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Presented By:Ms. Harpreet Kaur PannuMpharm 1st semesterRoll No: 206
Guided By:Dr Amit. G. NerkarM.pharm, PhD
Department of Pharmaceutical Chemistry
1. Introduction
2. Nature of Geometrical isomers
3. Geometrical isomers due to C N and N N═ ═
4. Physical properties of geometrical isomers
5. Stability of geometrical isomers
6. Stereochemistry of addition reactions
7. Conclusion
8. References 2
Isomers: Molecules with same chemical formula but different spatial arrangement of atoms
Term - invented by Jons Jakob Berzelius (1830)
Constitutional isomersConstitutional isomers:: isomers with a different connectivity
Urea
CH4N2O
H2N NH2
O
Ammonium cyanateCH4N2O
NH
H
H
H
O C N
3
Compounds with thesame molecular formula
ConformationalIsomers
rotation aboutsingle bonds
with chiral centers
Stereoisomers
MesoCompounds
Enantiomers
ConstitutionalIsomers
Cis,Trans (E,Z) Isomers(can be called
diastereomers)
Conformations
rotation restricted
differentconnectivity
Diastereomers
stereoisomersbut no chiral centers
Enantiomers
one chiral centerm ore than
one chiral center
chiralachiral
not mirror images
mirror images
Atropisomers
sameconnectivity
4
5
Stereoisomers - isomeric molecules having
same molecular formula & sequence of
bonded atoms but which differ only in 3-D
orientations of their atoms in space
Stereoisomerism is of two types:
3. Enantiomers
4. Diastereomers6
Many biomolecules exist as stereoisomersthat are non-superimposable mirrorimages of one another, called Enantiomers.Eg:
C
C
HO CH3H
OHO
C
C
OHCH3H
O OH
Fig: Enantiomers of lactic acid 7
Stereoisomerism is of following types: Geometrical isomerism
Fig: Geometrical isomerism in cis 2-butene & trans 2-butene 8
Diastereomers - stereoisomers not related through a reflection operation
Not mirror images of each other Include meso compounds, cis-trans (E-Z)
isomers, and non-enantiomeric optical isomers
Fig: Meso compound9
CH3
CH3
Cl
Cl
Optical Isomerism-
optical isomers are called enantiomers.
OH
CH CH3
COOH
OH
CHH3C
HOOC
(-) lactic acid (+) lactic acidin sour milk in muscles
10
Enantiomers- Stereoisomers that are non-superimposable mirror images; only properties that differ are direction (+ or -) of optical rotation
Drug molecules exist in various optical isomers with only one isomer having the biological activity
H2CCH2
C
NHO O
H
N
O
O
Fig: (S)-thalidomide (effective drug)
Fig: (R)-thalidomide (dangerous drug)
11
Structures containing double bonds or rings
exhibit geometrical isomerism
Examples of Geometrical Isomers
Fig: Geometrical Isomers
12
The double bond leads to increase in the number of optical isomers
Here ‘A’ groups have the same configuration
From the structures it is clear that the structures are dissymmetric & mirror images of each other
13
Structures with n different double bonds exist in 2n geometrically isomeric forms
example where n =2 is shown as Geometrical Isomerism in a diene
Fig: Geometrical Isomerism in a diene 14
Configuration of Oximes identified by prefixes
“syn” & “anti” instead of cis & trans
In Aldoxime the syn isomer- in which –OH group
of the oxime is on the side of the hydrogen of
the aldehyde carbon
In Ketoxime - specify the group with respect to
which the oxime -OH group is syn
15
Fig: Geometrical isomerism due to C N and N N═ ═16
Following are the Physical Properties of Geometrical Isomerism:2.Dipole moment 3.Melting Point, Boiling Point, Densities4.Acid Strength5.Ultraviolet Spectra6.Infrared and Raman Spectra7.NMR Spectra8.X-ray & Electron Diffraction
17
Dipole Moment is variable for cis and trans
isomer, sometimes higher for trans and at
times for cis isomer
compound of the type abC = Cab, C-a has a
strong bond moment but C-b has not, the
cis isomer should have a considerable over-
all dipole moment18
Dipole Moments of:
Cl
H H
Cl
cis-1,2dichloro-ethylene
Br
H H
Br
cis-1,2dibromo-ethylene
(1.89) (1.35)
whereas the moments of the corresponding trans isomer are zero
19
Trans isomer has greater symmetry than the cis - therefore trans has higher melting point
Examples are maleic acid m.p. 130˚, and fumaric acid m.p. 300˚
HHOOC
HOOC H
Maleic acid
COOHH
HOOC H
Fumaric acid
20
Boiling point, Density and Refractive indices- not
