butane we saw that the
first step involves homolytic cleavage of
chlorine by light or heat to yield a free radical.
• The free radical then abstracts a secondary
hydrogen to give a secondary free radical of
the butane
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C l C l +
h v
o r h e a t
+ + H C l
C l C l
C l C
H
H 3 C
H
C
H
H
C H 3 C
H
H 3 C C
H
H
C H 3
Cl Cl +
hv
or heat
+ + HCl
Cl Cl
Cl C
H
H3C
H
C
H
H
CH3 C
H
H3C C
H
H
CH3
100. • The intermediate free radical of butane is
trigonal (flat) and when it attacks a chlorine
molecule attachment of the chloride atom can
be above or below the plane of the flat
intermediate. Look at Fundamentals of Organic
Chemistry Reaction Mechanisms and Spectroscopy
for University Students, 2022 by Wilson N. William
page, 4-7, and 50 to 51.
100
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101. • The enantiomers are formed in equal amounts
C.
C2H5
Cl2
a b
C
H
Cl
C2H5
H3C
C
Cl
H
C2H5
H3C
a b
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102. • Generally, synthesis of chiral compounds from
achiral reactants always yields the racemic
modification.
• In other words optically inactive reactants
always yield optically inactive products.
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103. • Reaction of chiral molecules:
• Consider the halogenation of sec-butylchloride.
C H 3 C H 2 C H C H 3
C l
C H 3 C H 2 C H C H 2
C l C l
1 , 2 - d i c h l o r o b u t a n e
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104. Conti….
• This product is formed
without breaking any chiral
bond and therefore
configuration is retained.
• A reaction involving an
optically active reactant
that does not involve
breaking of a chiral bond
results in retention of
configuration, see example
28/01/2024 William W 104
OH
(S)-methyl-1-butanol
Cl
(S)-methyl-1-butanol
HCl
H H
105. • Next let us consider the reaction of an
optically reactive alcohol with HCl:
• This reaction also does not involve breaking a
chiral bond.
• We expect it to results in retention of
configuration.
CH3CH2CHCH2-OH
CH3
CH3CH2CHCH2-Cl
CH3
HCl
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106. • Let us look at a third reaction in which (-)-2-methyl-1-
butanol is oxidized by potassium permanganate to 2-
methyl butanoic acid.
C
C H 3
C 2 H 5
C
H 2
H O H
(S )-(-)-2 -m e th y l-1 -
b u tan o l
C
C H 3
C 2 H 5
C
H 2
H C l
(S )-(+ )-1 -ch lo ro -2
-m e th y l b u tan e
H C l
C
C H 3
C 2 H 5
C
H O H
(S )-(-)-2 -m eth y l-1 -
b u tan o l
C
C H 3
C 2 H 5
C O O H
H
(S )-(+ )-2 -m eth y l-
b u tan o ic acid
K M n O 4
H
H
106
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107. • Here again no chiral bond is broken and so
configuration is retained.
• In the first example a –CH3 group in the chiral
centre is replaced by a –CH2Cl group which is of
higher priority and results in change of
configuration in the product in spite of the
reaction retaining configuration.
• In the second example 2-methyl-1-butanol is
converted to 1-chloro-2-methyl butane.
• The first priority alcohol group in the chiral
centre is replaced by a –CH2Cl group which is
also first priority and so there is no change in 107
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108. • In the third example 2-methyl-1-butanol is
converted to 2-methyl butanoic acid with
retention of configuration.
• Here too, a first priority CH2OH group is
replaced by a first priority COOH group thus,
conserving configuration.
108
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109. • Generation of a second chiral centre:
• Consider the halogenation of sec-butyl
chloride, but this time concentrating on the
2,3-dichlorobutane product.
• This compound we have seen exists in three
stereoisomers, meso and a pair of
enantiomers.
