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Dr.S.Alexandar,M.Pharm,Ph.D,
Associate Professor
Vinayaka Missions College of Pharmacy,
Yercaud main road,
Kondappanaickanpatty,
Salem, Tamilnadu,
Pin:636008
STEREOCHEMISTRY
 Berzelius coined the term isomerism (Greek: isos
= equal; meros = part) to describe the relationship
between two clearly different compounds having the
same elemental composition. Such pairs of
compounds differ in their physical and chemical
properties and are called isomers. For example,
 Ethyl alcohol (CH3CH2OH) and
 Dimethyl ether (CH3OCH3) are isomers.
IsomersIsomersIsomersIsomers
StereoisomersStereoisomersStereoisomersStereoisomers ConstitutionalConstitutional
isomersisomers
ConstitutionalConstitutional
isomersisomers
GeometricGeometric
Cis/transCis/trans
GeometricGeometric
Cis/transCis/trans
ConformationalConformational
IsomersIsomers
ConformationalConformational
IsomersIsomers
Enantiomers orEnantiomers or
optical isomersoptical isomers
Enantiomers orEnantiomers or
optical isomersoptical isomers
DiastereomersDiastereomersDiastereomersDiastereomers
MesoMeso
compoundcompound
MesoMeso
compoundcompound
EpimersEpimersEpimersEpimers
chapter 6chapter 6
These differ from each other in the way
their atoms are connected, i.e., in
their structures. It’s six types
signifying the main difference in the
structural features of the isomers are:
I. Chain/Skeletal/Nuclear Isomerism
II. Position Isomerism
III. Functional Isomerism
IV. Metamerism
V. Tautomerism
VI. Ring Chain Isomerism
 These have same molecular formula but
different arrangement of carbon chain within
the molecule.
C4H10
n-Butane
(straight chain)
Same molecular
formula
2-Methylpropane (Isobutane)
(Branched chain)
H3C—CH2—CH2—CH3 H3C—CH—CH3
CH3
CH3CH2CH2CH2CH3
C5H12 H3C CH CH2 CH3
CH3
n-Pentane
Same
molecular formula
2-Methylbutane
(Iso-pentane)
2, 2-Dimethylpropane
(Neo-pentane)
CH3
H3C C CH3
CH3
These have same carbon skeleton but
differ in the position of attached atoms
or groups or in position of multiple
(double or triple) bonds.
Propan-1-ol (The OH group at
CH3CH2CH2OH
Propan-2-ol (The OH group atC1) C2)
OH
CH3—CH—CH3
CH3CH2C CH CH3 C C CH3
But-1-yne But-2-yne(Triple bond at C1) (Triple bond at C2)
1234 4 3 2 1
 These have same molecular formula but
different functional groups.
CH3CH2OH CH3 O CH3
Ethanol Dimethyl ether
CH3 C OH
O
Ethanoic acid
O
H C OCH3
Methyl methanoate
Propanal (Propionaldehyde)
CH3CH2 C H
O
Propanone (Acetone)
O
CH3 C CH3
and
 These have different number of carbon atoms (or
alkyl groups) on either side of a bifunctional group
(i.e., -O- , -S-, -NH-, -CO- etc.). Metamerism is
shown by members of the same family, i.e., same
functional groups.
CH3CH2CH2—O—CH3CH3CH2—O—CH2CH3 or
Ethoxy ethane
(Diethyl ether)
1-Methoxy propane
(Methyl n-propyl ether)
2-Methoxypropane
(Isopropyl methyl ether)
is a metamer of
CH3
CH3CH2CH—O—CH3
is a metamer of or
Pentan-3-one
(Diethyl ketone)
Pentan-2-one
(Methyl n-propyl ketone)
3-Methylbutan-2-one
(Isopropyl methyl ketone)
CH3CH2—C—CH2CH3 CH3CH2CH2—C—CH3
OO
CH3—C—CHCH3
O CH3
 Structural or constitutional isomers existing in
easy and rapid equilibrium by migration of an
atom or group are tautomers (keto-enol
tautomerism).
Vinyl alcohol (enol form)
(Negligible amount)
CH2 C—H
OH
Acetaldehyde (keto form)
O
CH3—C—H
Prop-1-ene-2-ol (enol form)
(Negligible amount)
CH2 C—CH3
OH
Acetone (keto form)
O
CH3—C—CH3
 Open chain and cyclic compounds having
the same molecular formula are called
ring - chain isomers
CH3CH CH2
Propene
and
Cyclopropane
Cyclopropene
and
Propyne
CH3 C CH
 Isomers which have the same
molecular formula and same structural
formula but differ in the manner their
atoms or groups are arranged in the
space are called stereoisomers. It is of
two types:
I. Configurational Isomerism
II. Conformational Isomerism
 The stereoisomers which cannot be
interconverted unless a covalent bond is
broken are called configurational
isomers. These isomers can be
separated under normal conditions.
 The configurational isomerism is again of
two types:
a) Optical Isomerism or Enantiomerism
b) Geometrical Isomerism
 The stereoisomers which are related to
each other as an object and its non-
superimposable mirror image are called
optical isomers or enantiomers (Greek:
enantion means opposite).
 The optical isomers can also rotate the
plane of polarised light to an equal degree
but in opposite direction.
 The property of rotating plane of polarised
light is known as optical activity.
 The optical isomers have similar physical
and chemical properties.
 Molecular formula C3H6O3 represents two
enantiomeric lactic acids as shown below:
H
CH3
HO
COOH
( +) - Lactic acid
(Rotates the plane of polarized
light towards right hand side i.e.
clockwise)
COOH
OH
CH3
H
( -) - Lactic acid
(Rotates the plane of polarized
light towards left hand side i.e.
anticlockwise)
Mirror
 Geometric isomers are the stereoisomers
which differ in their spatial geometry due
to restricted rotation across a double
bond.
 These isomers are also called as cis-
trans isomers. For example, molecular
formula C2H2Cl2 corresponds to two
geometric isomers as follows:
C C
H
ClCl
H H
Cl
Cl
H
CC
cis-1,2-Dichloroethene trans-1,2-Dichloroethene
 The stereoisomers which can be
interconverted rapidly at room temperature
without breaking a covalent bond are called
conformational isomers or conformers.
 Because such isomers can be readily
interconverted, they cannot be separated
under normal conditions.
 Two types of conformational isomers are:
a) Conformational isomers resulting from
rotation about single bond
b) Conformational isomers arising from
amine inversion
 Because the single bond in a molecule
rotates continuously, the compounds
containing single bonds have many
interconvertible conformational
isomers.e.g, 'boat' and 'chair' forms of
cyclohexane.
H
H
H
H
H
H
H
H
H
H
H
H
Cyclohexane
(Chair form)
Cyclohexane
(Boat form)
H
H
H
H
H
HH
H
H
H
H
H
 Nitrogen atom of amines has a pair of
non-bonding electrons which allow the
molecule to turn "inside out" rapidly at
room temperature. This is called amine
inversion or Walden inversion.
Transition state
R3
N
R2
R1
R1
R2
N
R3
R1
R2
N
R3
 Light passes through a plane polarizer
 Plane polarized light is rotated in solutions
of optically active compounds
 Measured with polarimeter
 Rotation, in degrees, is [α]
 Clockwise rotation is called
dextrorotatory
 Anti-clockwise is levorotatory
1919
 A polarimeter measures the rotation of plane-
polarized that has passed through a solution
 The source passes through a polarizer and then is
detected at a second polarizer
 The angle between the entrance and exit planes is
the optical rotation.
2020
 To have a basis for comparison, define
specific rotation, [α]D for an optically active
compound
 [α]D = observed rotation
(pathlength x concentration)
= α = degrees
 Specific rotation is that observed for 1 g/mL in
solution in cell with a 10 cm path using light
from sodium metal vapor (589 nm)
2121
 Enantiomers are known to possess same
physical and chemical properties but
they differ in the way they interact with
plane polarised light.
 Substances which can rotate the plane of
polarised light are said to be optically
active.
 Dextrorotatory (Latin: dextre means right)
and is indicated by (+) sign.
 Laevorotatory (Latin: laeves mean left)
and is indicated by (-) sign.
 Those substance which do not rotate the
plane of polarised light are called
optically inactive.
 Angle of rotation (α) is the angle
(degrees) by which the analyser is rotated
to get maximum intensity of light. It
depends upon:
 (i) Nature of the substance;
 (ii) Concentration of the solution in g/ml;
 (iii) Length of the polarimeter tube;
 (iv) λ of the incident monochromatic light
(598nm).
 (v) Temperature of the sample.
Discrimination of Enantiomers byDiscrimination of Enantiomers by
Biological MoleculesBiological Molecules
Discrimination of Enantiomers byDiscrimination of Enantiomers by
Biological MoleculesBiological Molecules
 An object which cannot be superimposed
on its mirror-image is said to be chrial
(ky - ral) [Greek : Cheir 'Handedness']
and the property of non-
superimposability is called chirality. Thus
our hands are chiral.
 Similarly, alphabets R,F,J are chiral and A, M,
O are achiral.
 
A A MM O O
(Achiral objects)
R R J J F F
Chiral objects
Chiral objects -Chiral objects - human hand, gloves, shoes, etc.
Achiral objects - a sphere, a cube, a button, socks
without thumb, etc.
Chirality or molecular dissymmetry is the
necessary and sufficient condition for a molecule
to be optically active.
• The cis isomer is achiral.
• The trans isomer is chiral.
• Enantiomers: nonsuperimposable mirror images,
different molecules.
• One enantiomeric form of limonene smells like
oranges, while its mirror image smells like lemons.
• The one enantiomer of carvone is the essence of
caraway, and the other, the essence of spearmint.
• Most molecules in the plant and animal world are
chiral and usually only one form of then enantiomer is
found.
• Nineteen of the twenty known amino acids are chiral,
and all of them are classified as left handed.
chapter 6chapter 6
A 50:50 mixture of two chiral or enantiomers
compounds that are mirror images does not rotate
light – called a racemic mixture (named for
“racemic acid” that was the double salt of (+) and (-)
tartaric acid
 The pure compounds need to be separated or
resolved from the mixture (called a racemate)
 To separate components of a racemate (reversibly)
we make a derivative of each with a chiral
substance that is free of its enantiomer (resolving
agent)
 This gives diastereomers that are separated by their
differing solubility The resolving agent is then
removed
1. Physical methods:
- Spontaneous resolution
- Inclusion compounds
- Chromatography
1. Chemical methods:
- Diastereomeric salt formation
3. Biochemical methods:
- Enzymatic decomposition
Usual methods of separation such as
fractional distillation, fractional
crystallization or adsorption techniques
cannot be used for the separation of
enantiomers. Therefore, some special
procedures are needed for resolution of
racemic mixtures. Some of the more
important methods are:
1 Preferential Crystallization
2 Biochemical Method
3 Resolution through the formation of
diastereomers: The Chemical Method
Chromatographic Method
 Fractional crystallization is closely related
to mechanical separation of crystals.
 A supersaturated solution of the racemic
mixture is inoculated with a crystal of one of
the enantiomers or an isomorphous crystal
of another chiral compound. For example,
when the saturated solution of (±) sodium
ammonium tartarate is seeded with the
crystal of one of the pure enantiomer or a
crystal of (–) asparagine, (–) sodium
ammonium tartarate crystalises out first.
 This method is also called as entrainment
 Microorganisms or enzymes are highly
stereoselective.
 Fermentation of (±) tartaric acid in presence
of yeast or a mold, e.g., Pencillium glaucum.
The (+) tartaric acid is completely consumed
leaving behind (–) tartaric acid.
 (±) Amino acids can be separated using hog-
kidney acylase until half of acetyl groups are
hydrolysed away, only acetyl derivative of L-
amino acid is hydrolysed leaving behind
acetyl derivative of D-amino acid.
Limitations:
(i) These reactions are to be carried out in dilute
solutions, so isolation of products becomes difficult.
(ii)There is loss of one enantiomer which is consumed
by the microorganism. Hence only half of the
Basic Principle
Step 1. A racemic mixture (±)-A reacts with an
optically pure reagent (+) or (–)-B to give a
mixture of two products which are
diastereomers. The reagent (+) or (–)-B is
called the resolving agent.
(±) - A + (+)-B → (+)A(+)B +
(-)A(+)B
Step 2. The mixture of diastereomers obtained
above can be separated using the methods of
fractional distillation, fractional
crystallization, etc.
Step 3. The pure diastereomers are then
decomposed each into the corresponding
enantiomer and the original optically active
reagent, which are then separated.
