pharmaceutical organic chemistry stereochemistry

Pharmaceutical

ORGANIC CHEMISTRY

StereochemistryStereochemistry

StereochemistryStereochemistry

• is the study of molecules on spaceis the study of molecules on space i.e. how atoms or groups in a molecule i.e. how atoms or groups in a molecule arranged in space relative to each otherarranged in space relative to each other •it is that part of the science which deals with structure in three it is that part of the science which deals with structure in three dimensionsdimensions

• is the field of chemistry that concerned with isomerism in space is the field of chemistry that concerned with isomerism in space

( stereoisomerism )( stereoisomerism )

Lecture contentsLecture contents

Isomerism Structural Isomerism

1. Chain isomerism2. Position isomerism3. Functional isomerism Stereoisomerism1.Optical active isomers. 2.Geometrical isomers. 3.Conformational isomers.

Isomerism

When two or more organic compounds have the same molecular

formula but differ in their physical or chemical properties they are

called Isomers and the phenomenon called isomerism.

Isomerism (stereoisomerism ) Isomerism (stereoisomerism )

A phenomenon resulting from molecules having the A phenomenon resulting from molecules having the

same molecular formula but different arrangement In same molecular formula but different arrangement In

spacespace

Stereoisomerism• Greek, Stereos=occupying space).• The stereoisomers have the same

structural formulas but differ in the spatial arrangement of atoms or groups in the molecule.

• In other words, stereoisomerism is exhibited by such compounds which have identical molecular structure but different configurations.

StereochemistryStereochemistry

Type of IsomerismType of Isomerism

1- 1- StructuralStructural – – The resulting isomerism are known asThe resulting isomerism are known as Structural isomersStructural isomers

2- Geometrical2- Geometrical – – The resulting isomerism are known asThe resulting isomerism are known as Diastereoisomers Diastereoisomers

3- Optical3- Optical – – The resulting isomerism are known asThe resulting isomerism are known as EnantiomersEnantiomers

They are compounds that contain the same atoms bonded

together in different ways they include:-

1. Constitutional (Structural) isomers.

2. Stereoisomers.

They are compounds that contain the same atoms bonded

together in different ways they include:-

1. Constitutional (Structural) isomers.

2. Stereoisomers.

Isomers Isomers

Isomers IsomersIsomerismIsomerism

Constitutional (Structural) isomers

Constitutional (Structural) isomers

Stereoisomers.Stereoisomers.

Geometrical isomerism

Geometrical isomerism

Positional isomerismPositional

isomerism

Optical isomerism

Optical isomerism

Functional isomerismFunctional isomerism

Chain isomerism

Chain isomerism

Constitutional Isomers

• They differ in the way their atom are connected.

– 1. Chain isomerism– 2. Position isomerism– 3. Functional isomerism

Chain Isomerism (or Skeletal Isomerism)

• Chain isomers have the same molecular formula but differ in order in which the carbon atoms are bonded.

CC44HH1010

CC55HH1212

Predict

Position Isomerism• Position isomers have the same molecular formula

but differ in the position of functional group on the carbon chain.

• Examples are:-

CC66HH66OO22

CC33HH88OO

Predict

Functional Isomerism• Functional isomers have the same molecular formula

but different functional groups. Examples are;

StereochemistryStereochemistry

Geometric isomerismGeometric isomerism

An isomerism resulting from rigidity in molecules An isomerism resulting from rigidity in molecules and accures only in two class of compoundsand accures only in two class of compounds alkenes and cyclic compoundsalkenes and cyclic compounds

Rigidity ≠ Flexibility Rigidity ≠ Flexibility

σσ – bond free rotation ( flexibility ) – bond free rotation ( flexibility )

- bond C = C no free rotation ( rigidity )- bond C = C no free rotation ( rigidity )

σσ – bond restricted rotation ( semi-fexable ) – bond restricted rotation ( semi-fexable )

Free rotation' of carbon- carbon single bonds

Restricted rotation' of carbon-carbon double bonds

StereochemistryStereochemistry

1- Geometric isomerism in alkenes1- Geometric isomerism in alkenes

The requirement for this type of isomerism is that each carbon The requirement for this type of isomerism is that each carbon atom involved in the double bond has different substitution atom involved in the double bond has different substitution

C C

E

A

B

D

D ≠ ED ≠ E A ≠ BA ≠ B

C

H

Cl

H

Cl

C

C

H

H

Cl

Cl

C

On same sideOn same side ciscis On differ sideOn differ side

transtrans

StereochemistryStereochemistry

DiastereoisomersDiastereoisomers are designed are designed ciscis or or transtrans according to according to the priority orders or sequence rules the priority orders or sequence rules [ atomic number = atomic weight \ 2 ][ atomic number = atomic weight \ 2 ]

1- Geometric isomerism in alkenes1- Geometric isomerism in alkenes

126126I >I > 80 80Br > Br > 3535Cl > Cl > 3232S > S > 1919F > F > 1616O > O > 1414N > N > 1212C > C > 11H H

StereochemistryStereochemistry

Sequence Rules or Priority OrderSequence Rules or Priority Order

1- If the two atoms in question are different, the atom of 1- If the two atoms in question are different, the atom of highest atomic number receives the highest priority highest atomic number receives the highest priority

