Stereochemistry (optical isomerism)

PHARMACEUTICAL ORGANIC CHEMISTRY-III
(theory)
MRS. JAYSHREE VANSHIKUMARI
SHARMA
M.PHARM (PHARM CHEM)
1

Syllabus
1. UNIT-I: Stereo isomerism- Optical isomerism (10 Hours)
2. UNIT-II: Stereo isomerism-Geometrical isomerism (10 Hours)
3. UNIT-III: Heterocyclic compounds (10 Hours)
4. UNIT-IV: Synthesis, reactions and medicinal uses of following compounds (8
Hours)
5. UNIT-V: Reactions of synthetic importance (07 Hours)
2

UNIT-I: Stereo isomerism-
Optical isomerism (10 Hours)
i. Optical activity
ii. Enantiomerism
iii. Diastereoisomerism
iv. Meso compounds
v. Elements of symmetry
vi. Chiral and achiral molecules
vii. DL system of nomenclature of optical isomers
viii. Sequence rules, RS system of nomenclature of optical isomers
ix. Reactions of chiral molecules
x. Racemic modification and resolution of racemic mixture.
xi. Asymmetric synthesis: partial and absolute
3

stereochemistry
 Stereochemistry helps to define the structure of a molecule
and orientation of the atoms and functional groups present, in
three dimensions.
4

 Stereoisomers possess the same molecular and structural formulae and the
same functional groups but differ in the three- dimensional spatial orientation
of these atoms or groups within the molecule.
 Due to the difference in orientation of the functional group and geometry of
the molecule, stereoisomers differ in their physical, chemical, physicochemical
and biochemical properties.
5

C5H12 7
2-Methyl Butane
N-Pentane
2,2-Dimethyl propane

What is Isomerism?
 The organic compounds having the same molecular formula but different
structures are known as Isomers.
 This phenomenon is known as Isomerism.
 In other words, the organic compounds having the same molecular
formula but different arrangements of carbon atoms in them, are known as
Isomers.
8

CLASSIFICATION OF ISOMERS 9
Isomers
Structural
isomerism
Chain isomerism
Positional isomerism
Functional isomerism
Metamerism
Tautomerism
Stereoisomerism
Geometrical
isomerism
Optical isomerism

STEREOISOMERISM
 This type of Isomerism differs in the
spatial arrangement of atoms or groups. It
is of two types –
 Optical Isomerism.
 Geometrical Isomerism.
10

1.Plane polarized light
 According to wave theory, an ordinary beam of light has vibrations in all
directions perpendicular to its path of propagation.
 When such a beam of light is passed through Nicol prism, which is a special
type of prism composed of doubly refracting substance like calcite, so the
emergent light passes through this prism vibrates in one plane only.
12

14
Such a light vibration in one plane only is called
Plane Polarised Light

 This has been observed that when plane polarised light is passed through certain
substances or through solutions.
 The latter have a remarkable property of turning the plane polarisation either
towards right (Clockwise) or towards left (anticlockwise).
 The phenomenon of turning or rotating plane of polarised light is known as
optical activity.
 The substance exhibiting this property are called optical active.
 Some optically active compounds are glucose, lactic acid, tartaric acid, etc.
16

 A substance which rotates the plane of polarisation towards right or clockwise
is called Dextro rotatory or d or(+) compound and the one which rotates the
plane of of polarisation towards left or anticlockwise is called laevo rotatory or l
or (-) compound.
19

 A substance which is unable to rotate the plane of
polarisation is called optically inactive.
 Optical activity of a compound is measured by an
instrument called Polarimeter.
21

 The rotatory power of an optically active substance is measured
by a term, called Specific rotation.
 It can be defined as “The number of degrees of rotation
observed when plane polarised light is passed through one
decimetre length of its solution having concentration 1 gm per
mililiter”.
23

 In 1815, Biot found that a number of organic and inorganic compounds in
the solution form, have the ability to rotate the plane of polarized light in
opposite directions but in identical amplitude, passing through them.
 Optical isomerism is seen in compounds that can rotate plane polarised
light.
 A carbon atom connected to four chemically different functional groups is
known as asymmetric or chiral carbon and the presence of at least one
asymmetric carbon atom in the structure is the pre- requirement for a
molecule to show optical isomerism.
24