109
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110. If we start with the (S)-isomer, we expect the
following products:
110
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Cont
H 3 C C C C H 3
C l
H
*
C l 2
h v o r h e a t
H 3 C C C C H 3
C l
H
*
C l
+ o t h e r
p r o d u c t s
s e c - b u t y l c h l o r i d e 2 , 3 - d i c h l o r o b u t a n e
H
H
H
112. • Since no bond is broken to the original chiral
centre, its configuration is retained in all
products.
• There are two possible configurations about the
new chiral centre resulting from attack above or
below the flat intermediate on C3.
• These are S, S or R, S diastereomeric products.
• The R, S product is a meso isomer.
• The diastereomeric products will be formed in
unequal amounts because attack (a) and attack
(b) are not equally likely.
• This is unlike the reaction in which a single chiral
112
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113. • Suppose the products from halogenation of
(S)-sec-butyl chloride show an S,S: meso ratio
of 29:71.
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114. • The halogenation of (R)-sec-butyl chloride would
also yield exactly the same R,R: meso ratio of
29:71.
• Whatever factor favours meso product over S,S
product will favour meso over R,R and exactly to
the same extent.
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115. • Optically inactive racemic sec-butyl chloride
would also yield racemic: meso ratio of 29:71.
• Diastereomeric products are formed in
unequal amounts because the intermediate,
3-chloro-2-butyl radical already contains a
chiral centre and lacks the symmetry
necessary for attack at the two faces to be
equal.
115
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116. • Resolution of Racemates
• As noted earlier, chiral compounds synthesized
from achiral starting materials and reagents
are generally racemic (i.e. a 50:50 mixture of
enantiomers).
• Separation of racemates into their component
enantiomers is a process called resolution.
• Since enantiomers have identical physical
properties, such as solubility and melting
point, resolution is extremely difficult.
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117. • Diastereomers, on the other hand, have
different physical properties, and this fact is
used to achieve resolution of racemates.
• Reaction of a racemate with an
enantiomerically pure chiral reagent gives a
mixture of diastereomers, which can be
separated.
• Reversing the first reaction then leads to the
separated enantiomers plus the recovered
reagent.
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118. • Many kinds of chemical and physical reactions,
including salt formation, may be used to
achieve the diastereomeric intermediates
needed for separation.
• Consider the racemic mixture of R,S-3-butyn-
2-amine with specific rotation of 0o:
H 3 C
H
N H 2
C C H C
H
N H 2
C H 3
H C
(S )-b u ty n -2 -am in e (R )-b u ty n -2 -am in e
118
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119. • To resolve this mixture, it is reacted with
(2R,3R)-tartaric acid (acid-base reaction).
H3C
H
NH2
C CH C
H
NH2
CH3
HC
(S)-butyn-2-amine (R)-butyn-2-amine
CO2H
OH
H
H
OH
CO2H
(2R,3R)-(+)-tartaric acid
H2O
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120. • A diastereomeric mixture of tartrate salt of the
amine is obtained.
• The mixture is then subjected to fractional
crystallization.
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121. • Since the diastereomers have different physical
properties (e.g. melting points) one crystallizes
and becomes a solid the other remains in
solution. They are hydrolyzed back into the
enantiomers.
H3C
H
NH2
C CH C
H
NH2
CH3
HC
(S)-butyn-3-amine
specific rotation=-52.7o
bp= 82-4o
(R)-butyn-3-amine
specific rotation=+53.2
bp=82-4o
Solid salt
K2CO3
H2O
(R,R,R) diasteriomer
in solution
K2CO3
H2O
121
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122. Enantiomeric and Racemic Pharmaceuticals
• About more than half of the drugs currently in use are chiral
compounds and nearly 90% of these are marketed as racemates
consisting of an equimolar mixture of two enantiomers.
• Although they have the same chemical structure, most isomers of
chiral drugs exhibit marked differences in biological activities such
as pharmacology, toxicology, pharmacokinetics, and metabolism.
This important characteristic can be observed in the slide 127 to
130.