(±) - Tartaric acid + (−)-Cinchonidine
(Racemic modification) (Resolving agent)
(+) - Tartaric acid - (−) - cinchonidine
+
(−) - Tartaric acid - (−) - cinchonidine
Diastereomers
(separable)
(+) - Tartaric acid - (−) - cinchonidine (−) - Tartaric acid - (−) - cinchonidine
Dil.
(+) - Tartaric acid
(crystallizes out)
(−) - Tartaric acid
(crystallizes out)
Separated by crystallization
H2SO4
H2SO4Dil.
(+) - base
(−) - base
+ (+) - acid
(+) - (+) - salt (+) - base
HO
(−) - (+) - salt (−) - base
Racemic
modification
Diastereomers
(separable)
HO
Similarly resolution of a (±) base with an optically active acid.Similarly resolution of a (±) base with an optically active acid.
The chemical method of resolution is widely
used and has the advantage that both the
enantiomers are obtained. This method will be
successful if the following conditions are
fulfilled:
(i) The resolving agent should be
optically pure.
(ii) The substrate (racemic mixture) and the
resolving agent should have suitable
functional groups for reaction to occur.
(iii) The resolving agent should be cheap and
be capable of regeneration and
recycling.
(iv) The resolving agent should be such which
produces easily crystallizable
diastereomeric products.
 The rates of movement of the two enantiomers
through the column should be different (due to
difference in the extent of adsorption). They
should thus be separable by elution with
suitable solvent.
 This method has an advantage over chemical
separation as the enantiomers need not be
converted into diastereomers.
 The techniques used include paper, column,
thin layer, gas and liquid chromatography.
Stereoisomers - Compounds that have the same molecular formula and the same
connectivity, but different arrangement of the atoms in 3-dimensional space.
Stereoisomers cannot be converted into each other without breaking bonds.
Stereoisomers can be subdivided into two general categories: enantiomers and
diastereomers.
Enantiomers are Stereoisomers whose molecules are non super imposable mirror
images of each other.
Diastereomers - Stereoisomers which are not enantiomers (or mirror images).
Chiral or asymmetric carbon - A tetrahedral carbon atom bearing four different
substituents.
Chirality centers, or stereocenters - Asymmetrically substituted atoms in a
molecular structure.
The most common type encountered in this course will be the chiral carbon
described above.
 Meso compounds, or meso forms - Symmetric, or achiral molecules that contain
stereocenters. Meso compounds and their mirror images are not stereoisomers, since
they are identical.
 Optical activity - The ability of chiral substances to rotate the plane of polarized light
by a specific angle.
 Dextrorotatory - Ability of chiral substances to rotate the plane of polarized light to the
right.
 Levorotatory - Ability of chiral substances to rotate the plane of polarized light to the
left.
 Specific rotation - The measured angle of rotation of polarized light by a pure chiral
sample under specified standard conditions (refer to textbook for a description of these).
 Racemic mixture, racemic modification, or racemate - A mixture consisting of equal
amounts of enantiomers. A racemic mixture exhibits no optical activity because the
activities of the individual enantiomers are equal and opposite in value, therby canceling
each other out.
 Optical purity - The difference in percent between two
enantiomers present in a mixture in unequal amounts. For
example, if a mixture contains 75% of one enantiomer and
25% of the other, the optical purity is 75-25 = 50%.
 Absolute configuration - A description of the precise 3-
dimensional topography of the molecule.
 Relative configuration - A description of the 3-dimensional
topography of the molecule relative to an arbitrary standard.
Absolute and relative configurations may or may not coincide.
 Enatiomerism depends on whether a
molecule in not superimposable on its
mirror image. If it is superimposable, the
molecule is optically inactive otherwise
is optically active. The most convenient
method of inspecting superimposability
is to determine whether the molecule has
any of the following four elements of
symmetry:
1. Plane of symmetry (s)
2. Centre of symmetry (i)
3. Simple or proper axis of symmetry
(Cn)
 A plane of symmetry is defined as an imaginary
plane which divides a molecule in such a way
that one half is mirror image of the other half.
 A molecule with atleast a plane of symmetry
can be superimposed on its mirror image and is
achiral. A molecule that does not have a plane
of symmetry is usually chiral; it cannot be
superimposed upon its mirror image.
•A plan of symmetry
may pass through
atoms, between
atoms or both.
H
COOH
COOH
OH
OHH
Plane
of
symmetry
meso-Tartaric acid
4242
 There is no mirror
plane for a hand
 The plane has
the same thing on
both sides for the
flask
 A molecule that has a plane of symmetry is
achiral.
 Cis-1,2-dichlorocyclohexane is achiral because the
molecule has an internal plane of symmetry. Both
structures above can be superimposed (they are
identical to their mirror images).
 Trans-1,2-dichlorocyclohexane does not have a
plane of symmetry so the images are
nonsuperimposable and the molecule will have two
enantiomers.
 The center of symmetry i is a point in space such that if a line is
drawn from any part (atom) of the molecule to that point and
extended an equal distance beyond it, an analogous part (atom)
will be encountered. In other words it is a point at which all
the straight lines joining identical points in the molecule cross
each other.
HH
H H
COOH
COOH
CH3
CH3
Centre
of
symmetry
2,4-Dimethylcyclobutane
-1,3-dicarboxylic acid has
Ci
H
HH3C
CH3
NHCO
C
NH CO
C
trans (achiral)
NHCO
C
NH CO
C
CH3H3C
HH
cis (chiral)
 Symmetry axis Cn, also called n-fold axis, is an axis which
rotates the object (molecule) around by 360°/n, such that the
new position of an object is superimposable with the original
one.
 For example, cis-1,3-dimethylcyclobutane has a two fold axis of
symmetry (C2) i.e. rotation by 180o
gives indistinguishable
appearance.
H
H
HH
CH3
H3C
C2-Axis of
Symmetry
H3C
CH3
H H
H
H
HH
Rotation
by 180o
HH
 Rotary reflection axis is an axis which rotates the
object (molecule) around by 360°/n, followed by
rotation in a plane perpendicular to the axis, such that
the new position of an object is superimposable with
the original one.
4. Alternating or improper axis of symmetry (Sn)
Rotation
by 90o
Reflaction through
mirror plane
perpendicular to
axis of rotation
43
(a)
H3C
H
2
CH3
H
H
H
H
CH3
CH3
1
23
4
B
A
CH3
H
H
H
CH3
CH3
(a)
3 4
2 1
H
H3C
H
CH3H
1
CH3
(b)
H
CH3
H3C
1,2,3,4-Tetramethyl-
cyclobutane has S4
5151
 A molecule that is achiral but that can become
chiral by a single alteration is a prochiral
molecule
 When replacement of one hydrogen atom at a
time gives an enantiomer, such a hydrogen
atom is called enantiotopic hydrogen. That
enantiotopic hydrogen, the replacement of
which gives R-configuration is called pro-R and
the other which give S-configuration is called
pro-S
 The carbon atom to which the two hydrogen
atoms are attached is called prochirality centre
and the moelcule is called prochiral molecule.
CHS HR
OH
CH3 CH3
OH
H D D H
OH
CH3
or
Replacement of
HR or HS by D
Ethanol (R-isomer) (S-isomer)
Prochiral centre
Pro-S
Pro-R
 Absolute configuration denotes the actual
arrangement of atoms or groups of atoms in
the space of a particular stereoisomer of a
compound. Absolute configuration can be
ascertained by x-ray studies of the crystals of
pure compound.
 Relative configuration denotes the
arrangement of atoms or groups of atoms in
the space of a particular stereoisomer relative
to the atoms or groups of atoms of another
compound chosen as arbitrary standard for
comparison.
Relative configurationRelative configuration compares thecompares the
arrangement of atoms in space of onearrangement of atoms in space of one
compound with those of another.compound with those of another. UUntill thentill the
1950s, all configurations were relative.1950s, all configurations were relative.
Absolute configurationAbsolute configuration is the preciseis the precise
arrangement of atoms in space.arrangement of atoms in space. WWe can nowe can now
determine the absolute configuration of almostdetermine the absolute configuration of almost
any compound.any compound.
 Rosanoff (1906) was the first scientist, who tried to give names to the
different optically active configurational forms of the molecule. He
arbitrarily chose Glyceraldehyde for naming the enantiomeric forms.
Rosanoff represented the glyceraldehyde molecule in a specific manner,
following the convention set up by Fischer (1809) for the structural
representation of a carbohydrate molecule. According to the convention
established by Fischer, the carbon chain was represented on the vertical
line drawn on a plane piece of paper. The groups attached to the carbon
chain were represented on the horizontal line. The carbonyl group
belonging to the carbohydrate was placed at the top of the vertical line.
Glyceraldehyde molecule was considered as the first member of the
carbohydrate series and Rosanoff represented the Glyceraldehyde
molecule like any other carbohydrate.
Structure V deflected the plane of the plane polarized light
to the right i.e. showed dextrorotation and was assigned
‘D’ as the name of its configurational form; Structure VI
deflected the light towards the left i.e. showed
leoveorotaiton and was assigned ‘L’ as the name to its
configurational form.
 The configuration (A) was arbitrarily
assigned to designate the configuration
of (+)-glyceraldehyde. Taking this as
standard, the relative configuration of (–)
lactic acid was assigned as shown
below:
H OH
CH2Br
COOH
P/Br2
H OH
CH2OH
COOH
Bromine
water
[O]
H OH
CH2OH
CHO
H OH
CH3
COOH
(+)-Glyceraldehyde (−)-Glyceric acid 1-Bromo-2-
hydroxypropanoic
acid
(Arbitrarily assigned that
OH group is on right hand
and H on left hand side)
(−)-Lactic acid
Redn.
(A)
Two commonly used conventions are:
1. D-L System 2. R-S System
1. D-L System: This is one of the oldest and the most
commonly used system for assigning configuration
to a given enantiomer. It is based upon the
comparison of the projection formula of one
enantiomer to which the name is to be assigned,
with that of a standard substance arbitrarily
chosen for comparison.
 To overcome the problem of D-L system, R.S.
Cahn (England), Sir Christopher Ingold
(England), and V. Prelog (Zürich) evolved a
new and unambiguous system for assigning
absolute configuration to chiral molecules.
This system is named as CIP (Cahn, Ingold,
Prelog) system after their names. It is called
as R-S system as the prefixes R-and S-are
used to designate the configuration at a
particular chirality centre. A racemic mixture
is named as (RS). This system is based on
certain rules called as sequence rules and
also as CIP rules.
 Cahn, Ingold and Prelog helped in introducing a new system
for assigning the configurational form to the molecule. The
system replaced the DL system. This system, adopted by
IUPAC, is called the RS convention or the sequence rule
system.
 In the sequence rule system, the four atoms or groups directly
attached to the asymmetric carbon atom, are to be ranked and
to be placed in a priority order. Use of the following rules was
made to decide the priority order of the groups attached to the
asymmetric carbon atom.
6161
 Priority rules (Cahn, Ingold, Prelog)
◦ Each atom bonded to the stereocenter is assigned a priority, based on
atomic number. The higher the atomic number, the higher the priority.
◦ Of the four atoms directly attached to the asymmetric carbon atom, the
atom with the highest atomic number was given the highest priority and
the atom with the lowest atomic number the lowest priority.
Increasing Priority
H CH3 NH2 OH SH Cl Br I
1 6 7 8 16 17 35 53
6262
◦ If priority cannot be assigned on the basis of the atoms
bonded to the stereocenter, look to the next set of atoms.
Priority is assigned at the first point of difference.
CH2 H CH2 CH3 CH2 NH2 CH2 OH
1 6 7 8
Increasing Priority
2. In case, the molecule has more than one group, having the same atom
through which the groups are attached to the asymmetric carbon atom,
then to decide the priority order between the groups the next atoms
attached to the first atom are taken into consideration. For example in 2-
butanol, CH3CHOHC2H5, the four different groups attached are –CH3,
-C2H5, -OH and H. The highest priority group would be –OH and the
lowest priority group would be H. As both the groups –CH3
and –C2
H5
,
are attached to the asymmetric carbon atom through carbon therefore to
decide the priority between these two the next atoms attached in the
groups are to be taken into consideration. In –CH3 the next atoms are
hydrogen whereas in –C2H5 the next atoms are one carbon and two
hydrogens; therefore the priority goes to the ethyl group.
