Unit II Geometrical isomerism

Unit II
GEOMETRICAL
ISOMERISM
Lecture by
SOWMIYA PERINBARAJ, M.Pharm
Assistant Professor
Dept. of Pharmaceutical Chemistry
SVCP

INTRODUCTION
+ In 1875, Vant’t Hoff and Le Bel recognised another type of stereoisomerism in
organic molecules having two differently substituted atoms to each other by
means of a double bond (C=C).
+ The geometrical isomerism arises when atoms or groups are arranged
differently in space due to restricted rotation of a double bond in a molecule.
+ The carbon-carbon double bonds consist of σ bond and π bond.
+ The presence of π bond locks the molecule in one position, therefore rotation
around the C=C bond is not possible.
+ Geometrical isomer have same molecular formula and structural formula
+ But it has different orientation (spatial arrangement of atoms) due to presence of
double bonds or rings.
2

+ In general Geometrical isomerism is shown by alkenes or their
derivatives in which two different atoms or groups are attached to
each carbon containing the double bond.
+ Eg: Two different spatial arrangements of methyl groups about a
double bond in 2-butene give rise to the following geometrical
isomers.
+ i.e., cis-2-butene and trans-2-butene
3

NOMENCLATURE OF GEOMETRICAL
ISOMERISM
+ To represent the various geometrical isomers following nomenclatures are used.
❖ Cis-Trans nomenclature
❖ E-Z nomenclature
❖ Syn-Anti nomenclature
Cis-Trans nomenclature:
✓ Geometrical isomerism is commonly known as Cis-Trans isomerism.
Cis-isomer: Cis is a Latin words and it means “this side of”
✓ Cis indicates that the identical atoms or groups are on the same side of the
carbon double bond or ring.
4

❖Trans isomer: Trans is a Latin word which means “the other side of”
Trans indicates that the identical atoms or groups are on opposite side of
the carbon double bond or ring.
+ Thus, cis-trans isomers are stereoisomers, that is pairs of
molecules which have the same molecular formula but whose
identical atoms or groups are in different orientation in three
dimensional space.
5

Examples:
2) 3-Hexene CH3CH2CH=CHCH2CH3
+ Geometric isomerism is possible because each double
bonded carbon is attached to two different groups
(CH3CH2 and H) attached to it.
6

Examples:
3) Butenedioic Acid COOH-CH=CH-COOH
+ Geometric isomerismis possible because each double
bonded carbon is attached to two different groups (COOH
and H) attached to it.
7

Properties:
➢ Cis-trans isomers do not different much in chemical properties.
➢ They differ in physical properties like boiling point, melting point, crystal structure,
solubility and refractive index.
➢ In cis isomer because the similar groups are very near each other, Vander Waals repulsion
and Stearic hindrance (bulky groups) make the molecule much unstable.
➢ Whereas in trans isomer, similar groups are diagonally opposite to each other. Hence there
is no such steric interaction and it is more stable.
8

Properties:
➢ Hence reactivity of cis isomer is little higher than trans isomer.
➢ Dipole moment studies is one of the best method to identify cis-trans
isomers. Cis isomer has larger DPM and trans is zero.
9

Comparison between cis and trans
isomer
S.no Cis isomer Trans isomer
1
It has same connectivity and identical atoms
of same side.
It has same connectivity and identical atoms of
opposite side.
2 Steric interaction is present No steric interaction
3 Less stable isomer More stable isomer
4 Energy and reactivity is more Energy and reactivity is less
5 Cis isomer has polar molecule Trans isomer has less polar or non polar
6 Dipole moment value is higher Dipole moment value is zero
7 Melting point is comparatively low Melting point is comparatively high
8 Boiling point is comparatively high Boiling point is comparatively low
9 Solubility is comparatively high Solubility is comparatively low
10

Limitations:
+ Cis-Trans nomenclature is not available for molecules which
contain four different connective substituents.
+ Cis-trans nomenclature is also not applicable for molecules
containing C=N which contain four different connective
substituents.
11