I > Br I > Br > Cl > ……> Cl > ……

C C

H

H2C=HC

H

CH3

C C

H

H3C

Br

Cl

C C

H

H3C

CH2CH2CH3

OH

StereochemistryStereochemistry

Sequence Rules or Priority OrderSequence Rules or Priority Order

2- If the two atoms are identical, the atomic numbers of next 2- If the two atoms are identical, the atomic numbers of next atoms are used, until the priority is determined at the first atoms are used, until the priority is determined at the first points of difference along the chainpoints of difference along the chain

C C

H

H3C

CH2OH

CH2NH2

C C

H

H3C

CH2CH2CL

CH2CH2Br

C C

H

H3C

CH2CH2CH3

CH2CH3

StereochemistryStereochemistry

Sequence Rules or Priority OrderSequence Rules or Priority Order

3- Atoms attached to double or triple bonds are given 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom issingle-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds ) duplicated ( or triplicated for triple bonds )

R-C-R

O

R-C-R

O

R-C-OH

O

R-C-OH

O

R-C-H

O

R-C

N N

N

NCR

O

O

OHCR

O

O

RCR

RCHRCH22OHOH RCNRCN -CH=CR-CH=CR22>> >> >> >> >> >>

StereochemistryStereochemistry

Sequence Rules or Priority OrderSequence Rules or Priority Order

3- Atoms attached to double or triple bonds are given 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom issingle-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds ) duplicated ( or triplicated for triple bonds )

C C

H

H3C

CHO

COOH

C C

H

H3C

CH2NH2

CN

C C

H2C=HCCOOH

OCH3

StereochemistryStereochemistry

Sequence Rules or Priority OrderSequence Rules or Priority Order

3- Atoms attached to double or triple bonds are given 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom issingle-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds ) duplicated ( or triplicated for triple bonds )

C C

H3CCCCH2Cl

Cl

OO

ClH2C

C C

H3CCCl

CCH2Cl

O

ClH2C

O

DiastereoisomerDiastereoisomer

StereochemistryStereochemistry

E , Z – system of nomenclatureE , Z – system of nomenclature

Diastereoisomers can also be designted by :Diastereoisomers can also be designted by :

1- E instead of trans1- E instead of trans

2- Z instead of cis2- Z instead of cis

StereochemistryStereochemistryStereochemistryStereochemistry

• Compounds which have the same molecular formulaCompounds which have the same molecular formula but differ in arrangement of atoms or groups in spacebut differ in arrangement of atoms or groups in space different configurationdifferent configuration

• Diastereoisomers have different physical and chemical Diastereoisomers have different physical and chemical properties, as solubility and boiling pointsproperties, as solubility and boiling points

thus: thus: - if are liquids……. Fractional distillation- if are liquids……. Fractional distillation

- if are solids …….. Fractional crystallization - if are solids …….. Fractional crystallization

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

The most illustrative example is cyclohexaneThe most illustrative example is cyclohexane

H H

Rotation of group ( atoms ) around sigma bonds, Rotation of group ( atoms ) around sigma bonds, result in different conformations ( conformer )result in different conformations ( conformer )

CH3

OH

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

All cyclic compounds except cyclopentane would beAll cyclic compounds except cyclopentane would be strained because …… strained because ……

60 90 108 120

flat puckered

109

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

Conformation is different arrangement ….Conformation is different arrangement ….

In ethaneIn ethaneH

HH

H

HH

C C

Newman projectionNewman projection Ball and stickBall and stick 3D formula 3D formula

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

Cyclohexane is not flat ….Cyclohexane is not flat ….

Axial hydrogen ( Ha ) : H parallel to axisAxial hydrogen ( Ha ) : H parallel to axis

Equatorial hydrogen ( He ) : H in planeEquatorial hydrogen ( He ) : H in plane

upon flipping and reflipping between conformers, axial becomes upon flipping and reflipping between conformers, axial becomes equatorial and equatorial becomes axialequatorial and equatorial becomes axial

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

Mono-substituted cyclic compounds, do not exhibit Mono-substituted cyclic compounds, do not exhibit geometrical ………geometrical ……… cis or trans cis or trans

CH3

12

34

5

6

mono-substituted

CH3

12

34

5

6

1,2

CH3

CH3

12

34

5

6

1,3

CH3

CH3

12

34

5

6

1,4

CH3

CH3

CH3

opposite side [trans] a,a or e,e

CH3

CH3

same side [cis] a,e or e,a

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

1,2-disubstituted : same as 1,4-disubstituted 1,2-disubstituted : same as 1,4-disubstituted

CH3

CH3CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

Cis Cis both down = e,aboth down = e,a both up = a,eboth up = a,e

Trans Trans up and down = a,aup and down = a,a down and up = e,edown and up = e,e

In summary : a,e e,aIn summary : a,e e,a a,a e,e a,a e,e

1,4-disubistuted cyclohexane as 1,21,4-disubistuted cyclohexane as 1,2

StereochemistryStereochemistry

2- Geometric isomerism in cyclic compounds2- Geometric isomerism in cyclic compounds

1,3-disubstituted : 1,3-disubstituted :

CH3

CH3

CH3

CH3

CH3

CH3

a,a both up

e,e both down

cis

CH3

CH3

CH3

CH3

a.eup and down

e,adown and up

trans

CH3

CH3

both down = e,eboth down = e,e both up = a,aboth up = a,a

up and down = a,eup and down = a,e down and up = e,adown and up = e,a

Label each of the following disubistiuted rings as cis or trans and as a,a ; e,e ; or a,e

H

Cl

H

Cl

Cl

H

H

Cl

Cl

H

H

Cl

H

BrH3C

H