6464
◦ Atoms participating in a double or triple bond are considered
to be bonded to an equivalent number of similar atoms by
single bonds
C
H
O C
H
O
O
C
6565
1. Locate the stereocenter
2. Assign a priority to each substituent from 1 (highest)
to 4 (lowest)
3. Orient the molecule so that the group of lowest
priority (4) is directed away from you
4. Read the three groups projecting toward you in order
from highest (1) to lowest priority (3)
5. If reading is clockwise, configuration is R (from the
Latin rectus). If it is counterclockwise, configuration
is S (from the Latin sinister).
6666
2clockwise counter
clockwise
(rectus) (sinister)
view with
substituent
of lowest
priority in
back
1 2
4
3
C C
1
4
3
R S
6767
I
C
BrCl
F
I
C
ClBr
F
1
2
3
4
RR SS
1
3
2
4
Enantiomers
6868
1. -OH
2. -COOH
3. -CH3
4. -H (R)-(-)-lactic acid
C
H
HO COOH
CH3
C
H
CH3
HOOC OH
(S)-(+)-lactic acid
Lowest priority 4 on vertical line
1
4
2
3F
Br Cl
H
F
Cl Br
H 4
1
3
2
CHO
OHH
CH2OH3
1
2
4
Lowest priority 4 on horizontal line
4
3
1
2 CH2CH3
H OH
CH3
R-configurationR-configuration
S-configurationS-configuration
R-configurationR-configuration
R-configurationR-configuration
S-configurationS-configuration
4
2
13
H3C
H
OH
COOH
CHO
HHO
CH2OH
HO H H OH
CH2OH
HO H
CHO CHO
HHO
CH2OH
OHH
L-Erythrose
(2S, 3S)
D-Threose
(2S, 3R)
L-Threose
(2R, 3S)
 Geometric or cis-trans or E-Z isomers.
 This type of isomerism arises if there is
no free rotation about the double bond.
 Due to different arrangement of atoms or
groups in the space, geometric isomerism
is designated as stereoisomerism.
 The geometric isomers belong to the
category of configurational isomers
because they cannot be interconverted
without breaking two covalent bonds.
 Further, geometric isomers are examples
of diastereomers because they are not
mirror images of each other.
Geometric isomerism is not confined only to theGeometric isomerism is not confined only to the
compounds having carbon-carbon doublecompounds having carbon-carbon double
bonds. In fact the following compounds exhibitbonds. In fact the following compounds exhibit
this type of isomerism:this type of isomerism:
i) Compounds having a double bond, i. e.,
olefins (C=C), imines (C=N) and azo
compounds (N=N).
ii) Cyclic compounds.
iii) Compounds exhibiting geometric isomerism
due to restricted rotation about carbon-
carbon single bond.
 Configuration of a chiral molecule is
three dimensional structure and it is not
very easy to depict it on a paper having
only two dimensions. To overcome this
problem the following four two
dimensional structures known as
projections have been evolved.
 1. Fischer Projection
 2. Newman Projection
 3. Sawhorse Formula
 4. Flying Wedge Formula
 Characteristic features of Fischer projection:
Rotation of a Fischer projection by an angle of 1800
about the axis which is perpendicular to the plane of
the paper gives identical structure. However, similar
rotation by an angle of 900
produces non - identical
structure.
or
(I)
CH2OH
OH
COOH
H C
Towards the
veiwer
Away from
the veiwer
(I)
OHH
CH2OH
COOH
Since structures I and II are indistinguishable, the moleculeSince structures I and II are indistinguishable, the molecule
has Chas C2 axis of symmetry. But it is non-superimposable on
its mirror image so it is dissymmetric and not asymmetric
and exhibits optical activity.
Br H
Br
CH3
CH3
H H
CH3
CH3
Br
HBr
I II
Rotation
by 180o
III
H Br
H
CH3
CH3
Br
All asymmetric molecules are dissymmetric but allAll asymmetric molecules are dissymmetric but all
dissymmetric molecules are not asymmetric.dissymmetric molecules are not asymmetric. However,However, bothboth
these types of molecules show optical activity andthese types of molecules show optical activity and are chiral.
Hence, to avoid any confusion, in using these terms, -
asymmetry or dissymmetry - the term chirality is used.
 Fischer projections give the impression that the
molecule exists in the eclipsed form. Actually it
exists in the staggered form in which the bulky
substituents are as far apart as possible.
 Therefore, an erythro isomer corresponds to that
diastereomer, which when viewed along the bond
connecting the chiral carbons has a rotational
isomer in which all similar groups are eclipsed.
The threo diastereomers, on the other hand, does
not have an isomer in which all similar groups are
H
H
CH2OH
CHO
OH
HO
(+)-Threose
H
H
CH2OH
CHO
OH
OH
(−)-Erythrose
CHO
CH2OH
HO
HO
H
H
(+)-Erythrose
HO
CHO
CH2OH
H
H OH
(−)-Threose
 The isomers having two similar chirality
centres such as III are optically inactive due
to presence of a plane of symmetry and are
termed meso compounds (internal
compensation). Hence, meso compounds are
optically inactive compounds whose molecule
Pair of enantiomers
Mirror IV
HO H
HO
COOH
COOH
HH
COOH
COOH
OH
OHH
IIII
HHO
OH
COOH
COOH
H
OH
COOH
COOH
H
IIMirror
HO H
Meso- tartaric acid
 Carbon atoms involved in double bond
formation and all the atoms attached to these
doubly bonded carbon atoms must lie in the
same plane because π-bond can be formed only
by parrallel overlap of the two p-orbitals. There
will be decrease in the overlap of p-orbitals if
an attempt is made to destroy this coplanarity.
In other words, neither of the doubly bonded
carbon atom can be rotated about the double
bond without destroying the π-orbital.
Rotation about a C = C bond.
Overlap of π-orbitals
not possible as they
are perpendicular to
each other.
Rotation by
90o
This process of rotation which is really a transfer
of electrons from the π-molecular orbital to the p-
atomic orbital is associated with high energy
(271.7 kJ mol-1
). Thus at ordinary temperatures,
rotation about a double bond is prevented and
hence compounds such as CH3CH =CHCH3 exist
as isolable and stable geometrical isomers.
H
C C
H
H3C CH3
CC
Cis-But-2-ene Trans-But-2-ene
H3C
CH3H
H
Cis-Cinnamic acid Trans-Cinnamic acid
HH
C C
H
COOH
CC
COOH
HH5C6 H5C6
 Geometrical isomerism will not be possible if
one of the unsaturated carbon atoms is bonded
to two identical groups.
 No two stereoisomers are possible for
CH3HC=CH2, (CH3)2C=CH2 and Cl2C=CHCl.
 Examples of compounds existing in two stereo-
isomeric forms are:
H
CH3
Trans-Pent-2-eneCis-Pent-2-ene
C C
CH3
H
CC
H
H3C H2C H3C H2C
H
HH
C C
H
COOH
CC
Cis-Cinnamic acid Trans-Cinnamic acid
COOH
HH5C6 H5C6
I. Physical methods
(a) Melting points and boiling points: Trans
isomer has a higher m. p. due to symmetrical
packing.
Cis isomer has a higher b. p. due to higher
dipole moment which cause stronger
attractive forces.
H3C H
CH3
b.p. 274K
C C
H
HOOC
CC
m.p. 575K
H
COOHH
H3C
b.p. 277K
CH3
H
CC
H
H
C C
H
COOH
m.p. 403K
HOOC
(c) Dipole moment : In general, cis isomers
have the greater dipole moment.
HH
C C
H
CH3
CC
µ = 0.4 D µ = 0
CH3
HH3C H3C
ClCl H
Cl
µ = 0
µ = 1.85 D
C C
Cl
H
CC
H H
 IR: Trans isomer is readily identified by the
appearance of a characteristic band near 970-
960 cm-1
. No such band is observed in the
spectrum of the cis isomer.
 NMR: The protons in the two isomers have
different coupling constants e.g. trans – vinyl
protons have a larger value of the coupling
constant than the cis-isomer, e.g. cis- and trans-
cinnamic acids.
C6H5
cis-Cinnamic acid
(JH,H = 12Hz)
CC
HH
CO2H
CO2HH
H
C C
trans-Cinnamic acid
(JH,H = 16Hz)
C6H5
a) Methods of formation from cyclic compounds:
Oxidation of benzene or quinone gives
maleic acid (m. p. 403K). From the structure
of benzene or quinone, it becomes clear that
the two carboxyl groups must be on the
same side (cis).
 Therefore, maleic acid i.e. the isomer having m. p.
403K, must be cis and the other isomer fumaric acid
(m. p. 575K) must be trans.
or
CO2H
CO2H
H
H
m.p. 403 KO
O
[O]
 Cis isomer will undergo ring closure much more
readily than the trans isomer.
C
C
CO2H
CO2H
H
H H
H
CO
CO
C
C
O
H
H
HO2C
CO2H
C
C
573K423K
-H2O -H2O
Maleic acid Maleic anhydride Fumaric acid
H
H
CO2H
CO2H
C
C
Maleic acid
Hydrolysis
 Suppose configuration of a geometric isomer, say A is
known. Let A be converted under mild conditions to a
geometric isomer A', of another compound. Since
under mild conditions interconversion of the
geometric isomers will not take place, therfore, the
configuration of A' will be the same as that of A.
A’A’AA
NH2
CO2 Ba/2
H
CC
H
Cis isomer of
1. HNO2
2. H3PO2
H
C C
H
CO2H
Cis, m.p. 341K
Allocinnamic acid
Cinnamic acid
Trans, m.p. 406K
1. HNO2
2. H3PO2
Trans isomer of
H
C C
H
CO2 Ba/2
NH2
H
C C
H
CO2H
ortho-aminocinnamic acid salt
ortho-aminocinnamic acid salt
(i) Hydroxylation of double bond is
stereospecifically cis.
Maleic acid
or Os O4
aq. KMnO4
H
H
COOH
COOH
C
C
H
H
COOH
COOH
OH
OH
meso-Tartaric acid
(+) - Tartaric acid
(50%)
H
OH
COOH
COOH
HO
H
C
C
COOH
HOOC
H
H
aq. KMnO4
or Os O4
Fumaric acid
COOH
COOH
OH
H
(−) - Tartaric acid
(50%)
HO
H
Racemic mixture
+
 In contrast to hydroxylation, addition of bromine
to alkenes is stereospecifically trans.
Therefore, addition of bromine to trans-isomer
will give rise to meso and to cis-isomer gives
racemic mixture.
+
Racemic mixture
H
H
CH3
CH3Cis-But-2-ene
Br2 / CCl4
H
H3C H
C
C
H
CH3
CH3
H
H3C
Br
Br
Br
Br
Br
Br
H
H
CH3
CH3
H
C
C
HH3C
CH3
Br2 / CCl4
Meso-2,3-Dibromobutane
Trans-But-2-ene
 Consider a molecule in which the two carbon
atoms of a double bond are attached with four
different halogens.
 When we say that Br and CI are trans to each
other we can also say with equal degree of
confidence that I and CI are cis to each other. It is
thus difficult to name such a substance either the
cis or the trans isomer. To eliminate this
confusion, a more general and easy system for
designating configuration about a double bond has
been adopted. This method, which is called the E
and Z system, is based on a priority system
originally developed by Cahn, Ingold and Prelog
for use with optically active substance
F
I
Br
CC
Cl
CC
1
2
2
1 2
1
2
1
C C
E Z
Z-But-2-ene-1,4-dioic acid
(Maleic acid)
E-But-2-ene-1,4-dioic acid
(Fumaric acid)
C C
COOH
HHOOC
HHOOC
H H
COOH
CC
2
1
2
1
1
2
2
1
C C
F
ClI
Br
1
2
1
2
2
12
1
Br
I
Cl
F
CC
Z-1-Bromo-2-chloro-
2-fluoro-1-iodoethene
E-1-Bromo-2-chloro-
2-fluoro-1-iodoethene
Z-2-Butene
2
1
2
1 H3C
H H
CH3
CC C C
CH3
H
H
H3C1
2 1
2
E-2-Butene
 Dienes in which the two termini are different
(i.e. XHC=CH–CH=CHY), has four geometrical
isomers .
C
C
H
H
Y
C
C
H
H
X
C
C
Y
H
H
C
C
H
H
X
C
C
X
H
H
H
HY
C
C
Z,E, or cis-trans Z,Z, or cis-cis E,E or trans-trans
C
C
H Y
H
H
H
X
C
C
E,Z or trans-cis
It means the number of geometrical isomers is 2n
where n is
the number of double bonds.
 The carbon and nitrogen atoms of oximes are
sp2-hybridized, as in alkenes.