Optical isomerism
 It is a type of stereoisomerism in which isomers have same
molecular formula and same structural formula but they rotate the
plane of polarised light to the same extent, but in different
directions.
25

Conditions for optical activity
 A compound would become optically active if it satisfies the
following condition:
1. It should have a chiral or asymmetric carbon atom
26
C
a
d b
e

2. The compound should be capable of forming non-super
imposable mirror image (known as enantiomorphs or
enantiomers)
27

3. The compound should not have any element of symmetry i.e;
Plane of the symmetry, Center of symmetry, and axis of
symmetry.
29

Elements of symmetry
 A chiral object is not identical (i.e. non-superimposable) in all respects.
 An achiral object is identical (hence superimposable) with its mirror image.
 Chiral objects have a "handedness". Like gloves or shoes, chiral objects come
in pairs, a right and a left.
 Achiral objects do not have a handedness just like a plain round ball.
 Thus, chirality of an object is related to its symmetry.
 Certain symmetry elements like a point, a line or a plane may be useful to
check the symmetry of the molecule.
30

1. Center of symmetry: a center of symmetry is a point from which if lines
are drawn on any group on both sides to an equal distance, it divides the
molecule into two halves which are mirror images of each other.
32

2. Plane of symmetry: it is define as a plane that
divides the molecule into two identical halves one
part of which appears to be the mirror image of the
other part.
33

3. Axis of symmetry: A molecule has an axis of symmetry if rotating
the molecule about the axis by an angle of 360/n produces a new
structure indistinguishable from the original molecule.
34

35
Sr. no Terms Symbol
1. Plane of symmetry δ
2. Center or point of symmetry i
3. Rotational axis where the degrees of rotation that restore the object is
360/n (C2 = 180° rotation; C3 = 120° rotation; C4 = 90° rotation; C5 = 72°
rotation; At C1 = (i.e. 360° rotation), the molecule returns to its original
orientation
Cn
4. Only a single plane of symmetry Cs
5. Only a single point of symmetry Ci
6. Vertical plan
Horizontal plan
Diagonal plane
v
h
d

37
* *
Enantiomers are chiral molecules that are mirror
images of one another that are non-
superimposable

 If there is one asymmetric carbon then two optically active isomers
are possible.
 Isomer rotating plane of polarized light to the right is said to be
dextrorotatory (Latin, dexter : right) while isomer showing rotation to
the left is known as laevorotatory (Latin, laevus : left).
 Both isomers are mirror images of each other yet are not
superimposable.
 They are called as enantiomers and the pair of enantiomers is called
as enantiomorph.
 An enantiomer does not possess a plane or center of symmetry.
39

Characteristics of enantiomers
 Enantiomers have exactly identical physical properties such
as M.P, Density, etc
 They have identical chemical properties. They differ in their
reactivity towards other optically active substance.
 Enantiomers have different biological properties
40
Acid M.P Density Specific rotation
(+)Lactic acid 26 deg 1.248 +2.24
(-) Lactic acid 26 deg 1.248 -2.24
(±) Lactic acid 18 deg 1.248 0

 racemic mixtures:
 It is a mixture of equal amount of (+) and (-) enantiomers of chiral
compounds.
 It shows no net rotation of plane polarized light.
41

42
Racemization:
When one enantiomers equilibrates with its mirror image
the process is called Racemization.

43
Resolution:
While the separation of racemic mixture into individual
enantiomers is called as resolution.

 The maximum number of optically active isomers possible for a molecule
having more than one asymmetric carbon atoms may be given by the
formula
 N = 2n
 where,
 N= Number of optically active isomers, and
 n = Number of asymmetric carbon atoms.
44

IMPORTANCE OF OPTICAL ISOMERISM
 Nearly all naturally occurring substances having asymmetric carbon atoms are in
either the d or the l form rather than as racemic mixtures.
 In drugs and pharmaceuticals, most of the adverse effects and low potency may be
related to the utilization of the drug in the form of its racemic mixture.
 Since, enantiomer in its pure form, is more active and selective, there is now an
increasing interest to present the drug in the market in its active enantiomeric form
instead of its racemic form.
 Optical isomerism has also been successfully utilized in elucidating the mechanism
of many chemical reactions.
45