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123. Cont…..
• It is true that
enantiomers have the
same physical
properties, they usually
have different biological
properties. For
example, (+)
enantiomer of limonene
has the odor of
oranges, but the (-)
enentiomer has the
odor of pine trees.
• Why do different
enantiomers have
different biological
properties? In order to
have a biological effect,
a
28/01/2024 William, W 123
H
H
(+ )-L im o n en e
in citru s fru it
(-)-L im o n en e
in p in e tree
124. Cont…..
• Typically must fit into an
appropriate receptor
• That has exactly complementary
shape see slide 145 regarding
protein receptor. But because
reptors are chiral, only one
enentiomer of a chiral
substrate/medicine can fit in, just
as only a right hand fit into right-
handed glove.
• Chira drugs
• It is a fact that many drugs are
isolated from plants, bacteria and
others are made by chemical
modification of natural occuring
compounds, but 33% are sythesized
in the laboratory.
• Those drugs that come from
natural sources, either directly
or after chemical modification
are often chiral and found as a
single enantiomer rather than a
recemic mixture.
• Penicillin V, an antibiotic
isolated from penillium mold,
has 2S, 5R, 6R configuration. Its
enantiomer, which does not
occur naturally, but can be
synthesized in the laboratory
has no antibiotic activity. This
property is exactly the same as
what happens in slide 129 and
130 regarding thalidomide
enantiomers.
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125. Cont…
• Penicillin V Structure
• Can you determine the configurations of chiral center in this compound?
28/01/2024 William W 125
O
N
O
N
H
S
O
H
H
C H 3
C H 3
H
C O 2 H
P e n ic illin V ( 2 S , 5 R , 6 R )
127. • Thalidomide was first marketed in 1957 in West
Germany by the drug company Chemie
Grünenthal.
• It was primarily prescribed as a sedative/
hypnotic.
• Afterwards, it was used against nausea and to
alleviate morning sickness in pregnant women.
• The 'S' enantiomer of thalidomide is teratogenic
28/01/2024 William W 127
128. • Shortly after the drug was sold in Germany,
between 5,000 and 7,000 infants were born
with phocomelia (malformation of the limbs).
28/01/2024 Chambuso 2019 128
129. • Only 40% of these children survived. The
negative effects of thalidomide led to the
development of more structured drug
regulations and control over drug use and
development.
• In ibuprofen, the R (dextrorotatory) isomer is
the more biologically active.
28/01/2024 Chambuso 2019 129
130. Continues
• In drug generally, wrong enantiomer in a racemic mixture
affect the body ability to utilize the right enantiomer or has un
intended pharmacological effects of its own. For example, the
presence of R-ibuprofen in racemic mixture, slaw substantially
the rat at which the S enantiomer takes effect in the body
from 12 minutes to 38 minutes.
• Such a problem is resolved by using enantioselective synthetic
approach, whereby a single enentiomer is formed rather than
racemic mixture. So far viable methods have been developed
to prepare (S)-ibuprofen, which is being marketed around the
world.
28/01/2024 William W 130
131. • Salbutamol
(RS)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol
• However, recently the R-enantiomer of
salbutamol has been introduced into clinical
practice in the treatment of asthma in humans
and this has been suggested to be an
improvement on the racemic form of the drug.
• This is because the S-enantiomer has been
demonstrated to have adverse effects in the
lung and thus using the R-enantiomer may
improve the therapeutic ratio.
28/01/2024 Chambuso 2019 131
132. • The prescription analgesic tramadol is also a
racemate.
• In some cases (e.g., ibuprofen and
thalidomide), the enantiomers interconvert
or racemize in vivo.
• Some drug companies have patented and
developed a racemic drug, with the
intention of patenting and developing a
single enantiomer later. When the patent on
the racemate expires, the company can
undercut generic competition by launching
the single-enantiomer 132
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133. • The following table lists pharmaceuticals that
have been available in both racemic and single
enantiomer form:
133
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134. Stereoselective and stereospecific reactions
• When we discussed the reactions of alkanes we
noticed that SN2 reactions take place with
complete inversion of stereochemical
configuration.