 Thus, all groups in oximes lie in the same plane
and hence they should also exhibit geometric
isomerism if groups R and R1
are different.
Accordingly Beckmann (1889) observed that
benzaldoxime existed in two isomeric forms and
Hantzsh and Werner (1890) suggested that
these oximes exist as the following two
geometric isomers (I and II).
OH
N
C
H5C6 H HH5C6
C
N
HO
I II I II
HO
N
C
H5C6 HHH5C6
C
N
OH
or
 The prefixes syn and anti are used in
different context for aldoximes and
ketoximes.
 Aldoximes
 Ketoximes
H
H5C6
C N
OH
anti-Benzaldoxime
II
OH
NC
H5C6
H
syn-Benzaldoxime
I
syn-Ethylmethylketoxime
OH
NC
H5C2
H3C
anti-Ethylmethylketoxime
H3C
H5C2
C N
OH
HO
N
C
CH3H5C6
C
N
OH
CH3
E-Methylphenylketoxime Z-Methylphenylketoxime
H5C6(2)
(2)
(1)
(1)
(1)
(1)
(2)
(2)
E-Acetaldoxime Z-Acetaldoxime
H3C H
OH
N
C
H3C H
C
N
HO
 a) Aldoximes: The acetyl derivative of one
isomer regenerated the original oxime whereas
that of the other isomer eliminated acetic acid
by E2 mechanism to form aryl cyanide.
N
C
HAr
C
N
OH
H
E or syn - Oxime
Ac2O
Ar
OAc OH
Ar
Aq. Na2CO3
H
C
N
(Hydrolysis)
Elimination
N
CAq. Na2CO3
Ar
Ac2O
Z or anti -Oxime
H
N
C
Ar H
C
N
HO AcO
|
+ Acetic
acid
Ar
Original oxime
Aryl cyanide
 The configuration of the geometric isomers of
the unsymmetrical ketoximes are determined by
Beckmann rearrangement which consists in
treating ketoxime with acidic reagents such as
PCI5, H3PO4, P2O5, etc. when the oxime
isomerizes to a substituted amide by migration
of the group (R1
or R2
) which is anti to the
hydroxyl group.R1
C
R2
N R2 CO NHR1 R2COOH + R1NH2
OH
Determination of structure of amine formed in the aboveDetermination of structure of amine formed in the above
sequence of reactions plays a key role in deciding whichsequence of reactions plays a key role in deciding which
group has migrated during Beckmann rearrangement.group has migrated during Beckmann rearrangement.
 Cyclic compounds such as the disubstituted
derivatives of cyclopropane, cyclobutane,
cyclopentane and cyclohexane can also show
cis-trans isomerism, because the basic
condition for such isomerism- that there should
be sufficient hindrance to rotation about a
linkage between atoms- is also satisfied in
these systems. Atoms joined in a ring are not
free to rotate around the sigma bond.
Above the planeAway from us
Towards us Below the plane
CH3
Vertical line
CH3
1,2-Dimethylcyclohexane
Sometimes, a broken wedge is used to indicate a group
below the plane of the ring, and a solid line represent a
group above the plane.
CH3
CH3
Below the plane
Above the plane
 A carbon – carbon σ-bond is formed by an end-
on overlapping of sp3-orbitals of the two carbon
atoms.
 This bond is cylindrically symmetrical about the
axis and has the highest electron density along
the bond axis.
 Almost an infinite number of spatial
arrangements of atoms about the cabon-cabon
single bond exist. All those arrangements which
result from free rotation about a single bond
are called conformations or conformers or
rotational isomers or simply rotamers.
bond axis
A cylindrically symmetric MO of a single bond obtained by
sp3-sp3 overlap of two carbon atoms.
 Pitzer (1936) postulated that there exists a
potential energy barrier which causes restriction
in rotation.
 The extra energy of eclipsed conformation is
called torsional strain. The term torsional strain
is used for the repulsion felt by bonding
electrons on one substituent when it passes
close to the bonding electrons of another
substituent.
I II
H
H
H
H
H
H
Eclipsed conformation Staggered conformation
HH
H
H
H
H
EclipsedEclipsed
StaggeredStaggered
I I I
II II II
0 60 120 180 240 300 360
5
10
15
Torsion angle (degrees)
I at 0o, 120o and 240o
II at 60o, 180o and 300o
Fig. 3.7 Rotational or torsional energy in ethane
Eclipsed conformation
Staggered conformation
I
RelativeEnergy,kJmol-1
CH3
CH3
H
H
H H
Fully Eclipsed
(θ = 0o)
θ
H
CH3
H
CH3
H
H
Gauche (θ = 0o)
Partially Eclipsed
(θ = 120o)
HH3C
H
H
CH3
H
Anti or Trans (θ = 180o)
H
H
CH3
H
CH3
H
H
CH3
H H
H3C
H
Partially Eclipsed
(θ = 240o)
Gauche (θ = 300o)
H
H
H3C
H
CH3
H
I
II
III
IV
V
VI
Due to congestion in space a repulsive force acts between the methyl
groups which is called van der Waals strain or steric hindrance. In
butane, gauche conformation is less stable than anti-conformation due
to vander Waals strains i.e. n-butane gauche (or skew) intraction.
I
I = Fully Eclipsed
III and V = Partially Eclipsed
II and VI = Gauche
IV = Anti-conformation
Torsion angle (degrees)
15
10
5
0 60 120 180 240 300 360
VI
IV
II
V
III
I
20
25
4.0
16
Fig. 3.8 Rotational or torsional energy in n-butane
RelativeEnergy,kJmol-1
At room temperature, almost all molecules exist in staggered
conformation and amongst staggered conformations 78%
exist in anti and 22% in gauche conformations.
 On the basis of torsional strain and vander Waals
steric hindrance, staggered (anti) conformation of
1,2-dibromoethane is the most stable followed by
gauche.
 Dipole moment of anti-conformation is zero while
gauche conformation has some finite dipole moment
since the two C—Br dipoles are at an angle of 600
to
each other.
 Actual dipole moment of 1,2-dibromoethane is 1.0D,
therefore, the molecule cannot exist entirely in the
Fully Eclipsed
HH
H
H
Br
Br
Partially Eclipsed
HH
H
Br
H
Br H
H
H
Gauche Anti
H
Br
Br
H
Br
H
H
H
Br
Anti Gauche
 In case of ethylene glycol due to intramolecular H-
bonding the gauche form becomes more stable than
anti-conformation because there will be no such H-
bonding possible in anti-conformation. The formation
of such H-bond stabilizes the molecule by
approximately 20-30 kJ mol-1.
 Similarly due to intramolecular H- bonding ethylene
chlorohydrin, (CH2Cl — CH2OH), exists in gauche
conformation which is more stable than anti-form.
H
H
OH
H
H
H
OH
H
O
O
H
Gauche Anti
H
H
HHO
H
OH
H
H H
Partially Eclipsed
OH
OH
H
H
H H
Fully Eclipsed
 Cyclohexane can have two conformations free
from Baeyer or angle strain, called the chair
form (I) and the boat form (II), respectively.
I II
Chair conformations of cyclohexane with axial and equatorial bonds
H
H
H
H
H
H
ee
e e
e
e
H
H
H
H
H
H
a
a
a
a
a
a
H H
H
H
(fp) H
H
HH
H
H
H (fp)
H
1
23
4
5 6
Boat
Twist Boat Twist chair
H H
H
Ha
Hb
H
4
1
2
6
3
5
H H
H
H
Hb Ha
1
25
4
3 6
Boat
Twist boat
22.6
30.6
41.9
EkJmol
-1
a
b
d
c
Fig. 3.10 Potential energy of cyclohexane, a, chair; b, twist chair;
c twist boat; d, boat.
 In methylcyclohexane, the axial conformer will
have two more n-butane skew interactions (7.54
kJ mol-1
) whereas in the equatorial conformer
no additional interaction or torsional strain is
introduced since the two new n-butane
segments in it are both fully staggered (anti).2
H
CH3
3
6
5
1
4
H
H
H
H
H
CH3
H
H
1
3
5
6
The two new skew (gauche) interactions in the axial
conformer are best demonstrated by drawing the Newman
projection formula for the n-butane segment, CH3, C1, C2,
C3 and CH3, C1, C6, C5.
Newman projection for the equatorial conformer, as shown
below, clearly shows the absence of any additional skew
interaction.
6
5
3
1
H
H
CH3
H
H
H
H
H
We reach the same conclusion if we consider that in the
axial conformer the two axial hydrogens on C3 and C5 are
closer to the axial than to the equatorial methyl group.
H 1
H
CH3
H
2
3
4
5 6
H CH3
H
H
Axial methyl Equatorial methyl
 The interactions between the axial atoms or
groups at 1- and 3- or 5-positions are called
1,3-diaxial interactions and in the case of 1,3-
dimethylcyclohexane, the 1,3-diaxial interaction
has been assigned the value of 22.6kJmol-1
.
Thus cis 1,3-dimethylcyclohexane exists at
room temperatures almost wholly in the
diequatorial conformation.CH3
CH3 H
H
H
H
H3C
CH3
cis 1,3-Dimethylcyclohexane
(diaxial conformer; much
less stable)
cis 1,3-Dimethylcyclohexane
(diequatorial conformer;
much more stable)
tert-Butylcyclohexane exists 100 per cent in the
equatorial conformation (A), the ring being frozen
due to the prevention of the flip to a conformation
(B) in which the non-bonded 1,3-diaxial interactions
between the axially bound tert-butyl group and the
two axial hydrogens at the 3-and 5-positions will be
forbiddingly large.
H
H
H3C CH3
H
B
CH3
A
H
H
H
CH3
CH3
CH3
It is clear from the above considerations that the
axial bonds experience non-bonded interactions
with other axial bonds at 3-and 5-positions
whereas the equatorial bonds are free from such
steric interactions, i.e. axially bound groups will
experience more steric crowding than the
equatorially bound groups.
This explains why in most of the cases the
equatorially bound groups in cyclohexane
derivatives are more reactive than the axially
bound ones. E.g. equatorially bound hydroxyl
groups are more easily esterified than the axial
ones. Similarly, the equatorial acetoxy group
undergoes hydrolysis faster than the axial group.
 Conformations is used for various spatial
isomers which can be easily inter-
converted.
 Configurations is used for various spatial
isomers which can be interconverted
only by breaking and making of covalent
bonds.
 The energy difference between two
conformers is very small due to which
they can be interconverted by molecular
collisions even at room temperature.
 Conformational isomers cannot be
separated. But conformational isomers
can be separated easily.
H
H
C6H5
C6H5
Cl
Cl Cl
Cl C6H5
C6H5
H
H Cl
Cl
C6H5
H5C6 H
H
Rotate
through 120o through 120o
Rotate
I II III
through 120o
Rotate
through 120o
Rotate
Cl
Cl
C6H5
C6H5
H
H
H
H
C6H5
Cl
Cl
C6H5
H
HH5C6
C6H5
Cl
Cl
IV V VI
mesomeso-form
(+ or(+ or -) form
LiAIH4Ph C C Ph
OO
Benzil
OH OH
PhCCPh
H H
* *
1 2
1,2-Diphenylethane-1,2-diol
AsAs 1,2-diphenylethane-1,2-diol has two similar asymmetric
carbons (cf. tartaric acid) it exists as three steroisomers.
Ph
OH
HHO
H
Ph Ph
H
HO H
OH
Ph
Ph
H
OHH
OH
Ph
I II III
meso-formEnantiomers
1.1. Isomers -Isomers - Same molecular formula – differentSame molecular formula – different
compounds.compounds.
• Constitutional – Individual atoms are connected differentlyConstitutional – Individual atoms are connected differently
• Stereoisomers – Same connectivity – different 3DStereoisomers – Same connectivity – different 3D
arrangement.arrangement.
• Mirror-Image Stereoisomers – Related as image – mirrorMirror-Image Stereoisomers – Related as image – mirror
image.image.
2.2. Chiral Molecule -Chiral Molecule - Not superimposable on its mirrorNot superimposable on its mirror
image.image.
3.3. Stereocenter –Stereocenter – Carbon atom bearing 4 differentCarbon atom bearing 4 different
substituents.substituents.
4.4. Enantiomers –Enantiomers – Two stereoisomers, each a non-Two stereoisomers, each a non-
superimposable mirror images of the other.superimposable mirror images of the other.
5.5. Racemate –Racemate – A one to one mixture of enantiomers.A one to one mixture of enantiomers.
6.6. Mirror Plane –Mirror Plane – Chiral molecules cannot contain aChiral molecules cannot contain a
mirror plane.mirror plane.