E-Z nomenclature
+ This system can be used to specify the configuration about any carbon-carbon double
bond unambiguously by using a set of priority rules.
+ This system is devised in 1964 by R.S.Cahn, C.K.Ingold and V.Prelog.
E-Configuration:
+ E is taken from German word entgegen which means “opposite”
+ If the two groups of highest priority are on the opposite sides of the double bond,
the bond is assigned as “E” configuration.
Z-Configuration:
+ Z is taken from German word zusammen which means “together”
+ If the two groups of highest priority on the same sides of the double bond, the bond
is assigned as “Z” configuration.
Sample footer text 3/1/20XX 12

+ The E-Z system is based on a set of "priority rules", which allow to
rank any groups.
+ The general strategy of the E-Z system is to analyze the two groups at
each end of the double bond. At each end, rank the two groups, using
the CIP priority rules.
+ Then, see whether the higher priority group at one end of the double
bond and the higher priority group at the other end of the double bond
are on the same side (Z from German word zusammen = together) or
on opposite sides (E from German word entgegen = opposite) of the
double bond.

+ There are four CIP priority rules
Rule 1:
+ Each atom is assigned a priority. Priority is based on atomic number; higher
the atomic number, the higher the priority.
Rule 2:
+ For isotopes, the higher the atomic mass the higher the priority. For example,
deuterium (Hydrogen-2) has higher priority than protium (Hydrogen-1).

Rule 3:
+ If priority cannot be assigned on the basis of atomic number or atomic mass considering
the first atom of a group, then look at the next set of atoms and continue until a priority
can be assigned.
+ Priority can be assigned at the first point of difference.
+ If the atoms directly linked to the double bond are the same, then the second, third,
fourth,etc. atoms (away from the double bond) are ranked until a difference is found.

Rule 4:
+ In the case of double or triple bonds, atoms participating in
the double or triple bond are considered to be bonded to an
equivalent number of similar atoms by single bonds, that is,
atoms of double and triple bonds are duplicated or triplicated.

+ To assign E-Z system, first determine the groups of highest priority
on each carbon. If the two highest priority groups are on the same
side of the double bond, the configuration is Z. If they are on
opposite side of the double bond then the configuration is E.

Syn-Anti Nomenclature
+ Geometric isomerism is also possible in compounds containing
oximes (C=N) and Azo compounds (N=N).
+ Thus, Syn-Anti nomenclature is used to indicate the
geometrical isomerism containing C=N or N=N bonds such as
oximes and azo compounds.

+ In aldoxime, the syn or anti configuration is determined by the position
of the lone pair of electrons on nitrogen atom with respect to alkyl (R)
or aryl (Ar) group.
Syn configuration:
+ In aldoxime, syn configuration is one in which the lone pair on nitrogen
and the alkyl or aryl group on same side or H and OH is present in
same side.
Anti configuration:
+ In aldoxime, anti configuration is one in which the lone pair on nitrogen
and the alkyl or aryl group on opposite side or H and OH is present in
opposite side.

Example: Aldoxime

+ In ketoxime, the prefixes syn and anti indicate which alkyl (R) or aryl
(Ar) group of ketoxime is syn (on the same side) or anti (on the
opposite sides) with respect to the OH group.