• Free radical chlorination of alkanes proceeds
with complete racemization.
• On the other hand SN1 reactions proceed with
partial racemization.
• We also looked at reactions in which
stereoisomers are generated and those in which
they are consumed.
134
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135. • All these are examples of reactions involving
stereoisomers.
• They show us what can happen and what
cannot happen to stereoisomers in certain
general situations.
• The present discussion concentrates on the
selectivity of reactions that involve
stereoisomers.
135
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136. • Stereochemistry of addition to alkenes.
• Addition to bromine yields 2,3-dibromo butane.
• All these are examples of reactions involving
stereoisomers.
• Two chiral centres are generated in the reaction.
136
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C H 3 C H = C H C H 3 + B r 2 H 3 C C C C H 3
C H 3 C H 3
* *
2 , 3 - d i b r o m o b u t a n e
2 - b u t e n e
B r B r
137. • This product can exist as a pair of enatiomers
and a meso compound.
C H 3
B r
H
H
B r
C H 3
I
C H 3
H
B r
B r
H
C H 3
II
C H 3
B r
H
B r
H
C H 3
III
e n a n tio m e rs m e so c o m p o u n d
137
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138. • The reactants too exist as stereoisomers, the
geometric isomers cis and trans.
C
C
C H 3
C H 3
H
H
cis-2-butene
C
C
C H 3
H
H 3C
H
trans-2-butene
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139. • If the bromination reaction starts with the cis
isomers only the pair of enantiomers is obtained.
• A reaction that yields predominantly one
stereoisomer (or one pair of enantiomers) of several
possible diastereomers is called a stereoselective
reaction. Look at an example in next slide
C
C
CH3
CH3
H
H
cis-2-butene
Br2
CH3
Br
H
H
Br
CH3
I
CH3
H
Br
Br
H
CH3
II
racemic 2,3-dibromobutane
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141. Cont……
• Stereoselective reaction: Bromine attacks olefinic group from
less hindered part, i.e. away from R group.
• Water is forced to attack bromonium ion in a stereospecific
fashion through SN2.
• Treatment with NaOH to generate alkoxide allows another
Stereospecific SN2 reaction to remove bromide.
28/01/2024 William, W 141
142. Stereospesicific examples
28/01/2024 William W 142
Diels-Alder reaction you start with cis dienophile you end with cis
product and if you start with trans you end-up with trans product.
Generally stereoselectivity is more important for products
while stereospecificity is more important for reactants.
CH2
CH2 H CO2CH3
H
H3C
H
H
+
CH3
H
H
CO2CH3
1,3-Butadiene Methyl(E)-2-Butenoate
Trans product
143. Cont……..
• In Reduction of camphor using LiAlH4, attack from the axial is
not favored due to steric, but attack on equatorial is favored
because less Steric effect for approaching LiAlH4.
• Stereospecific reactions—reactions where the mechanism
means that the stereochemistry of the starting material
determines the stereochemistry of the product and there is no
choice involved.
• Stereospecific reactions-reactions where the mechanism
means that the stereochemistry of the starting material
28/01/2024 William W 143
144. Biological Reactions : Stereoselectivity
• Biological reactions take place in presence of enzymes and at
specific environmental conditions such as temperature, pH.
• Enzymes are chiral since amino acids are chirals and substrate
specific , therefore, they tend to be stereospecific in their
reactions
28/01/2024 William W 144
The enzyme that catalyzes the alkylation of (S)-glycerol phosphate,
for example, will not work at all with (R)-glycerol phosphate.
146. Cont….
• Enzymes in living systems are chiral and they are capable of
making distinction between enantiomers. As we have seen in
the previous slide levorotatory form of epinephrine is one of
hormones secreted by the adrenal medulla. When a synthetic
eponephrine is given to a patient, the (-) enantiomer fit into
the enzyme’s active site.