7.7. Diastereomers –Diastereomers – Stereoisomers not related to eachStereoisomers not related to each
other as mirror images (ie. cis/trans).other as mirror images (ie. cis/trans).
8.8. Two Stereocenters In A Molecule –Two Stereocenters In A Molecule – CreateCreate upup
to 4 stereoisomers: 2 diastereomerically related pairsto 4 stereoisomers: 2 diastereomerically related pairs
of enantiomers. If the 2 stereocenters generate aof enantiomers. If the 2 stereocenters generate a
mirror plane in the molecule, the molecule is known asmirror plane in the molecule, the molecule is known as
a meso compound and is achiral.a meso compound and is achiral.
9.9. Physical Properties of Stereoisomers –Physical Properties of Stereoisomers – MostMost
are the same except for the rotation of plane polarizedare the same except for the rotation of plane polarized
light. One enantiometer rotates the plane oflight. One enantiometer rotates the plane of
polarization to the right, the other to the left. Thispolarization to the right, the other to the left. This
rotation is expressed as the specific rotation, [rotation is expressed as the specific rotation, [αα].].
10.10. Absolute Configuration -Absolute Configuration - Determined by x-rayDetermined by x-ray
diffraction. Assignment of R or S, as determined bydiffraction. Assignment of R or S, as determined by
the Cahn, Ingold, and Prelog sequence rules.the Cahn, Ingold, and Prelog sequence rules.
11. Stereoselectivity -11. Stereoselectivity - Preference for the formation ofPreference for the formation of
one stereoisomer when several are possible.one stereoisomer when several are possible.
12. Resolution –12. Resolution – Separation of enantiomers.Separation of enantiomers.
• Reaction with a pure enantiomer of a second chiralReaction with a pure enantiomer of a second chiral
compound and separation of the diastereomers.compound and separation of the diastereomers.
• Chiral chromatography.Chiral chromatography.

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Alex stereo chemistry

  • 1. Dr.S.Alexandar,M.Pharm,Ph.D, Associate Professor Vinayaka Missions College of Pharmacy, Yercaud main road, Kondappanaickanpatty, Salem, Tamilnadu, Pin:636008 STEREOCHEMISTRY
  • 2.  Berzelius coined the term isomerism (Greek: isos = equal; meros = part) to describe the relationship between two clearly different compounds having the same elemental composition. Such pairs of compounds differ in their physical and chemical properties and are called isomers. For example,  Ethyl alcohol (CH3CH2OH) and  Dimethyl ether (CH3OCH3) are isomers.
  • 3. IsomersIsomersIsomersIsomers StereoisomersStereoisomersStereoisomersStereoisomers ConstitutionalConstitutional isomersisomers ConstitutionalConstitutional isomersisomers GeometricGeometric Cis/transCis/trans GeometricGeometric Cis/transCis/trans ConformationalConformational IsomersIsomers ConformationalConformational IsomersIsomers Enantiomers orEnantiomers or optical isomersoptical isomers Enantiomers orEnantiomers or optical isomersoptical isomers DiastereomersDiastereomersDiastereomersDiastereomers MesoMeso compoundcompound MesoMeso compoundcompound EpimersEpimersEpimersEpimers chapter 6chapter 6
  • 4. These differ from each other in the way their atoms are connected, i.e., in their structures. It’s six types signifying the main difference in the structural features of the isomers are: I. Chain/Skeletal/Nuclear Isomerism II. Position Isomerism III. Functional Isomerism IV. Metamerism V. Tautomerism VI. Ring Chain Isomerism
  • 5.  These have same molecular formula but different arrangement of carbon chain within the molecule. C4H10 n-Butane (straight chain) Same molecular formula 2-Methylpropane (Isobutane) (Branched chain) H3C—CH2—CH2—CH3 H3C—CH—CH3 CH3 CH3CH2CH2CH2CH3 C5H12 H3C CH CH2 CH3 CH3 n-Pentane Same molecular formula 2-Methylbutane (Iso-pentane) 2, 2-Dimethylpropane (Neo-pentane) CH3 H3C C CH3 CH3
  • 6. These have same carbon skeleton but differ in the position of attached atoms or groups or in position of multiple (double or triple) bonds. Propan-1-ol (The OH group at CH3CH2CH2OH Propan-2-ol (The OH group atC1) C2) OH CH3—CH—CH3 CH3CH2C CH CH3 C C CH3 But-1-yne But-2-yne(Triple bond at C1) (Triple bond at C2) 1234 4 3 2 1
  • 7.  These have same molecular formula but different functional groups. CH3CH2OH CH3 O CH3 Ethanol Dimethyl ether CH3 C OH O Ethanoic acid O H C OCH3 Methyl methanoate Propanal (Propionaldehyde) CH3CH2 C H O Propanone (Acetone) O CH3 C CH3 and
  • 8.  These have different number of carbon atoms (or alkyl groups) on either side of a bifunctional group (i.e., -O- , -S-, -NH-, -CO- etc.). Metamerism is shown by members of the same family, i.e., same functional groups. CH3CH2CH2—O—CH3CH3CH2—O—CH2CH3 or Ethoxy ethane (Diethyl ether) 1-Methoxy propane (Methyl n-propyl ether) 2-Methoxypropane (Isopropyl methyl ether) is a metamer of CH3 CH3CH2CH—O—CH3 is a metamer of or Pentan-3-one (Diethyl ketone) Pentan-2-one (Methyl n-propyl ketone) 3-Methylbutan-2-one (Isopropyl methyl ketone) CH3CH2—C—CH2CH3 CH3CH2CH2—C—CH3 OO CH3—C—CHCH3 O CH3
  • 9.  Structural or constitutional isomers existing in easy and rapid equilibrium by migration of an atom or group are tautomers (keto-enol tautomerism). Vinyl alcohol (enol form) (Negligible amount) CH2 C—H OH Acetaldehyde (keto form) O CH3—C—H Prop-1-ene-2-ol (enol form) (Negligible amount) CH2 C—CH3 OH Acetone (keto form) O CH3—C—CH3
  • 10.  Open chain and cyclic compounds having the same molecular formula are called ring - chain isomers CH3CH CH2 Propene and Cyclopropane Cyclopropene and Propyne CH3 C CH
  • 11.  Isomers which have the same molecular formula and same structural formula but differ in the manner their atoms or groups are arranged in the space are called stereoisomers. It is of two types: I. Configurational Isomerism II. Conformational Isomerism
  • 12.  The stereoisomers which cannot be interconverted unless a covalent bond is broken are called configurational isomers. These isomers can be separated under normal conditions.  The configurational isomerism is again of two types: a) Optical Isomerism or Enantiomerism b) Geometrical Isomerism
  • 13.  The stereoisomers which are related to each other as an object and its non- superimposable mirror image are called optical isomers or enantiomers (Greek: enantion means opposite).  The optical isomers can also rotate the plane of polarised light to an equal degree but in opposite direction.  The property of rotating plane of polarised light is known as optical activity.  The optical isomers have similar physical and chemical properties.
  • 14.  Molecular formula C3H6O3 represents two enantiomeric lactic acids as shown below: H CH3 HO COOH ( +) - Lactic acid (Rotates the plane of polarized light towards right hand side i.e. clockwise) COOH OH CH3 H ( -) - Lactic acid (Rotates the plane of polarized light towards left hand side i.e. anticlockwise) Mirror
  • 15.  Geometric isomers are the stereoisomers which differ in their spatial geometry due to restricted rotation across a double bond.  These isomers are also called as cis- trans isomers. For example, molecular formula C2H2Cl2 corresponds to two geometric isomers as follows: C C H ClCl H H Cl Cl H CC cis-1,2-Dichloroethene trans-1,2-Dichloroethene
  • 16.  The stereoisomers which can be interconverted rapidly at room temperature without breaking a covalent bond are called conformational isomers or conformers.  Because such isomers can be readily interconverted, they cannot be separated under normal conditions.  Two types of conformational isomers are: a) Conformational isomers resulting from rotation about single bond b) Conformational isomers arising from amine inversion
  • 17.  Because the single bond in a molecule rotates continuously, the compounds containing single bonds have many interconvertible conformational isomers.e.g, 'boat' and 'chair' forms of cyclohexane. H H H H H H H H H H H H Cyclohexane (Chair form) Cyclohexane (Boat form) H H H H H HH H H H H H
  • 18.  Nitrogen atom of amines has a pair of non-bonding electrons which allow the molecule to turn "inside out" rapidly at room temperature. This is called amine inversion or Walden inversion. Transition state R3 N R2 R1 R1 R2 N R3 R1 R2 N R3
  • 19.  Light passes through a plane polarizer  Plane polarized light is rotated in solutions of optically active compounds  Measured with polarimeter  Rotation, in degrees, is [α]  Clockwise rotation is called dextrorotatory  Anti-clockwise is levorotatory 1919
  • 20.  A polarimeter measures the rotation of plane- polarized that has passed through a solution  The source passes through a polarizer and then is detected at a second polarizer  The angle between the entrance and exit planes is the optical rotation. 2020
  • 21.  To have a basis for comparison, define specific rotation, [α]D for an optically active compound  [α]D = observed rotation (pathlength x concentration) = α = degrees  Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nm) 2121
  • 22.  Enantiomers are known to possess same physical and chemical properties but they differ in the way they interact with plane polarised light.  Substances which can rotate the plane of polarised light are said to be optically active.  Dextrorotatory (Latin: dextre means right) and is indicated by (+) sign.  Laevorotatory (Latin: laeves mean left) and is indicated by (-) sign.  Those substance which do not rotate the plane of polarised light are called optically inactive.
  • 23.  Angle of rotation (α) is the angle (degrees) by which the analyser is rotated to get maximum intensity of light. It depends upon:  (i) Nature of the substance;  (ii) Concentration of the solution in g/ml;  (iii) Length of the polarimeter tube;  (iv) λ of the incident monochromatic light (598nm).  (v) Temperature of the sample.
  • 24. Discrimination of Enantiomers byDiscrimination of Enantiomers by Biological MoleculesBiological Molecules Discrimination of Enantiomers byDiscrimination of Enantiomers by Biological MoleculesBiological Molecules
  • 25.  An object which cannot be superimposed on its mirror-image is said to be chrial (ky - ral) [Greek : Cheir 'Handedness'] and the property of non- superimposability is called chirality. Thus our hands are chiral.  Similarly, alphabets R,F,J are chiral and A, M, O are achiral.  
  • 26. A A MM O O (Achiral objects) R R J J F F Chiral objects Chiral objects -Chiral objects - human hand, gloves, shoes, etc. Achiral objects - a sphere, a cube, a button, socks without thumb, etc. Chirality or molecular dissymmetry is the necessary and sufficient condition for a molecule to be optically active.
  • 27. • The cis isomer is achiral. • The trans isomer is chiral. • Enantiomers: nonsuperimposable mirror images, different molecules. • One enantiomeric form of limonene smells like oranges, while its mirror image smells like lemons. • The one enantiomer of carvone is the essence of caraway, and the other, the essence of spearmint. • Most molecules in the plant and animal world are chiral and usually only one form of then enantiomer is found. • Nineteen of the twenty known amino acids are chiral, and all of them are classified as left handed. chapter 6chapter 6
  • 28. A 50:50 mixture of two chiral or enantiomers compounds that are mirror images does not rotate light – called a racemic mixture (named for “racemic acid” that was the double salt of (+) and (-) tartaric acid  The pure compounds need to be separated or resolved from the mixture (called a racemate)  To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent)  This gives diastereomers that are separated by their differing solubility The resolving agent is then removed
  • 29. 1. Physical methods: - Spontaneous resolution - Inclusion compounds - Chromatography 1. Chemical methods: - Diastereomeric salt formation 3. Biochemical methods: - Enzymatic decomposition
  • 30. Usual methods of separation such as fractional distillation, fractional crystallization or adsorption techniques cannot be used for the separation of enantiomers. Therefore, some special procedures are needed for resolution of racemic mixtures. Some of the more important methods are: 1 Preferential Crystallization 2 Biochemical Method 3 Resolution through the formation of diastereomers: The Chemical Method Chromatographic Method
  • 31.  Fractional crystallization is closely related to mechanical separation of crystals.  A supersaturated solution of the racemic mixture is inoculated with a crystal of one of the enantiomers or an isomorphous crystal of another chiral compound. For example, when the saturated solution of (±) sodium ammonium tartarate is seeded with the crystal of one of the pure enantiomer or a crystal of (–) asparagine, (–) sodium ammonium tartarate crystalises out first.  This method is also called as entrainment
  • 32.  Microorganisms or enzymes are highly stereoselective.  Fermentation of (±) tartaric acid in presence of yeast or a mold, e.g., Pencillium glaucum. The (+) tartaric acid is completely consumed leaving behind (–) tartaric acid.  (±) Amino acids can be separated using hog- kidney acylase until half of acetyl groups are hydrolysed away, only acetyl derivative of L- amino acid is hydrolysed leaving behind acetyl derivative of D-amino acid. Limitations: (i) These reactions are to be carried out in dilute solutions, so isolation of products becomes difficult. (ii)There is loss of one enantiomer which is consumed by the microorganism. Hence only half of the
  • 33. Basic Principle Step 1. A racemic mixture (±)-A reacts with an optically pure reagent (+) or (–)-B to give a mixture of two products which are diastereomers. The reagent (+) or (–)-B is called the resolving agent. (±) - A + (+)-B → (+)A(+)B + (-)A(+)B Step 2. The mixture of diastereomers obtained above can be separated using the methods of fractional distillation, fractional crystallization, etc. Step 3. The pure diastereomers are then decomposed each into the corresponding enantiomer and the original optically active reagent, which are then separated.