49
Example: Tartaric acid
Molecular Formula: C4H6O6
No. of assymetric carbon atom: 2
No. of isomers: 4
I and II Enantiomers
III and IV Enantiomers
I and III Distereomers
II and IV Distereomers
I and II Meso compounds

 Stereoisomers with two or more asymmetric or chiral carbons
(stereocenter) will show diasterioisomerism.
 The stereoisomers that are neither mirror images of one another
nor are superimposable, are known as diasterioisomers.
 Epimers: When two diastereoisomers differ from each other at
only one stereocenter they are known as epimers.
50

 In case of 3-bromo-2-butanol, we have four possible combinations as SS,
RR, SR and RS.
Out of these, two molecules SS and RR are enantiomers of each other while
the configurations RS and SR are diastereomers of SS and RR configurations
52

53
The molecules are different in the configuration of
chlorine atoms but same with the bromine atoms
hence they are diastereomers.

54
Similarly in cyclic compound 3-ethyl-1- chlorocyclohexane, ethyl groups
have same configuration but the chlorine atoms have opposite
configuration.
Hence, these molecules are diastereomers.
Configurations differ at some stereocenters but not at others can not
create mirror images. So they are not enantiomers, but are
diastereomers.

Characteristics of Diastereomers
1. A pair of diastereomers react similarly with a particular chemical
reagent, but at different rates.
2. They have got different m.p, b.p, solubility they can be separate
by fractional distillation of fractional crystallization.
3. A pair of diastereomers have identical configuration at one chiral
carbon, but mirror image configuration at second chiral carbon.
58

Meso compounds
 When multiple stereocenters present in a molecule create an internal
plane of symmetry, it leads to meso compounds. The meso form is also a
type of diastereomer
 Tartaric acid contains 2 asymmetric centers which give rise to 4
configurations.
59

 But there are really only 3 stereoisomers of tartaric acid: a pair of
chiral molecules (enantionmers of each other) and the achiral
meso compound.
 The melting point of both enantiomers of tartaric acid is about
170°C while the meso- tartaric acid has the melting point of 145°C.
60

 In meso compound, we have internal mirror plane that splits the
molecule into two symmetrical sides, the stereochemistry of both left
and right side should be opposite to each other. This leads to auto
cancellation of stereo activity of each other resulting into optical
inactivity.
 Each half must contain a stereocenter in order to be a meso
compound.
 Due to internal symmetry, the meso molecule is achiral. Hence, this
configuration is not optically active.
61

 A meso compound is 'superimposable' on its
mirror image. Examples in cyclic meso
compounds include.
62

63
Sr. no Parameters Enantiomer Diastereomer
1. No. of stereocenters One Two or more
2. Mirror images Yes No
3. Superimposition No No
4. Physical properties Same Different
5. Chemical Properties Same different

NOMENCLATURE OF
OPTICAL ISOMERS
D AND L SYSTEM OF NOMENCLATURE
65

 The D/L system was developed by Fischer and Rosanoff in
around 1900.
 Totally arbitrarily, (+) glyceraldehyde was defined as being D
because the OH group attached to the C2 is on the right hand
side of the molecule.
 While (–) glyceraldehyde was defined as L because the OH group
is on the left hand side.
66

 The D/L system names the molecule by relating them
to the molecule glyceraldehyde.
 This system of nomenclature represents an older
system for distinguishing enantiomers of amino acids
and carbohydrates.
 This arbitrary type of configuration (D/L system) is
known as Relative Configuration.
67

1. To name complex amino acids and carbohydrates in Fischer
projection, take carbonyl group (aldehyde, ketone or carboxylic acid)
on the top and CH2OH on the bottom.
68

2. The D descriptor is used when the –OH or –NH2
on the 2nd carbon (from bottom) points to the
right and L is used when the –OH or –NH2 points
to the left. Thus, from stereochemistry of only
one stereocenter (i.e. 2nd carbon from bottom)
the stereochemistry of all other stereocenters in
the molecule is defined.
69

 The D/L nomenclature does not indicate which
enantiomer is dextrorotatory and which is
levoratatory.
 It just says that the compound’s stereochemistry is
related to that of dextro - or levo - enantiomer of
glyceraldehyde.
 For example, D-fructose is levorotatory.
 Thus, (+) glucose has the D-configuration and
(+) ribose has the L-configuration
71