• This means biological systems often can distinguish between
enantiomers of many different chiral compounds. In short
one of the enantiomers produces characteristic effect; the
other, either produces no effect or has a different effect.
28/01/2024 William 146
147. Enantiomer and Receptor Discrimination
• S-isomer is anesthetic
• (R)-isomer is Hallucinogenic
•
28/01/2024 Chambuso 2019 147
HN Me
(S)-2-(methylamino)-2-phenylcyclohexan-1-one
1
2
O
148. Cont……
• An addition reaction occurs as part of the oxidation of fatty
acids:
• Enzymatic reactions are also highly stereospecific: this means
that an enzyme ‘recognizes’ the stereochemistry of a
substrate molecule and only catalyzes its reaction if the
substrate stereochemistry is correct.
28/01/2024 Chambuso 2019 148
149. Generation of a second chiral centre
28/01/2024 Chambuso 2019 149
Me
Me
Cl
H H
UV-light
Cl2 Me
Me
Cl
H
Cl
Cl
120o
Me
Me
Cl
H Cl
Me
Me
Cl
Cl H
S
R
R
R
(R)-2-chlorobutane
(2R,3R)-2,3-dichlorobutane
(2R,3S)-2,3-dichlorobutane
150. Reaction at Chiral Center proceeding with inversion of chiral
centre SN2
28/01/2024 Chambuso 2019 150
TsO H
NaCN
H CN
DCM
R
SN2
S
H
CN
OTs
Me
OH
S
O
O
Tosylate (OTs)
151. Resolution
• Resolution of Racemates
• Separation of racemates into their component enantiomers is
a process called resolution.
• Since enantiomers have identical physical properties, such as
solubility and melting point, resolution is extremely difficult.
28/01/2024 Chambuso 2019 151
155. • If a racemic mixture of a chiral acid is reacted
with a enantiomerically pure amine, the result
is a mixture of diastereomers: in this case,
because the pure (R) entantiomer of the
amine was used, the product is a mixture of
(R-R) and (R-S) diastereomeric salts, which can
be separated by their different physical
properties.
28/01/2024 Chambuso 2019 155
156. Bromination of trans-2-Butene
– reaction with bromine forms bridged bromonium
ion intermediates which are enantiomers
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Chambuso 2019
157. Bromination of trans-2-Butene
– attack of bromide ion in either carbon of either
enantiomer gives meso-2,3-dibromobutane
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Chambuso 2019
158. Bromination of cis-2-Butene
– reaction of cis-2-butene with bromine forms bridged
bromonium ions which are meso and identical
28/01/2024 158
Chambuso 2019
159. Bromination of cis-2-Butene
– attack of bromide ion at carbons 2 and 3 occurs
with equal probability to give enantiomeric
products as a racemic mixture
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Chambuso 2019
160. Problem:
• What is the relationship between the
brominium ions formed by attachment of
positive bromine to the top and bottom faces of
trans-2-butene?
• (b) In what proportions are they formed?
• (c) Answer the same for cis-2-butene
• (d) For trans-2-pentene
• (e) For cis-2-pentene
160
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161. • There are many reactions that are both
stereoselective and stereospecific.
• There are some reactions that are
stereoselective, but not stereospecific.
• There are also some reactions that are
stereospecific, but not stereoselective.
• Generally stereoselectivity is more important for
products while stereospecificity is more
important for reactants.
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162. • One of the major differences between laboratory
organic reactions (which generally take place free in
solution) and biological organic reactions (which
generally take place within the very specific, ordered
environment of an enzyme) involves the concepts of
stereoselectivity and stereospecificity. In a
stereoselective reaction, one stereoisomer is formed
preferentially over other possible stereoisomers:
28/01/2024 Chambuso 2019 162
163. • In one of the reactions of alkenes a water
molecule is ‘added’ to a double bond:
• In many cases, this reaction results in the
formation of one, or possibly two new
stereocenters, depending on the symmetry of
the starting alkene double bond.