+ Azo compounds contain two lone
pair of electrons on each nitrogen
atom.
+ Syn configuration:
+ If both lone pair are present on same
side, then assigned as Syn
configuration.
+ Anti configuration:
+ If both lone pair are present on
opposite side, then assigned as anti
configuration.
3/1/20XX 23

Methods of
determination of
configuration of
geometrical isomers

Determination of configuration of
geometrical isomers
❑ Several methods are available to determine the configuration
❑ Method can be selected depending upon nature of compound
❑ Use of multiple methods gives more reliable results
❑ Some of the methods are
1. Method of cyclisation
2. By converting into compounds of known
configuration
3. Method of optical activity
4. Methods based on physical properties
5. By stereoselective reaction
6. By stereospecific reaction

1. Method of Cyclisation:
➢ This method is based on the fact, Intramolecular reactions are more
likely to take place if the reacting groups are closer.
➢ Eg: In case of maleic acid, anhydride is formed under mild
conditions because the two –COOH groups are closer (cis) but
fumaric acid does not give an anhydride under ordinary conditions.
➢ Under vigorous conditions it forms maleic anhydride, so in this case
the two –COOH groups are in opposite direction (trans).

2. By converting into compounds of known
configuration:
✓ This method is applicable in those cases in which one of the two isomers can
be converted into a compound of known configuration.
✓ Assuming that there is no isomerization during the process of conversion,
then the configuration of product and that of starting material will be same.
✓ Eg: one form of trichlorocrotonic acid can be hydrolyzed to give fumaric
acid, so this form of trichlorocrotonic acid must be the tans-isomer.
✓ The other form of acid does not give fumaric acid on hydrolysis and forms
isocrotonic acid on reduction.
✓ Hence this form of trichlorocrotonic acid and isocrotonic acid are cis-
isomers.
27

3. Method of optical activity:
+ In geometrical isomers if one is optically active and
other is optically inactive, then optically active
compound can be easily resolved.
+ Eg: In hexahydrophthalic acids-
+ cis form possesses a plane of symmetry and is optically
inactive and trans is active.
+ Trans form of hexahydrophthalic acid can be resolved.

4. Methods based on physical
properties
A) Dipole moment:
+ The dipole moment of cis form is generally higher than that of trans
form
+ Eg: In the case of 1,2 dichloroethylene cis isomer is generally have
1.80 D and trans isomer have zero dipole moment.

b) Melting point, boiling point, solubility, Density
& Refractive index
+ The physical constants are varying in cis and trans isomer is
shown in following table

Solubility:
+ Cis-isomers have higher solubilities.
+ Maleic acid (cis) - 79.0g/100ml at 293K
+ Fumaric acid (trans) - 0.7g/100ml at 293K
c) X-ray and electron diffraction
➢ Configuration can be determined using X-ray crystallography.
➢ X-Ray crystallographic analysis of sorbic acid gave its trans
configuration.

d) Spectroscopic method:
+ Spectroscopic method based upon,
trans isomer will have higher λ- max
than corresponding cis isomer.
+ NMR spectroscopy also used to
distinguish geometrical isomers,
because trans vinyl protons are more
strongly coupled to each than other cis
vinyl protons.
+ In IR Spectroscopy, Trans isomer is
readily identified by the appearance of
a characteristic band near 970-960cm-1.
No such band is observed in the
spectrum of the cis isomer.

5) By stereoselective reaction
+ In these reactions, one stereoisomer is formed in more amount than the other.
+ Hydrogenation of alkyne with sodium or lithium in liquid ammonia gives a
mixture of trans and cis alkenes in which trans isomer predominates.
+ On the otherhand hydrogenation of alkyne using palladised charcoal gives cis
alkene with a small amount of trans alkene.
+ Reactions which yield predominantly one stereoisomer of several possible
stereoisomers are called stereoselective reactions.

6) Stereospecific reactions
+ In these reactions, the formation of
product is specific with respect to the
stereoisomer. That is different
stereoisomeric starting materials give
rise to different stereoisomeric
products.
+ Reduction: The catalytic
hydrogenation of cis isomer gives a
meso compound.
+ A (+-) product is obtained if starting
material is trans isomer.

Hydroxylation:
+ The hydroxylation of alkenes if carried out by means of OsO4,
KMnO4, H2O2 proceeds in cis fashion.
+ Maleic acid (cis) and fumaric acid (trans) give meso and (+-) –tartaric
acid respectively.