  • 34. (±) - Tartaric acid + (−)-Cinchonidine (Racemic modification) (Resolving agent) (+) - Tartaric acid - (−) - cinchonidine + (−) - Tartaric acid - (−) - cinchonidine Diastereomers (separable) (+) - Tartaric acid - (−) - cinchonidine (−) - Tartaric acid - (−) - cinchonidine Dil. (+) - Tartaric acid (crystallizes out) (−) - Tartaric acid (crystallizes out) Separated by crystallization H2SO4 H2SO4Dil. (+) - base (−) - base + (+) - acid (+) - (+) - salt (+) - base HO (−) - (+) - salt (−) - base Racemic modification Diastereomers (separable) HO Similarly resolution of a (±) base with an optically active acid.Similarly resolution of a (±) base with an optically active acid.
  • 35. The chemical method of resolution is widely used and has the advantage that both the enantiomers are obtained. This method will be successful if the following conditions are fulfilled: (i) The resolving agent should be optically pure. (ii) The substrate (racemic mixture) and the resolving agent should have suitable functional groups for reaction to occur. (iii) The resolving agent should be cheap and be capable of regeneration and recycling. (iv) The resolving agent should be such which produces easily crystallizable diastereomeric products.
  • 36.  The rates of movement of the two enantiomers through the column should be different (due to difference in the extent of adsorption). They should thus be separable by elution with suitable solvent.  This method has an advantage over chemical separation as the enantiomers need not be converted into diastereomers.  The techniques used include paper, column, thin layer, gas and liquid chromatography.
  • 37. Stereoisomers - Compounds that have the same molecular formula and the same connectivity, but different arrangement of the atoms in 3-dimensional space. Stereoisomers cannot be converted into each other without breaking bonds. Stereoisomers can be subdivided into two general categories: enantiomers and diastereomers. Enantiomers are Stereoisomers whose molecules are non super imposable mirror images of each other. Diastereomers - Stereoisomers which are not enantiomers (or mirror images). Chiral or asymmetric carbon - A tetrahedral carbon atom bearing four different substituents. Chirality centers, or stereocenters - Asymmetrically substituted atoms in a molecular structure. The most common type encountered in this course will be the chiral carbon described above.
  • 38.  Meso compounds, or meso forms - Symmetric, or achiral molecules that contain stereocenters. Meso compounds and their mirror images are not stereoisomers, since they are identical.  Optical activity - The ability of chiral substances to rotate the plane of polarized light by a specific angle.  Dextrorotatory - Ability of chiral substances to rotate the plane of polarized light to the right.  Levorotatory - Ability of chiral substances to rotate the plane of polarized light to the left.  Specific rotation - The measured angle of rotation of polarized light by a pure chiral sample under specified standard conditions (refer to textbook for a description of these).  Racemic mixture, racemic modification, or racemate - A mixture consisting of equal amounts of enantiomers. A racemic mixture exhibits no optical activity because the activities of the individual enantiomers are equal and opposite in value, therby canceling each other out.
  • 39.  Optical purity - The difference in percent between two enantiomers present in a mixture in unequal amounts. For example, if a mixture contains 75% of one enantiomer and 25% of the other, the optical purity is 75-25 = 50%.  Absolute configuration - A description of the precise 3- dimensional topography of the molecule.  Relative configuration - A description of the 3-dimensional topography of the molecule relative to an arbitrary standard. Absolute and relative configurations may or may not coincide.
  • 40.  Enatiomerism depends on whether a molecule in not superimposable on its mirror image. If it is superimposable, the molecule is optically inactive otherwise is optically active. The most convenient method of inspecting superimposability is to determine whether the molecule has any of the following four elements of symmetry: 1. Plane of symmetry (s) 2. Centre of symmetry (i) 3. Simple or proper axis of symmetry (Cn)
  • 41.  A plane of symmetry is defined as an imaginary plane which divides a molecule in such a way that one half is mirror image of the other half.  A molecule with atleast a plane of symmetry can be superimposed on its mirror image and is achiral. A molecule that does not have a plane of symmetry is usually chiral; it cannot be superimposed upon its mirror image. •A plan of symmetry may pass through atoms, between atoms or both. H COOH COOH OH OHH Plane of symmetry meso-Tartaric acid
  • 42. 4242  There is no mirror plane for a hand  The plane has the same thing on both sides for the flask
  • 43.  A molecule that has a plane of symmetry is achiral.
  • 44.  Cis-1,2-dichlorocyclohexane is achiral because the molecule has an internal plane of symmetry. Both structures above can be superimposed (they are identical to their mirror images).
  • 45.  Trans-1,2-dichlorocyclohexane does not have a plane of symmetry so the images are nonsuperimposable and the molecule will have two enantiomers.
  • 46.  The center of symmetry i is a point in space such that if a line is drawn from any part (atom) of the molecule to that point and extended an equal distance beyond it, an analogous part (atom) will be encountered. In other words it is a point at which all the straight lines joining identical points in the molecule cross each other. HH H H COOH COOH CH3 CH3 Centre of symmetry 2,4-Dimethylcyclobutane -1,3-dicarboxylic acid has Ci
  • 48.  Symmetry axis Cn, also called n-fold axis, is an axis which rotates the object (molecule) around by 360°/n, such that the new position of an object is superimposable with the original one.  For example, cis-1,3-dimethylcyclobutane has a two fold axis of symmetry (C2) i.e. rotation by 180o gives indistinguishable appearance. H H HH CH3 H3C C2-Axis of Symmetry H3C CH3 H H H H HH Rotation by 180o HH
  • 49.  Rotary reflection axis is an axis which rotates the object (molecule) around by 360°/n, followed by rotation in a plane perpendicular to the axis, such that the new position of an object is superimposable with the original one. 4. Alternating or improper axis of symmetry (Sn)
  • 50. Rotation by 90o Reflaction through mirror plane perpendicular to axis of rotation 43 (a) H3C H 2 CH3 H H H H CH3 CH3 1 23 4 B A CH3 H H H CH3 CH3 (a) 3 4 2 1 H H3C H CH3H 1 CH3 (b) H CH3 H3C 1,2,3,4-Tetramethyl- cyclobutane has S4
  • 51. 5151  A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule
  • 52.  When replacement of one hydrogen atom at a time gives an enantiomer, such a hydrogen atom is called enantiotopic hydrogen. That enantiotopic hydrogen, the replacement of which gives R-configuration is called pro-R and the other which give S-configuration is called pro-S  The carbon atom to which the two hydrogen atoms are attached is called prochirality centre and the moelcule is called prochiral molecule. CHS HR OH CH3 CH3 OH H D D H OH CH3 or Replacement of HR or HS by D Ethanol (R-isomer) (S-isomer) Prochiral centre Pro-S Pro-R
  • 53.  Absolute configuration denotes the actual arrangement of atoms or groups of atoms in the space of a particular stereoisomer of a compound. Absolute configuration can be ascertained by x-ray studies of the crystals of pure compound.  Relative configuration denotes the arrangement of atoms or groups of atoms in the space of a particular stereoisomer relative to the atoms or groups of atoms of another compound chosen as arbitrary standard for comparison.
  • 54. Relative configurationRelative configuration compares thecompares the arrangement of atoms in space of onearrangement of atoms in space of one compound with those of another.compound with those of another. UUntill thentill the 1950s, all configurations were relative.1950s, all configurations were relative. Absolute configurationAbsolute configuration is the preciseis the precise arrangement of atoms in space.arrangement of atoms in space. WWe can nowe can now determine the absolute configuration of almostdetermine the absolute configuration of almost any compound.any compound.
  • 55.  Rosanoff (1906) was the first scientist, who tried to give names to the different optically active configurational forms of the molecule. He arbitrarily chose Glyceraldehyde for naming the enantiomeric forms. Rosanoff represented the glyceraldehyde molecule in a specific manner, following the convention set up by Fischer (1809) for the structural representation of a carbohydrate molecule. According to the convention established by Fischer, the carbon chain was represented on the vertical line drawn on a plane piece of paper. The groups attached to the carbon chain were represented on the horizontal line. The carbonyl group belonging to the carbohydrate was placed at the top of the vertical line. Glyceraldehyde molecule was considered as the first member of the carbohydrate series and Rosanoff represented the Glyceraldehyde molecule like any other carbohydrate.
  • 56. Structure V deflected the plane of the plane polarized light to the right i.e. showed dextrorotation and was assigned ‘D’ as the name of its configurational form; Structure VI deflected the light towards the left i.e. showed leoveorotaiton and was assigned ‘L’ as the name to its configurational form.
  • 57.  The configuration (A) was arbitrarily assigned to designate the configuration of (+)-glyceraldehyde. Taking this as standard, the relative configuration of (–) lactic acid was assigned as shown below: H OH CH2Br COOH P/Br2 H OH CH2OH COOH Bromine water [O] H OH CH2OH CHO H OH CH3 COOH (+)-Glyceraldehyde (−)-Glyceric acid 1-Bromo-2- hydroxypropanoic acid (Arbitrarily assigned that OH group is on right hand and H on left hand side) (−)-Lactic acid Redn. (A)
  • 58. Two commonly used conventions are: 1. D-L System 2. R-S System 1. D-L System: This is one of the oldest and the most commonly used system for assigning configuration to a given enantiomer. It is based upon the comparison of the projection formula of one enantiomer to which the name is to be assigned, with that of a standard substance arbitrarily chosen for comparison.
  • 59.  To overcome the problem of D-L system, R.S. Cahn (England), Sir Christopher Ingold (England), and V. Prelog (Zürich) evolved a new and unambiguous system for assigning absolute configuration to chiral molecules. This system is named as CIP (Cahn, Ingold, Prelog) system after their names. It is called as R-S system as the prefixes R-and S-are used to designate the configuration at a particular chirality centre. A racemic mixture is named as (RS). This system is based on certain rules called as sequence rules and also as CIP rules.
  • 60.  Cahn, Ingold and Prelog helped in introducing a new system for assigning the configurational form to the molecule. The system replaced the DL system. This system, adopted by IUPAC, is called the RS convention or the sequence rule system.  In the sequence rule system, the four atoms or groups directly attached to the asymmetric carbon atom, are to be ranked and to be placed in a priority order. Use of the following rules was made to decide the priority order of the groups attached to the asymmetric carbon atom.
  • 61. 6161  Priority rules (Cahn, Ingold, Prelog) ◦ Each atom bonded to the stereocenter is assigned a priority, based on atomic number. The higher the atomic number, the higher the priority. ◦ Of the four atoms directly attached to the asymmetric carbon atom, the atom with the highest atomic number was given the highest priority and the atom with the lowest atomic number the lowest priority. Increasing Priority H CH3 NH2 OH SH Cl Br I 1 6 7 8 16 17 35 53
  • 62. 6262 ◦ If priority cannot be assigned on the basis of the atoms bonded to the stereocenter, look to the next set of atoms. Priority is assigned at the first point of difference. CH2 H CH2 CH3 CH2 NH2 CH2 OH 1 6 7 8 Increasing Priority
  • 63. 2. In case, the molecule has more than one group, having the same atom through which the groups are attached to the asymmetric carbon atom, then to decide the priority order between the groups the next atoms attached to the first atom are taken into consideration. For example in 2- butanol, CH3CHOHC2H5, the four different groups attached are –CH3, -C2H5, -OH and H. The highest priority group would be –OH and the lowest priority group would be H. As both the groups –CH3 and –C2 H5 , are attached to the asymmetric carbon atom through carbon therefore to decide the priority between these two the next atoms attached in the groups are to be taken into consideration. In –CH3 the next atoms are hydrogen whereas in –C2H5 the next atoms are one carbon and two hydrogens; therefore the priority goes to the ethyl group.