28/01/2024 Chambuso 2019 163
164. • Nonenzymatic laboratory reactions of this type
generally are not stereospecific – that is, they
result in the formation of mixtures of different
stereoisomers. In contrast, a crucial aspect of
enzyme-catalyzed biological chemistry is that
reactions are almost always highly
stereoselective, meaning that they result in the
formation of only one specific stereoisomer.
28/01/2024 Chambuso 2019 164
165. • For example, this water addition reaction
occurs as part of the oxidation of fatty acids:
• Enzymatic reactions are also highly
stereospecific: this means that an enzyme
‘’recognizes’’the stereochemistry of a substrate
molecule and only catalyzes its reaction if the
substrate stereochemistry is correct.
28/01/2024 Chambuso 2019 165
166. • The enzyme that catalyzes the alkylation of (S)-glycerol
phosphate, for example, will not work at all with (R)-
glycerol phosphate.
28/01/2024 Chambuso 2019 166
167. • After that story about thalidomide at the
beginning of our discussion of stereochemistry,
you have a good appreciation for the importance
of stereoisomerism in drug development. It is
much safer and more effective if a drug can be
provided in stereochemically pure form, without
the presence of other ineffective (and possibly
dangerous) enantiomers or diastereomers. Drugs
that are obtained from nature are generally in
stereochemically pure form to begin with, because
they are synthesized in a living organism by a
series of enzymatic reactions.
28/01/2024 Chambuso 2019 167
168. • Penicillin, with its three stereocenters and 8 possible
stereoisomers, is a good example: as a product
synthesized by specific enzymes in penicillium mold, it
exists as a single stereoisomer.
• Other chiral drugs must be synthesized by humans in the
laboratory, where it is much more difficult to produce a
single stereoisomer. Medicinal chemists are working
very hard to develop new laboratory synthetic
techniques which will allow them to better control the
stereochemical outcome of their reactions.
28/01/2024 Chambuso 2019 168
169. • We will encounter many such examples in PC
300 and PC 400. In addition, many researchers
are trying to figure out the enzymatic process
by which living things produce useful chiral
molecules, so that the enzymes involved may
be put to use as in vitro synthetic tools. This is
important because, while it may be easy to
obtain large quantities of penicillium mold,
many other useful chiral compounds come
from species that are difficult, or even
impossible, to grow in the laboratory.
28/01/2024 Chambuso 2019 169
170. Neighboring Group
• Neigboring group effects by Koening-Knorr
• Tetraacetyl-D-glucopyranosyl bromide (either or β )
undergoes a spontaneous SN1-like loss of Br-, followed by
internal reaction with the ester group at C2 to form an
oxonium ion. Since the acetate at C2 is on the bottom of the
glucose ring, the C-O bond also forms from the bottom.
• Backside SN2 displacement of the oxonium ion then it occurs
with usual inversion of configuration, yielding-glycoside and
regenerating the acetate at C2 as you can see in the following
scheme next slide.
28/01/2024 William W 170
171. Cont……..
• The participation shown by
nearby acetate group in the
Koenings-Knorr reaction is
referred to as a neighbouring-
group effect.
• This is a common reaction
occuring in organic chemistry.
• The neighbouring group
effects are often noticeable
only because they affect the
rate or stereochemistry of a
reaction; the nearby group
itself does not undergo any
event change during the
reaction.
28/01/2024 Chambuso 2019 171
O
AcO
AcO
AcOH2C
OAc
Br
O
AcO
AcO
AcOH2C
O
1. ArOH, Ag2O
2. NaOH, H2O
AcO
AcO
AcOH2C
OAc
OR
C
H3C
O
O
AcO
AcO
AcOH2C
O
C
H3C
O
ROH
Ag2O
A -glycoside
OR