Conformational isomerism
+ Conformational isomerism is a form of stereo isomerism in which the
isomers can be interconverted just by rotations about single bonds.
+ Conformational isomers or conformers are different shapes of the
same molecule resulting from rotation around a single C-C bond.
+ They are not different compounds (i.e. they have the same physical
and chemical properties) and are readily interconvertible.
+ It is unstable and exchange in short time duration to another
conformer.

Two types of projection structure are used to study the
conformational isomers.
1. Sawhorse projection:
• A representation of molecular structure, from an oblique angle.
• It is named after its similar look to sawhorse.

2. Newman projection:
+ In this projection, visualizes the conformations of a bond from
front to back.
+ The front atom represented by a bond line and the back
carbon represented as a circle.

+ Eclipsed conformation: A conformation about a carbon-carbon single bond
in which the atoms or groups on one carbon are as close as possible to the
atoms or groups on an adjacent carbon.
+ Staggered conformation: A conformation about a carbon-carbon single bond
in which the atoms or groups on one carbon are as far as possible to the atoms
or groups on an adjacent carbon.
Eclipsed Staggered

+ Dihedral angle: An angle created by two intersecting planes.
+ Anti conformation: A conformation about a single bond in which two
groups on adjacent carbons lie at a dihedral angle of 1800
+ Gauche conformation: A conformation about a single bond of an alkane
in which two groups of adjacent carbons lie at a dihedral angle of 600

CONFORMATION OF ETHANE
+ The molecular formula of ethane is C2 H6
+ If one of the methyl groups is allowed to rotate along the C-C axis
keeping the rest of the molecule undisturbed, an infinite number of possible
arrangements of the rotated methyl group with respect to the undisturbed
methyl group is generated.
+ Each of these possible arrangement represents a conformation.
+ So, six possible conformations are obtained, out of which three are
staggered form in which the two hydrogen atoms on the different carbon
atoms are as far as possible (1,3,5).
+ Other Three are eclipsed in which the two hydrogen atoms on the different
carbon are as close as possible (2,4,6).

Energy barrier diagram of ethane
+ Staggered and eclipsed conformer have different energy.
+ Staggered conformer has least energy due to least steric hindrance and
it is most stable conformer.
+ Eclipsed conformer has highest energy due to maximum steric
hindrance and it is least stable conformer.
+ Torsional energy: Eclipsed conformer has 3 kcal/mole (12.6 kJ/mol)
than staggered. This energy is known as torsional energy.
+ Torsional angle: The angle between the front and back hydrogen is
dihedral (or torsional) angle.

Why staggered conformation of ethane is lower in
energy than the eclipsed conformation?
➢ The potential energy of Staggered conformation is less than eclipsed
because in the latter case the hydrogen atoms on the two carbon
atoms are close to each other and hence exert a repulsive force
(steric repulsion due to non bonded interaction of hydrogen
atom).
Can be justified with two important reasons
1) The first is that the electrons in the bonds repel each other and this
repulsion is at a maximum in the eclipsed conformation.

2) The second is that there may be some stabilizing interaction between
the C–H σ bonding orbital on one carbon and the C–H σ* antibonding
orbital on the other carbon, which is greatest when σ* antibonding
orbital is unfilled: this only happens in the staggered conformation.

CONFORMATION OF BUTANE
+ The molecular formula of butane is C4 H10
+ It has two structural isomer ➔ n-butane and iso-butane
+ When rotating the n-butane at the axis of the C2-C3 bond at 60°
angle, it shows different conformation isomerism with the respect of
methyl groups present on back and front side of C2-C3 axis.
+ Butane has four conformation isomers:
1. Fully eclipsed
2. Gauche
3. Partially eclipsed
4. Anti butane conformer

1. Fully eclipsed conformer
+ In this conformer, methyl groups of back carbon and front carbon are
minimum distance (eclipse) to each other (0°) or dihedral angle
between methyl group is 0°
+ This conformer has maximum steric hindrance due to presence of
methyl group at eclipse position, so it has highest energy and hence
least stable conformer.