related directly to configuration
Boiling Point, density, and RI- Inverse function
of molecular volume
Isomer that has the higher value
for any of the above properties has the
higher value for the other two also 21
Acid strengths are strongly dependent on configuration
Depends upon Resonance Example: pka of cis and trans isomers of
crotonic acid
H
CH3 COOH
H
Cis- crotonic acid trans-crotonic acid (4.44) (4.70)
H
CH3 H
COOH
22
Cis isomer has absorption maxima at slightly
shorter wavelength than the trans isomer
Example:
C6H5
HH5C6
H C6H5
C6H5H
H
trans- Stilbene is planar, cis-Stilbene is coplanar and
Resonance between the double extremely crowded and thus
bond and phenyl rings is has less resonance energy and
at a maximum less stable
23
Differences in infrared spectra of geometrical
isomers is in the following regions:
e 1650cm-1 (C=C)
e 970-690cm-1 (=C-H out of plane vibration)
For trans-1,2-dichloroethylene dipole moment is
zero
Therefore it shows no double-bond streching in IR
but shows strong absorption in the raman at
1577cm-1
24
Comparison of trans & cis 1,2-dichloro ethylene: Cl
H
Cl
H
Cl
Cl
H
H
Shows no IR
absorption Shows Raman
absorption at
1577cm-1
Shows strong
IR absorption
at 1590cm-1 Shows no
raman
absorption
25
Difference exists between the coupling constants of cis and trans protons
Trans isomer- strongly coupled Coupling constant for cis: 8 to 11 c.p.s and Coupling constant for trans: 17 to 18 c.p.s Differences in chemical shifts- differentiates
cis & trans isomers Example:
Dimethyl citraconate Dimethyl mesaconate
δ= 190 c.p.s δ= 184 c.p.s
CH3
H3CO2C CO2CH3
H
26
CH3
H3CO2C H
CO2CH3
X- ray analysis of isomers- indicates which isomer is at hand
Example: Stretched rubber- all cis form of polyisoprene Gutta-percha- all trans form of polyisoprene
Rubber Gutta-percha
27
Thermochemical stability differences between
geometrical isomers measured as difference in
heat of combustion
Alternatively, Heat of hydrogenation used
Difference in the heat of hydrogenation =
Difference in the heat of formation
Therefore,
(∆Hcis – ∆Htrans)=(H trans – H cis)
The cis isomer has higher heat content
28
Difference in heat of hydrogenation of cis & trans stilbene= 5.7 kcal/mole
C6H5
C6H5H
H C6H5
HH5C6
H
Cis- stilbene Trans- stilbene
Stability of the cis- stilbene is less as compared to the trans isomer
29
Six different types of addition reactions:
2. Hydrogenation
3. Electrophilic addition
4. Molecular addition
5. Free radical addition
6. Addition of carbenes and methylenes
7. Nucleophilic addition30
Study is concerned to tetra substituted double bonds
E.g.
Hydrogenation is exclusively cis31
These involves addition of halogens, hydrogen halides,hypohalous acids, sulfenyl halides & formaldehyde etc.
Electrophilic addition reactions are generally trans
E.g.
32
Molecular addition reactions proceed in the cis fashion
E.g. oxidation of maleic acid= meso tartaric acid
oxidation of fumaric acid= (±)-tartaric acid
H
COOH
H
HOOC
K M n O 4
o r O s O 4
OH
HCOOH
H
OHHOOC
+H
OH
COOH
OH
H
HOOC
33
Addition of hydrogen bromide to 1-
methylcyclohexene(Br, Cl) under influence of
light proceeds in the trans fashion gives cis-1,2-
di substituted cyclohexanes E.g.
34
Involves addition of divalent carbon compounds: CR2 to olefins
Carbenes add stereospecifically: cis gives cis & trans gives trans
35
Nucleophilic reagents add to the double bond when activated by electron withdrawing groups
Trans product is dominant
36
Geometrical isomers differentiates between
various forms of drug molecules
Various physical properties aid in determining as
which isomer is dominant
Determines the dominant product in any chemical
reaction
The intercoversion between various isomers can
be brought about by various reagents
37
C.S. Marvel,Geometric Isomerism, in H. Gilman,ed., “Organic
Chemistry,” John Wiley & sons,Inc., New York,1943,pp. 444-477
L. Crombie, Geometrical isomerism about Carbon-Carbon double
Bonds, Quart. Revs., 6, 101
C.C. Price, “Mechanism Of Reactions at carbon- carbon Double
Bonds,” Interscience Publishers, Inc., New York,1946
W. E Truce, nucleophilic Reactions of Thiols with Acetylenes and
Chloroethylenes, in N. Kharasch, ed., “Organic Sulfur
Compounds” vol 1, Pergamon press,ltd., London, 1961
38
39