 It is clearly understood that capital letter D- and L- represents configurational
relationship taking glyceraldehyde as the arbitrary standard while d(or +) or l (or -
) represents direction of rotation. Both the letters have entirely different
meaning.
 For eg; D (+) glyceraldehyde on oxidation gives glyceric acid which has D-
configuration but its Laevorotatory
73

The Cahn Ingold Prelog (CIP) Sequence Rule
 The relative method of assigning configuration is not found suitable for
compounds not related with a particular glyceraldehyde.
 For such compounds Cahn-Ingold-Prelog proposed another method of
nomenclature.
 It is useful for compounds containing more than one asymmetric carbon
atoms.
 Every chiral carbon atom has either ‘R’ and ‘S’ configuration the racemic
mixture is designated as (R,S)
74

 2 steps are involved for naming an optical isomer by this method.
 First step.
 On the basis of sequence rule of CIP, the four atoms attached to the chiral
carbon are assigned number 1, 2, 3 and 4. The atom or group which has
highest priority is assigned number 1 and the atom or group which has
lowest priority is assigned no. 4.
 One criterion of priority is based on atomic numbers- an atom having
highest atomic number sets highest priority (1) and the atom having
lowest atomic number gets lowest priority (4) an assigned number 4.
75

 For example,
 (i) in fluoro chlorobromo iodo methane, the order of decrease priority
would be I, Br, Cl, F and in
 (ii) 1-lodo-1-dextro ethane the decreasing order would I, CH3 ,D, H
 I = 53, Br = 35, Cl = 17, F = 9
76

 Second step.
 The molecule is expressed or visualized tetrahedrally in such a way that group
of lowest priority (4) is directed away from us, i.e; the group having priority
number 4 is place away from us.
 The remaining three atoms of groups are directed towards us.
 It is then followed by observing the decreasing priority order (1-2-3)
arrangements of the remaining groups.
 A curved arrow is placed between 1 and 3 which origin from 1 and ends into 3
passing through 2.
 If this arrow is clockwise, the configuration is (R). If arrow is anticlockwise, the
configuration is (S).
77

 Example. In the following example, the order of priority is
1(1), Br(2), CI (3) and F (4).
 Tetrahedrally the molecule can be expressed in the
following two ways :
79

 The tetrahedral structure may be expressed by projection formula.
 The group which away from us in the tetrahedral structure is placed at the
bottom of the vertical line of projection of formula
80

 To get atom of the lowest priority at the bottom of the vertical
line, sometimes the position of the groups are also changed.
 When the position of two groups are interchanged, we get an
enantiomer and when the positions of remaining two groups are
interchanged then we get isomer having the original
configuration.
81

Sequence rules
 Rule I:
 When four different atoms are attached to the chiral carbon atom,
priority is given on their atomic number.
 The atom having highest atomic number gets highest priority and is
assigned lowest number (1).
 The atoms of lowest atomic number gets lowest priority and is assigned
highest number (4).
 For example, in bromochloroiodomethane (C, H, CI, Br, I) the decreasing
order of priority will be I (1), Br (2), CI (3), H (4).
83

 If the two atoms are isotopes of the same element, atom of higher
mass number has higher priority.
 For example, in the following case, the decreasing order
of priority will be Br, C, D, H.
 Isotope of higher atomic weight takes precedence. e.g.,
 3H (tritium) > 2H (deuterium) > 1H (hydrogen)
84

 Rule II.
 If two atoms (present in same groups) attached to the chiral carbon atom are
the same, the rule I cannot decide the priority.
 In such cases the order of priority is decided by comparing the atomic
numbers of the next atoms attached each.
 For eg; if two groups ethyl (-CH2-CH3) and methyl (-CH2) are attached to
same asymmetric carbon atom the first atom of both the groups attached to
asymmetric carbon atom is Carbon but in methyl group next atom is H and in
ethyl group it is C.
 Since, the atomic number of carbon atom is higher than that of Hydrogen,
the priority of C2H5 will be higher than that of CH3.
85

86
3-Chloro-5-Methyl pentane
1
2
3
4
–CO2CH3 > –CO2H > CONH2 > COCH3 > CHO > CH2OH

 Rule III
A doubly or triply bonded atom X is considered as
equivalent or two or three separate atoms (X)
respectively.
Therefore, the group
87
= =