2. Gauche (staggered conformer)
+ In this conformer, methyl groups of back and front carbon are 60°
angle or dihedral angle between methyl group is 60°
+ This type of conformation is more stable and has less conformer
energy as there is a little steric hindrance between the same
molecules like Me-Me and H-H and Me-H.

3. Partially eclipsed conformer
+ In this conformer, hydrogen atom of back and methyl group of front
carbon are 0° angle or dihedral angle between methyl /methyl group is
120°
+ This stage appeared 120° rotation from fully eclipsed.
+ This type of conformation is more stable than fully eclipsed and least
stable than gauche (staggered) due to presence of steric hindrance between
the hydrogen and methyl group.

4. Anti (staggered) conformer
+ In this conformer, methyl groups of back and front carbon are 180°
angle or dihedral angle between methyl /methyl group is 180°
+ This stage appeared 180° rotation from fully eclipsed.
+ This type of conformation is most stable than fully eclipsed, gauche
(staggered) and partially eclipsed conformer due to presence of least
steric hindrance between both methyl group.

Energy barrier diagram of butane
+ Energy order:
+ Anti < Gauche <
partially Eclipsed
< fully eclipsed
+ Stability order:
+ Anti > Gauche >
partially Eclipsed
> fully eclipsed

Conformation of cyclohexane
+ Cyclohexane is a six membered carbocycle with
the molecular formula of ➔ C6 H12
+ Cyclohexane exists mainly in four conformations:
1) Chair Conformation
2) Half chair conformation
3) Twist boat conformation
4) Boat conformation

1. Chair conformation
+ Cyclohexane exist in puckered conformation when it
achieves tetrahedral bond angle ➔109.5º and staggered
conformation.
+ There is no steric hindrance, so it has minimum energy
and maximum stability.

2. Half chair conformation
+ It has both angle strain and torsional
angle, so less stable than chair form.
+ Energy ➔ 50 KJ/mol
3. Twist boat conformation
+ More stable than boat conformation by
about energy ➔ 22 KJ/mol but less
stable than chair conformation.

4. Boat conformation
+ Eclipsed conformer
+ Due to steric interaction between the non-bonding atom, it is
less stable than chair conformation and has highest energy.
+ Energy ➔ 28 KJ/mol
61

Axial and equatorial of cyclohexane

Energy diagram of cyclohexane
Energy order:
chair < twist
boat < boat <
half chair
Stability order:
chair > twist
boat > boat >
half chair

Stereoisomers in biphenyl compounds
(Atropisomerism)
+ Atropisomers can be defined as isomers that can be isolated due to prevention or
restriction of rotation about a single bond, usually between two planar
moieties.
+ The term atropisomerism comes from the words a, Greek ➔ not (absence)
+ tropos, Greek ➔ turn.
+ Bulky group on ortho position of bi-phenyl leads to strained ring structural
features.
+ Bulky substituents or strained rings may enhance the barrier to rotation
between two distinct conformations to such an extent as to allow observation of
atropisomers. 65

+ Atropisomerism is also called axial chirality and the chirality is not
simply a centre or a plane but an axis.
+ Simple biphenyl can easily rotate by C-C bond and it is symmetric so
simple biphenyl is achiral.
+ C-C sigma bond is known as pivotal bond.

+ Biphenyl substituted on ortho position in molecule 1 (Figure 2), which
contains a chiral axis along the biphenyl linkage.
+ The biphenyl rings are perpendicular to each other in order to minimize
steric clashes between the four ortho substituents meaning that rotation
about the biphenyl bond through pivotal bond is restricted.
+ The interconversion between the two isomers is restricted (slow)
therefore two isomers are separate entities and can resolved to its separate
enantiomers.
+ The first chirality due to restricted rotation about a single bond was
described by Christie and Kenner in 1922, they successfully resolved the
enantiomers of 6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid.