  • 64. 6464 ◦ Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds C H O C H O O C
  • 65. 6565 1. Locate the stereocenter 2. Assign a priority to each substituent from 1 (highest) to 4 (lowest) 3. Orient the molecule so that the group of lowest priority (4) is directed away from you 4. Read the three groups projecting toward you in order from highest (1) to lowest priority (3) 5. If reading is clockwise, configuration is R (from the Latin rectus). If it is counterclockwise, configuration is S (from the Latin sinister).
  • 66. 6666 2clockwise counter clockwise (rectus) (sinister) view with substituent of lowest priority in back 1 2 4 3 C C 1 4 3 R S
  • 68. 6868 1. -OH 2. -COOH 3. -CH3 4. -H (R)-(-)-lactic acid C H HO COOH CH3 C H CH3 HOOC OH (S)-(+)-lactic acid
  • 69. Lowest priority 4 on vertical line 1 4 2 3F Br Cl H F Cl Br H 4 1 3 2 CHO OHH CH2OH3 1 2 4 Lowest priority 4 on horizontal line 4 3 1 2 CH2CH3 H OH CH3 R-configurationR-configuration S-configurationS-configuration R-configurationR-configuration R-configurationR-configuration S-configurationS-configuration 4 2 13 H3C H OH COOH
  • 70. CHO HHO CH2OH HO H H OH CH2OH HO H CHO CHO HHO CH2OH OHH L-Erythrose (2S, 3S) D-Threose (2S, 3R) L-Threose (2R, 3S)
  • 71.  Geometric or cis-trans or E-Z isomers.  This type of isomerism arises if there is no free rotation about the double bond.  Due to different arrangement of atoms or groups in the space, geometric isomerism is designated as stereoisomerism.  The geometric isomers belong to the category of configurational isomers because they cannot be interconverted without breaking two covalent bonds.  Further, geometric isomers are examples of diastereomers because they are not mirror images of each other.
  • 72. Geometric isomerism is not confined only to theGeometric isomerism is not confined only to the compounds having carbon-carbon doublecompounds having carbon-carbon double bonds. In fact the following compounds exhibitbonds. In fact the following compounds exhibit this type of isomerism:this type of isomerism: i) Compounds having a double bond, i. e., olefins (C=C), imines (C=N) and azo compounds (N=N). ii) Cyclic compounds. iii) Compounds exhibiting geometric isomerism due to restricted rotation about carbon- carbon single bond.
  • 73.  Configuration of a chiral molecule is three dimensional structure and it is not very easy to depict it on a paper having only two dimensions. To overcome this problem the following four two dimensional structures known as projections have been evolved.  1. Fischer Projection  2. Newman Projection  3. Sawhorse Formula  4. Flying Wedge Formula
  • 74.  Characteristic features of Fischer projection: Rotation of a Fischer projection by an angle of 1800 about the axis which is perpendicular to the plane of the paper gives identical structure. However, similar rotation by an angle of 900 produces non - identical structure. or (I) CH2OH OH COOH H C Towards the veiwer Away from the veiwer (I) OHH CH2OH COOH
  • 75. Since structures I and II are indistinguishable, the moleculeSince structures I and II are indistinguishable, the molecule has Chas C2 axis of symmetry. But it is non-superimposable on its mirror image so it is dissymmetric and not asymmetric and exhibits optical activity. Br H Br CH3 CH3 H H CH3 CH3 Br HBr I II Rotation by 180o III H Br H CH3 CH3 Br All asymmetric molecules are dissymmetric but allAll asymmetric molecules are dissymmetric but all dissymmetric molecules are not asymmetric.dissymmetric molecules are not asymmetric. However,However, bothboth these types of molecules show optical activity andthese types of molecules show optical activity and are chiral. Hence, to avoid any confusion, in using these terms, - asymmetry or dissymmetry - the term chirality is used.
  • 76.  Fischer projections give the impression that the molecule exists in the eclipsed form. Actually it exists in the staggered form in which the bulky substituents are as far apart as possible.  Therefore, an erythro isomer corresponds to that diastereomer, which when viewed along the bond connecting the chiral carbons has a rotational isomer in which all similar groups are eclipsed. The threo diastereomers, on the other hand, does not have an isomer in which all similar groups are H H CH2OH CHO OH HO (+)-Threose H H CH2OH CHO OH OH (−)-Erythrose CHO CH2OH HO HO H H (+)-Erythrose HO CHO CH2OH H H OH (−)-Threose
  • 77.  The isomers having two similar chirality centres such as III are optically inactive due to presence of a plane of symmetry and are termed meso compounds (internal compensation). Hence, meso compounds are optically inactive compounds whose molecule Pair of enantiomers Mirror IV HO H HO COOH COOH HH COOH COOH OH OHH IIII HHO OH COOH COOH H OH COOH COOH H IIMirror HO H Meso- tartaric acid
  • 78.  Carbon atoms involved in double bond formation and all the atoms attached to these doubly bonded carbon atoms must lie in the same plane because π-bond can be formed only by parrallel overlap of the two p-orbitals. There will be decrease in the overlap of p-orbitals if an attempt is made to destroy this coplanarity. In other words, neither of the doubly bonded carbon atom can be rotated about the double bond without destroying the π-orbital. Rotation about a C = C bond. Overlap of π-orbitals not possible as they are perpendicular to each other. Rotation by 90o
  • 79. This process of rotation which is really a transfer of electrons from the π-molecular orbital to the p- atomic orbital is associated with high energy (271.7 kJ mol-1 ). Thus at ordinary temperatures, rotation about a double bond is prevented and hence compounds such as CH3CH =CHCH3 exist as isolable and stable geometrical isomers. H C C H H3C CH3 CC Cis-But-2-ene Trans-But-2-ene H3C CH3H H Cis-Cinnamic acid Trans-Cinnamic acid HH C C H COOH CC COOH HH5C6 H5C6
  • 80.  Geometrical isomerism will not be possible if one of the unsaturated carbon atoms is bonded to two identical groups.  No two stereoisomers are possible for CH3HC=CH2, (CH3)2C=CH2 and Cl2C=CHCl.  Examples of compounds existing in two stereo- isomeric forms are: H CH3 Trans-Pent-2-eneCis-Pent-2-ene C C CH3 H CC H H3C H2C H3C H2C H HH C C H COOH CC Cis-Cinnamic acid Trans-Cinnamic acid COOH HH5C6 H5C6
  • 81. I. Physical methods (a) Melting points and boiling points: Trans isomer has a higher m. p. due to symmetrical packing. Cis isomer has a higher b. p. due to higher dipole moment which cause stronger attractive forces. H3C H CH3 b.p. 274K C C H HOOC CC m.p. 575K H COOHH H3C b.p. 277K CH3 H CC H H C C H COOH m.p. 403K HOOC
  • 82. (c) Dipole moment : In general, cis isomers have the greater dipole moment. HH C C H CH3 CC µ = 0.4 D µ = 0 CH3 HH3C H3C ClCl H Cl µ = 0 µ = 1.85 D C C Cl H CC H H
  • 83.  IR: Trans isomer is readily identified by the appearance of a characteristic band near 970- 960 cm-1 . No such band is observed in the spectrum of the cis isomer.  NMR: The protons in the two isomers have different coupling constants e.g. trans – vinyl protons have a larger value of the coupling constant than the cis-isomer, e.g. cis- and trans- cinnamic acids. C6H5 cis-Cinnamic acid (JH,H = 12Hz) CC HH CO2H CO2HH H C C trans-Cinnamic acid (JH,H = 16Hz) C6H5
  • 84. a) Methods of formation from cyclic compounds: Oxidation of benzene or quinone gives maleic acid (m. p. 403K). From the structure of benzene or quinone, it becomes clear that the two carboxyl groups must be on the same side (cis).  Therefore, maleic acid i.e. the isomer having m. p. 403K, must be cis and the other isomer fumaric acid (m. p. 575K) must be trans. or CO2H CO2H H H m.p. 403 KO O [O]
  • 85.  Cis isomer will undergo ring closure much more readily than the trans isomer. C C CO2H CO2H H H H H CO CO C C O H H HO2C CO2H C C 573K423K -H2O -H2O Maleic acid Maleic anhydride Fumaric acid H H CO2H CO2H C C Maleic acid Hydrolysis
  • 86.  Suppose configuration of a geometric isomer, say A is known. Let A be converted under mild conditions to a geometric isomer A', of another compound. Since under mild conditions interconversion of the geometric isomers will not take place, therfore, the configuration of A' will be the same as that of A. A’A’AA NH2 CO2 Ba/2 H CC H Cis isomer of 1. HNO2 2. H3PO2 H C C H CO2H Cis, m.p. 341K Allocinnamic acid Cinnamic acid Trans, m.p. 406K 1. HNO2 2. H3PO2 Trans isomer of H C C H CO2 Ba/2 NH2 H C C H CO2H ortho-aminocinnamic acid salt ortho-aminocinnamic acid salt
  • 87. (i) Hydroxylation of double bond is stereospecifically cis. Maleic acid or Os O4 aq. KMnO4 H H COOH COOH C C H H COOH COOH OH OH meso-Tartaric acid (+) - Tartaric acid (50%) H OH COOH COOH HO H C C COOH HOOC H H aq. KMnO4 or Os O4 Fumaric acid COOH COOH OH H (−) - Tartaric acid (50%) HO H Racemic mixture +
  • 88.  In contrast to hydroxylation, addition of bromine to alkenes is stereospecifically trans. Therefore, addition of bromine to trans-isomer will give rise to meso and to cis-isomer gives racemic mixture. + Racemic mixture H H CH3 CH3Cis-But-2-ene Br2 / CCl4 H H3C H C C H CH3 CH3 H H3C Br Br Br Br Br Br H H CH3 CH3 H C C HH3C CH3 Br2 / CCl4 Meso-2,3-Dibromobutane Trans-But-2-ene
  • 89.  Consider a molecule in which the two carbon atoms of a double bond are attached with four different halogens.  When we say that Br and CI are trans to each other we can also say with equal degree of confidence that I and CI are cis to each other. It is thus difficult to name such a substance either the cis or the trans isomer. To eliminate this confusion, a more general and easy system for designating configuration about a double bond has been adopted. This method, which is called the E and Z system, is based on a priority system originally developed by Cahn, Ingold and Prelog for use with optically active substance F I Br CC Cl
  • 90. CC 1 2 2 1 2 1 2 1 C C E Z Z-But-2-ene-1,4-dioic acid (Maleic acid) E-But-2-ene-1,4-dioic acid (Fumaric acid) C C COOH HHOOC HHOOC H H COOH CC 2 1 2 1 1 2 2 1 C C F ClI Br 1 2 1 2 2 12 1 Br I Cl F CC Z-1-Bromo-2-chloro- 2-fluoro-1-iodoethene E-1-Bromo-2-chloro- 2-fluoro-1-iodoethene Z-2-Butene 2 1 2 1 H3C H H CH3 CC C C CH3 H H H3C1 2 1 2 E-2-Butene
  • 91.  Dienes in which the two termini are different (i.e. XHC=CH–CH=CHY), has four geometrical isomers . C C H H Y C C H H X C C Y H H C C H H X C C X H H H HY C C Z,E, or cis-trans Z,Z, or cis-cis E,E or trans-trans C C H Y H H H X C C E,Z or trans-cis It means the number of geometrical isomers is 2n where n is the number of double bonds.