 Rule IV:
 If there are multiple chiral carbons in a molecule,
the configuration of entire molecule can be
defined by using number that specifies the location
of the stereocenter preceding configuration e.g.,
(1R, 4S). e.g.,
88

90
C
C
F3
C
H
C
H
3
H
S
H
2C
H
2C
C
H
2C
l
C
H
3
C
C
C H C H 3
H S H 2 C H 2 C
C
C H 3
F
F
F
H H
C l
1
4
3
2
R S

RACEMIC MODIFICATION
 A racemic modification or racemate is a 1 : 1 mixture of (+) and (–)
enantiomers.
 When enantiomers are mixed together in equal amount, 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.
 Hence, the overall optical rotation of racemate is zero.
 A racemic modification is thus optically inactive.
 The prefix (±) is used to denote the racemic nature of the sample. e.g., (±)-2-
methyl-1-butanol.
91

 When one of the starting material is chiral, the product
of the reaction will always be formed as a racemate in
the absence of chiral catalyst.
 However, biologically active pure enantiomer can be
synthesized in the presence of chiral catalysts or agents.
92

Methods of Racemic Modification
1. Mixing
2. Chemical synthesis
3. Thermal racemization
4. Walden inversion
5. Epimerization
6. Mutarotation
93

1. Mixing:
 A racemic modification may be achieved by an intimate mixing of
exactly equal amounts of dextro (+) and levo (–) isomers.
2. Chemical synthesis:
 When one of the starting material is chiral the product of reaction will
always be formed as a racemate in the absence of chiral catalyst. e.g.,
when hydrogen cyanide reacts with acetaldehyde (chiral), equal
number of mole of two enantiomeric forms are produced.
94

3. Thermal recemization:
 Racemization may occur when an optically active
material is heated.
 It leads to temporarily breaking one of the 4 bonds
to a stereocenter.
 The atom/group separated exchanges the position
and joins back to stereocenter to form another.
96

4. Walden inversion:
 The racemization of 2-iodooctane by potassium
iodide in refluxing acetone involves a process known
as Walden inversion.
98

99
5. Epimerization:
It is the change in the configuration at one asymmetric
carbon atom in a compound having more than one
stereocenters. It thus leads to interconversion of
diastereomers.

6. Mutarotation:
 It is a spontaneous change with time, in the rotation of
freshly prepared solutions of optically active substance till
it reaches an equilibrium.
 Mutarotation is the result of either epimerization or a
spontaneous structural change.
 The rate of mutarotation depends on temperature, solvent
and catalyst.
 For example, the mutarotation of glucose is known to be
acid-base catalysed.
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0

Resolution of Racemic Mixture
 The process of separating a racemate into pure enantiomers is known as
resolution.
 Enantiomers have identical physical properties (b.p., m.p., solubility) and
hence it is difficult to separate enantiomers using conventional methods.
 If a pair of enantiomers is converted into a pair of diastereomers, the
diastereomers can be separated easily utilizing the difference in their physical
properties.
 Once separated, the pure enantiomer may be regenerated back from its
respective diastereomer.
102

Racemic mixture
Mixture of diastereomers
Resolving
agent
Diastereomer 1 Diastereomer 2
Enantiomer 1 Enantiomer 2
Resolution of
Racemic Mixture

 For example,
a. A racemic mixture of enantiomers of an acid can be converted to a salt using
a chiral base having D-configuration.
b. The salt obtained contains a mixture of two diastereomers: (D acid, D base)
and (L acid, D base).
c. Due to difference in their physical properties, the diastereomeric salts are
fully separated.
d. Dissociation of separated diastereomeric salt leads to regeneration of D-acid
and L-acid respectively
10
6

 Racemic acids may be resolved using
commercially available chiral bases like
brucine, strychnine, l-phenyl ethanamine.
 Similarly racemic bases may be resolved using
chiral acids such as (+) tartaric acid, (–) malic
acid, (–) mandelic acid and (+) camphoric acid.
10
7

