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

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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

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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)

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Structures containing double bonds or rings

exhibit geometrical isomerism

Examples of Geometrical Isomers

Fig: Geometrical Isomers

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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.

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Involves addition of divalent carbon compounds: CR2 to olefins

Carbenes add stereospecifically: cis gives cis & trans gives trans

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Nucleophilic reagents add to the double bond when activated by electron withdrawing groups

Trans product is dominant

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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

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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

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