Pharmaceutical ORGANIC CHEMISTRY Stereochemistry.
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Transcript of 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