Conditions of Atropisomerism (optical activity):
1. A rotationally stable axis
2. Presence of different substituents on both sides of the axis
3. The configurational stability of axially chiral biaryl compounds is
mainly determined by three following factors:
i. The combined steric demand of the substituent in the combined steric
demand of the substituents in the proximity of the axis.
ii. The existence, length and rigidity of bridges.
iii. Atropisomerisation mechanism different from a merely physical rotation
about the axis, e.g. photo chemically or chemically induced processes.

Stereochemical assignment:
+ Determining the axial stereochemistry of biaryl atropisomers can be
accomplished through the use of a Newman projection along the axis
of hindered rotation.
+ The ortho, and in some cases meta substituents are first assigned
priority based on Cahn–Ingold–Prelog priority rules.
+ Starting with the substituent of highest priority in the closest ring and
moving along the shortest path to the substituent of highest priority in
the other ring, the absolute configuration is assigned P or Δ for
clockwise and M or Λ for counterclockwise.

Stereoselective Reactions
+ A reaction that yields predominantly one stereoisomer (or one pair of
enantiomers) of several possible diastereomeric possibilities is called a
stereoselective reaction.
+ In a stereoselective reaction, one stereoisomer is formed (or destroyed)
more rapidly than another, thus resulting in predominance of the favoured
stereoisomer in the mixture of products.
+ Due to differences either in the free energies of activation of the reaction
or thermodynamic stabilities of the products, one isomer is formed
predominantly.
+ A ➔ B + C
+ B is formed more than C whereas B and C are stereo isomers.

+ Stereo selectivity can be further subdivided into enantioselectivity and
diastereoselectivity.
+ Enantioselectivity is defined as the formation of one of the two
enantiomers predominantly or exclusively.
+ Diasteroselectivity is defined as the formation of one of the two or more
diastereomers predominantly or exclusively.

Enantioselectivity:
+ It is achieved by using chiral substrate, reagent, catalyst or solvent.
+ Examples:

Diastereoselectivity:
+ It is most commonly achieved through the presence of steric
hindrance.
+ Examples:
+ 4-methylcyclohexenone
Sample footer text 76

+ Epoxidation of cyclic alkenes:
+ 4-methylcyclopentene

Stereospecific Reactions
+ A reaction in which stereochemically different reactants gives
sterochemically different products is called a stereospecific
reaction.
+ A reaction or synthesis in which a particular stereoisomer reacts to
give one specific stereoisomer of the product is called a sterospecific
reaction.
+ Such a reaction is said to display stereospecificity.
+ A ➔ B
+ C ➔ D
+ A and C are stereoisomers; B and D are stereoisomers.

Examples: 1
+ Addition of bromine to cis-2-butene gives racemic 2,3-dibromobutane,
while the trans isomer gives meso-2,3-dibromo butane.
+ This reaction is stereospecific because different stereoisomer gives
different stereoisomer.

Examples: 2
+ The formation of epoxides from alkenes on treatment with peracids is a
stereospecific reaction.
+ Cis-2-butene gives cis-2,3-dimethyloxirane, while trans-2-butene gives
trans-2,3-dimethyloxirane.

Examples: 3
+ 1,2-diols may be prepared from alkenes using stereospecific
oxidative reaction.
+ Reaction of cyclohexene with osmium tetroxide gives the osmate
ester which may be cleaved to give the product with two hydroxyl
groups on same side of the molecule.

Examples: 3
+ Reaction of cyclohexene with peracid gives an epoxide which on
hydrolysis gives the product with two hydroxyl groups on different
side of the molecule.

Examples: 4
+ Diels- Alder reaction is stereospecifically cis with respect to the
dienophile.
+ 1,3-butadiene reacts with maleic acid to give cis-1,2,3,6-
tetrahydrophthalic acid, while fumaric acid gives trans isomer.

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Unit II Geometrical isomerism

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