 A racemic alcohol may be resolved by converting the racemate into a mixture
of diastereomeric esters using a chiral acid.
 The separation of these diastereomeric ester becomes difficult if they are
liquid.
 In such cases, instead of full ester, half ester is synthesized containing one free
carboxylic group.
 A chiral base, brucine then forms solid diastereomeric salts which can be later
separated by crystallization.
 The pure enantiomer of 2-butanol is regenerated through hydrolysis of
respective diastereomeric salt.
10
8

ii. Resolution by biochemical means:
 Certain mold, bacteria or fungi selectively destroy one
enantiomer at a faster rate than the other enantiomer.
 For example, the mold Pencillium glaucum if allowed to
grow with racemic mixture, it selectively destroys the
dextro isomer leaving pure levo isomer behind
110

11
1
Drug Biological response Enantiomer
Terbutaline Trachea relaxation (–)
Propranolol -blockade (S)
Amosulalol -blockade (+)
-blockade (–)
Warfarin Anticoagulation (S)
Verapamil Negative chronotropic (–)
Atenolol -blocker (S)
Nitrendipine Ca++ channel blocker (S)
Zopiclone Sedation (R)
Terfenadine Antihistaminic (S)
Albuterol Antiasthmatic (S)
Flurbiprofen Anti-inflammatory (S)
Ketoprofen Anti-inflammatory (S)
Thalidomide Immunosuppresive (S)
Tetramisole Anthelmintic (S)-form
(levamisole)
Propoxyphene Analgesic Dextro form
Antitussive Laevo form
Tranylcypromine Antidepressant (–)
Improvement in (+)
performance
Sotalol Antihypertensive (–)
Antiarrhythmic (+)

 Advantages of Resolution:
(i) To avoid side effects of unwanted enantiomer leading to
improved therapeutic profile and less chances of drug
interaction.
(ii) Reduction in the therapeutic dose and hence the cost of
treatment.
(iii) Lesser metabolic, renal and hepatic load of a drug on
the body as the dose (for a pure enantiomer) reduces to the
half of racemic mixture.
11
2

REACTIONS OF CHIRAL MOLECULES
 Chiral molecules react with the reagents in variety of ways and
accordingly reactions are classified as follows:
1. Reactions where bonds with the chiral center are not broken.
2. Reactions leading to generation of chiral center.
3. Reactions of chiral compounds with optically active reagents.
4. Reactions where bonds with the chiral center are broken.
11
3

114
1. Reactions where bonds with the chiral center are not broken.

i. Configuration is retained when reaction does not involve breaking of a bond
to a chiral center.
ii. Here as the bond to the chiral center is not broken 'S' configuration is
retained, because '–CH2–Cl' occupies same relative position as that was
occupied by –CH2OH in the reactant.
115

11
6
2.Reactions leading to generation of chiral center

i. Generation of first chiral center in a compound usually yields equal
amounts of enantiomers (Racemic mixture) but reactions that form
second/new chiral center yields unequal amounts of diastereomers
depending on the side of attack.
ii. Retention of configuration(s) occurs as there is no bond breaking to the
chiral center.
iii. For new chiral center, depending on side of attack from the same or
opposite side, diastereomers are formed but in unequal amounts.
11
8

iv. This is because the intermediate 3-chloro-2-butyl radical
contains a chiral center and it lacks symmetry.
v. So two faces of the molecule for attack are not equal to each
other.
vi. Here S isomer would yield the SS and meso compound in
ratio of 29 : 71.
vii. Similarly R isomer would yield RR and meso compound in
ratio of 29 : 71.
viii. If the reactant is optically inactive, it yields optically inactive
products.
119

3.Reactions of chiral compounds with optically active reagents
i. Such reactions are commonly used in resolution or separation of a racemic
mixture/modification into individual enantiomers.
ii. Because enantiomers have similar physical properties (except optical rotation)
they are not separated by usual methods of fractional distillation or
crystallization.
iii. So to obtain pure enantiomers from racemic modification, use of optically active
reagents is made.
iv. Such optically active reagent is easily obtained from natural sources or
generated from naturally available reagents.
v. Common reactions are reactions of organic acids and bases to form salts.
12
0

 e.g. Reaction of racemic acid (+) HA with alkaloid reagent (–) B.
12
1

vi. Formed diastereomers have different physical properties and can
be easily separated by fractional distillation or crystallization.
Further by addition of mineral acid resolved enantiomers can be
recovered from the solution.
vii. Alkaloid bases commonly used are (–) brucine, (–)
quinine, (–) strychnine etc.
viii. Similarly, racemic bases can be separated with acid reagents e.g. (–
) malic acid. Compounds other than acids, bases can also be
resolved.
122

12
3
• To separate the enantiomers of 2-hydroxylpropionic acid. We add as the
resolving agent an enantiomerically pure amount of (R)-2-phenyl-ethylamine.
• The two enantiomers interact with (R)-2-phenyl-ethylamine to form two
distinct salt species that are diastereomers of each other.
• The diastereomers can then be crystallized separately.