  • 92.  The carbon and nitrogen atoms of oximes are sp2-hybridized, as in alkenes.  Thus, all groups in oximes lie in the same plane and hence they should also exhibit geometric isomerism if groups R and R1 are different. Accordingly Beckmann (1889) observed that benzaldoxime existed in two isomeric forms and Hantzsh and Werner (1890) suggested that these oximes exist as the following two geometric isomers (I and II). OH N C H5C6 H HH5C6 C N HO I II I II HO N C H5C6 HHH5C6 C N OH or
  • 93.  The prefixes syn and anti are used in different context for aldoximes and ketoximes.  Aldoximes  Ketoximes H H5C6 C N OH anti-Benzaldoxime II OH NC H5C6 H syn-Benzaldoxime I syn-Ethylmethylketoxime OH NC H5C2 H3C anti-Ethylmethylketoxime H3C H5C2 C N OH
  • 95.  a) Aldoximes: The acetyl derivative of one isomer regenerated the original oxime whereas that of the other isomer eliminated acetic acid by E2 mechanism to form aryl cyanide. N C HAr C N OH H E or syn - Oxime Ac2O Ar OAc OH Ar Aq. Na2CO3 H C N (Hydrolysis) Elimination N CAq. Na2CO3 Ar Ac2O Z or anti -Oxime H N C Ar H C N HO AcO | + Acetic acid Ar Original oxime Aryl cyanide
  • 96.  The configuration of the geometric isomers of the unsymmetrical ketoximes are determined by Beckmann rearrangement which consists in treating ketoxime with acidic reagents such as PCI5, H3PO4, P2O5, etc. when the oxime isomerizes to a substituted amide by migration of the group (R1 or R2 ) which is anti to the hydroxyl group.R1 C R2 N R2 CO NHR1 R2COOH + R1NH2 OH Determination of structure of amine formed in the aboveDetermination of structure of amine formed in the above sequence of reactions plays a key role in deciding whichsequence of reactions plays a key role in deciding which group has migrated during Beckmann rearrangement.group has migrated during Beckmann rearrangement.
  • 97.  Cyclic compounds such as the disubstituted derivatives of cyclopropane, cyclobutane, cyclopentane and cyclohexane can also show cis-trans isomerism, because the basic condition for such isomerism- that there should be sufficient hindrance to rotation about a linkage between atoms- is also satisfied in these systems. Atoms joined in a ring are not free to rotate around the sigma bond. Above the planeAway from us Towards us Below the plane CH3 Vertical line CH3 1,2-Dimethylcyclohexane
  • 98. Sometimes, a broken wedge is used to indicate a group below the plane of the ring, and a solid line represent a group above the plane. CH3 CH3 Below the plane Above the plane
  • 99.  A carbon – carbon σ-bond is formed by an end- on overlapping of sp3-orbitals of the two carbon atoms.  This bond is cylindrically symmetrical about the axis and has the highest electron density along the bond axis.  Almost an infinite number of spatial arrangements of atoms about the cabon-cabon single bond exist. All those arrangements which result from free rotation about a single bond are called conformations or conformers or rotational isomers or simply rotamers. bond axis A cylindrically symmetric MO of a single bond obtained by sp3-sp3 overlap of two carbon atoms.
  • 100.  Pitzer (1936) postulated that there exists a potential energy barrier which causes restriction in rotation.  The extra energy of eclipsed conformation is called torsional strain. The term torsional strain is used for the repulsion felt by bonding electrons on one substituent when it passes close to the bonding electrons of another substituent. I II H H H H H H Eclipsed conformation Staggered conformation HH H H H H
  • 102. I I I II II II 0 60 120 180 240 300 360 5 10 15 Torsion angle (degrees) I at 0o, 120o and 240o II at 60o, 180o and 300o Fig. 3.7 Rotational or torsional energy in ethane Eclipsed conformation Staggered conformation I RelativeEnergy,kJmol-1
  • 103. CH3 CH3 H H H H Fully Eclipsed (θ = 0o) θ H CH3 H CH3 H H Gauche (θ = 0o) Partially Eclipsed (θ = 120o) HH3C H H CH3 H Anti or Trans (θ = 180o) H H CH3 H CH3 H H CH3 H H H3C H Partially Eclipsed (θ = 240o) Gauche (θ = 300o) H H H3C H CH3 H I II III IV V VI Due to congestion in space a repulsive force acts between the methyl groups which is called van der Waals strain or steric hindrance. In butane, gauche conformation is less stable than anti-conformation due to vander Waals strains i.e. n-butane gauche (or skew) intraction.
  • 104. I I = Fully Eclipsed III and V = Partially Eclipsed II and VI = Gauche IV = Anti-conformation Torsion angle (degrees) 15 10 5 0 60 120 180 240 300 360 VI IV II V III I 20 25 4.0 16 Fig. 3.8 Rotational or torsional energy in n-butane RelativeEnergy,kJmol-1 At room temperature, almost all molecules exist in staggered conformation and amongst staggered conformations 78% exist in anti and 22% in gauche conformations.
  • 105.  On the basis of torsional strain and vander Waals steric hindrance, staggered (anti) conformation of 1,2-dibromoethane is the most stable followed by gauche.  Dipole moment of anti-conformation is zero while gauche conformation has some finite dipole moment since the two C—Br dipoles are at an angle of 600 to each other.  Actual dipole moment of 1,2-dibromoethane is 1.0D, therefore, the molecule cannot exist entirely in the Fully Eclipsed HH H H Br Br Partially Eclipsed HH H Br H Br H H H Gauche Anti H Br Br H Br H H H Br Anti Gauche
  • 106.  In case of ethylene glycol due to intramolecular H- bonding the gauche form becomes more stable than anti-conformation because there will be no such H- bonding possible in anti-conformation. The formation of such H-bond stabilizes the molecule by approximately 20-30 kJ mol-1.  Similarly due to intramolecular H- bonding ethylene chlorohydrin, (CH2Cl — CH2OH), exists in gauche conformation which is more stable than anti-form. H H OH H H H OH H O O H Gauche Anti H H HHO H OH H H H Partially Eclipsed OH OH H H H H Fully Eclipsed
  • 107.  Cyclohexane can have two conformations free from Baeyer or angle strain, called the chair form (I) and the boat form (II), respectively. I II Chair conformations of cyclohexane with axial and equatorial bonds H H H H H H ee e e e e H H H H H H a a a a a a
  • 108.
  • 109. H H H H (fp) H H HH H H H (fp) H 1 23 4 5 6 Boat Twist Boat Twist chair H H H Ha Hb H 4 1 2 6 3 5 H H H H Hb Ha 1 25 4 3 6 Boat Twist boat
  • 110. 22.6 30.6 41.9 EkJmol -1 a b d c Fig. 3.10 Potential energy of cyclohexane, a, chair; b, twist chair; c twist boat; d, boat.
  • 111.  In methylcyclohexane, the axial conformer will have two more n-butane skew interactions (7.54 kJ mol-1 ) whereas in the equatorial conformer no additional interaction or torsional strain is introduced since the two new n-butane segments in it are both fully staggered (anti).2 H CH3 3 6 5 1 4 H H H H H CH3 H H 1 3 5 6 The two new skew (gauche) interactions in the axial conformer are best demonstrated by drawing the Newman projection formula for the n-butane segment, CH3, C1, C2, C3 and CH3, C1, C6, C5.
  • 112. Newman projection for the equatorial conformer, as shown below, clearly shows the absence of any additional skew interaction. 6 5 3 1 H H CH3 H H H H H We reach the same conclusion if we consider that in the axial conformer the two axial hydrogens on C3 and C5 are closer to the axial than to the equatorial methyl group. H 1 H CH3 H 2 3 4 5 6 H CH3 H H Axial methyl Equatorial methyl
  • 113.  The interactions between the axial atoms or groups at 1- and 3- or 5-positions are called 1,3-diaxial interactions and in the case of 1,3- dimethylcyclohexane, the 1,3-diaxial interaction has been assigned the value of 22.6kJmol-1 . Thus cis 1,3-dimethylcyclohexane exists at room temperatures almost wholly in the diequatorial conformation.CH3 CH3 H H H H H3C CH3 cis 1,3-Dimethylcyclohexane (diaxial conformer; much less stable) cis 1,3-Dimethylcyclohexane (diequatorial conformer; much more stable)
  • 114. tert-Butylcyclohexane exists 100 per cent in the equatorial conformation (A), the ring being frozen due to the prevention of the flip to a conformation (B) in which the non-bonded 1,3-diaxial interactions between the axially bound tert-butyl group and the two axial hydrogens at the 3-and 5-positions will be forbiddingly large. H H H3C CH3 H B CH3 A H H H CH3 CH3 CH3
  • 115. It is clear from the above considerations that the axial bonds experience non-bonded interactions with other axial bonds at 3-and 5-positions whereas the equatorial bonds are free from such steric interactions, i.e. axially bound groups will experience more steric crowding than the equatorially bound groups. This explains why in most of the cases the equatorially bound groups in cyclohexane derivatives are more reactive than the axially bound ones. E.g. equatorially bound hydroxyl groups are more easily esterified than the axial ones. Similarly, the equatorial acetoxy group undergoes hydrolysis faster than the axial group.
  • 116.  Conformations is used for various spatial isomers which can be easily inter- converted.  Configurations is used for various spatial isomers which can be interconverted only by breaking and making of covalent bonds.  The energy difference between two conformers is very small due to which they can be interconverted by molecular collisions even at room temperature.  Conformational isomers cannot be separated. But conformational isomers can be separated easily.
  • 117. H H C6H5 C6H5 Cl Cl Cl Cl C6H5 C6H5 H H Cl Cl C6H5 H5C6 H H Rotate through 120o through 120o Rotate I II III through 120o Rotate through 120o Rotate Cl Cl C6H5 C6H5 H H H H C6H5 Cl Cl C6H5 H HH5C6 C6H5 Cl Cl IV V VI mesomeso-form (+ or(+ or -) form
  • 118. LiAIH4Ph C C Ph OO Benzil OH OH PhCCPh H H * * 1 2 1,2-Diphenylethane-1,2-diol AsAs 1,2-diphenylethane-1,2-diol has two similar asymmetric carbons (cf. tartaric acid) it exists as three steroisomers. Ph OH HHO H Ph Ph H HO H OH Ph Ph H OHH OH Ph I II III meso-formEnantiomers
  • 119. 1.1. Isomers -Isomers - Same molecular formula – differentSame molecular formula – different compounds.compounds. • Constitutional – Individual atoms are connected differentlyConstitutional – Individual atoms are connected differently • Stereoisomers – Same connectivity – different 3DStereoisomers – Same connectivity – different 3D arrangement.arrangement. • Mirror-Image Stereoisomers – Related as image – mirrorMirror-Image Stereoisomers – Related as image – mirror image.image. 2.2. Chiral Molecule -Chiral Molecule - Not superimposable on its mirrorNot superimposable on its mirror image.image. 3.3. Stereocenter –Stereocenter – Carbon atom bearing 4 differentCarbon atom bearing 4 different substituents.substituents. 4.4. Enantiomers –Enantiomers – Two stereoisomers, each a non-Two stereoisomers, each a non- superimposable mirror images of the other.superimposable mirror images of the other.
  • 120. 5.5. Racemate –Racemate – A one to one mixture of enantiomers.A one to one mixture of enantiomers. 6.6. Mirror Plane –Mirror Plane – Chiral molecules cannot contain aChiral molecules cannot contain a mirror plane.mirror plane. 7.7. Diastereomers –Diastereomers – Stereoisomers not related to eachStereoisomers not related to each other as mirror images (ie. cis/trans).other as mirror images (ie. cis/trans). 8.8. Two Stereocenters In A Molecule –Two Stereocenters In A Molecule – CreateCreate upup to 4 stereoisomers: 2 diastereomerically related pairsto 4 stereoisomers: 2 diastereomerically related pairs of enantiomers. If the 2 stereocenters generate aof enantiomers. If the 2 stereocenters generate a mirror plane in the molecule, the molecule is known asmirror plane in the molecule, the molecule is known as a meso compound and is achiral.a meso compound and is achiral. 9.9. Physical Properties of Stereoisomers –Physical Properties of Stereoisomers – MostMost are the same except for the rotation of plane polarizedare the same except for the rotation of plane polarized light. One enantiometer rotates the plane oflight. One enantiometer rotates the plane of polarization to the right, the other to the left. Thispolarization to the right, the other to the left. This rotation is expressed as the specific rotation, [rotation is expressed as the specific rotation, [αα].].
  • 121. 10.10. Absolute Configuration -Absolute Configuration - Determined by x-rayDetermined by x-ray diffraction. Assignment of R or S, as determined bydiffraction. Assignment of R or S, as determined by the Cahn, Ingold, and Prelog sequence rules.the Cahn, Ingold, and Prelog sequence rules. 11. Stereoselectivity -11. Stereoselectivity - Preference for the formation ofPreference for the formation of one stereoisomer when several are possible.one stereoisomer when several are possible. 12. Resolution –12. Resolution – Separation of enantiomers.Separation of enantiomers. • Reaction with a pure enantiomer of a second chiralReaction with a pure enantiomer of a second chiral compound and separation of the diastereomers.compound and separation of the diastereomers. • Chiral chromatography.Chiral chromatography.