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4
4. Reactions where bonds with chiral center are broken

i. Stereochemistry of such reactions depend on the mechanism of
the reaction.
ii. Hence, stereochemistry can be helpful to give evidence of a
particular mechanism.
iii. As the product is optically inactive and a racemic mixture, it
implies second chlorine can be attached from either face of the
intermediate, which can be a free alkyl radical with loss of
chirality.
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6

ASYMMETRIC SYNTHESIS
 The conversion of achiral molecules or symmetric
molecule into chiral or asymmetric molecule by
chemical reaction is called Asymmetric synthesis.
 Glucose (dl) Glucose Glucose
50% D & 50% L D= 80% L= 20%
D= 40% L= 60%
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8
C
a
a b
c
d
C
a
d c
b
+ a
+

 In racemic mixture the dextro and Levo compounds are present in
equimolar ratio so they are optically inert.
 By the asymmetric synthesis, racemic mixture change into dextro
or levo rotatry compound by changing the ratio of dextro and levo
compound.
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9
C
O
C 2 H 5 C H 3
C
O H
C 2 H 5 C H 3
C N
HCN
Achiral Chiral

Types of asymmetric synthesis
It is of 2 types:
Partial asymmetric synthesis
Absolute asymmetric synthesis
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0

Partial asymmetric synthesis
 When racemic mixture of any compound is converted
into 2 different dextro and levo solutions in different
ratio (other than 50-50) then it is called Partial
asymmetrical synthesis
 The ratio of D & L solution will never be same but both
of them are present in the mixture.
13
1

 Decarboxylation of ethyl methyl malonic
acid to give a methylbutyric acid is one of
the first recorded asymmetric synthesis
13
2

Absolute asymmetric synthesis
 When racemic mixture of any compound is completely converted into
any one either detro or levo 100% then it is called absolute
asymmetrical synthesis.
 In this optically pure product is form from optically inactive substrate.
 This phenomenon needs high amount of energy.
 In this type of synthesis only one isomeric form is present in the
solution and other form is completely vanished or converted.
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3

Typical asymmetric syntheses
include
1. Asymmetric hydrogenation
2. Asymmetric epoxidation
3. Asymmetric dihydroxylation
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4

1. Asymmetric Hydrogenation(Reduction)
1. It is used for asymmetric synthesis of analgesic drug Naproxen.
2. Reaction is carried out in presence of chiral catalyst to hydrogenate double
bond.
3. The catalystselectsasingle enantiotopic faceofthedouble bondandadds
hydrogens acrossit.
4. BINAP is a chelating diphosphine. Chirality is due to restricted rotation of the
bond joiningtwonaphthalene ringsystems.
5. Along withRuthenium itactsasexcellent catalystfor hydrogenation.
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5

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6
(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

 For double bonds bearing amino group, better catalysts are based on
rhodium.
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7

 Important application of
asymmetric hydrogenation is in
synthesis of L menthol from (R)
citronellal.
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8

2. Asymmetricepoxidation
 Oxidation of alkenes by asymmetric epoxidation is
one of the popular sharpless reaction.
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9

 Catalyst is a transition metal, Titanium
tetraisopropoxide with tertiary butyl hydroperoxide.
The ligand is diethyl tartarate which is chiral and
imparts selectivity to the reaction
140

3. Asymmetric dihydroxylation
 Dihydroxylation of alkenes by osmium tetroxide in catalytic amount
is carried out.
 Osmium (VIII) act as oxidizing agent and K3Fe (CN)6
(Potassium ferricyanide) is commonly used to reoxidize the
osmium after each catalytic reaction.
 Chiral ligands are usually alkaloids dihydroquinidine and
dihydroquinine.
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3

 Trans alkenes dihydroxylates more
selectively than other alkenes because of
alignment of ligand and catalyst.
 Reaction has been successfully used for
synthesis of antibiotic chloramphenicol in
few steps.
14
4

Stereochemistry (optical isomerism)

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