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Pharmaceutical ORGANIC CHEMISTRY
Optical Isomerism Polarimeter Chirality Chiral compounds Enantiomers and diastereomers Racemate
More Than One Chiral Carbon
Enantiomers and Diastereomers
Meso Compounds
Isomerism (stereoisomerism )
A phenomenon resulting from molecules
having the same molecular formula but
different arrangement In space
Isomerism
Structural Isomerism
1. Chain isomerism
2. Position isomerism
3. Functional isomerism
Stereoisomerism
1.Optical active isomers.
2.Geometrical isomers.
3.Conformational isomers.
Type of Isomerism
1- Structural – The resulting isomerism are known as
Structural isomers
2- Geometrical – The resulting isomerism are known as
Diastereoisomers
3- Optical – The resulting isomerism are known as
Enantiomers
StereochemistryStereochemistry
Optical isomerismOptical isomerism
An isomerism resulting from ability of certain molecules An isomerism resulting from ability of certain molecules to rotate plane of polarized lightto rotate plane of polarized light
-- the light is rotated either to the right or left-- the light is rotated either to the right or left
right ( clockwise ) + d ( dexter ) dextroright ( clockwise ) + d ( dexter ) dextro
left ( anticlockwise ) - l ( laevous ) levoleft ( anticlockwise ) - l ( laevous ) levo
PolarimeterPolarimeterPolarimeterPolarimeter
Any material that rotates the plane of polarized
light is said to be optically active. Optically active compound is
nonsuperimposable on its mirror image. If a molecule is superimposable on its mirror
image, the compound does not rotate the plane polarized light; it is optically inactive.
Example:Example: - Alanine(amino acid)
C COOHH2N
CH3
H
The Two Optical Isomers of Alanine
(space-filling models)
• For example, most amino acids (and so proteins) are chiral, along with many other molecules.
• In nature, only one optical isomer occurs (e.g. all natural amino acids are rotate polarised light to the left).
• Many natural molecules are chiral and most natural reactions are affected by optical isomerism.
Ball-and-stick modelsBall-and-stick models andand space-filling modelsspace-filling models areare 3D or spatial3D or spatial molecular models.molecular models.
CHIRALITYCHIRALITY AND AND
CHIRAL CHIRAL COMPOUNDSCOMPOUNDS
CHIRALITYCHIRALITY AND AND
CHIRAL CHIRAL COMPOUNDSCOMPOUNDS
Chirality (cheir, Greek for handhand).
The property of nonsuperimposability of an object on its mirror image is called chiralitychirality..
If a molecule is not superimposable on its mirror image, it is chiralchiral. If it is superimposable on its mirror image, it is achiralachiral.
Carbons with four different groups attached to them are handed, or chiral.
Optical isomers or stereoisomers If one stereoisomer is “right-handed,” its
enantiomer is “left-handed.”
Compounds which contain chiral carbonchiral carbon.
Chiral carbon:Chiral carbon:
It is an sp3-hybridized carbon atom with four different groups attached to it.
Chiral compound exists in a pair of enantiomers.enantiomers.
Many pharmaceuticals are chiral. Often only one enantiomer is
clinically active.
S-ibuprofen
HC CH2CH3
CH3CHCOH
NH2
O
O
CH
CH
CH2OH
HO
CH3CCH2CH
Cl
Br
CHCH3
a.
c.
b.
d.
SAMPLE EXERCISE
PRACTICE EXERCISEHow many chiral carbon atoms are there in the open-chain form of fructose
Answer: three
Solve: The carbon atoms numbered 2, 3, 4, and 5 each have four different groups attached to them, as indicated here:
PRACTICE EXERCISEHow many chiral carbon atoms are there in the open-chain form of glucose
Enantiomers have identical physical and chemical properties except in two two important respects:important respects:
1. They rotate the plane polarized light in opposite directions, however in equal amounts.
The isomer that rotates the plane to the left (anticlockwise) is called the levo isomer and is designated (-)
While the one that rotates the plane to the right (clockwise) is called the dextro isomer and designated (+).
2. They react at different rates with other chiralchiral compounds.
This is the reason that many compounds are biologically active while their enantiomers are not.
They react at the same rates
with achiralachiral compounds.
A racemic mixture dose not rotate the plane of
polarization of plane-polarized light because the
rotation by each enantiomer is cancelled
by the equal and opposite rotation by the other.
A solution of either a racemic mixture or of
achiral compound said to be optically inactive
Many drugs are optically active, with one enantiomer only having the beneficial effect.
In the case of some drugs, the other enantiomer can even be harmful, e.g. thalidomide.
In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness.
This led to many disabilities in babies and early deaths in many cases.
H2CCH2
C
NHO O
H
N
O
O
H2CCH2
C
NH OO
H
N
O
O
S thalidomide (effective drug)
The body racemises each enantiomer, so even pure S is
dangerous as it converts to R in the body.
R thalidomide (dangerous drug)
Thalidomide was banned worldwide when the effects were discovered.
However, it is starting to be used again to treat leprosy and HIV.
Its use is restricted though and patients have to have a pregnancy test first (women!) and use two forms of contraception (if sexually active).
S carvone (caraway seed) R carvone (spearmint)
O
CH3
H C CH2
H3C
O
CH3
HCH2C
CH3
Caraway Seed has a warm, pungent, slightly bitter flavour with aniseed overtones.
S limonene (lemons) R limonene (oranges)
CH3
HCCH2
CH3
CH3
H C CH2
H3C
Stereochemistry
Optical isomerism
Determination of Number of Enantiomers [stereoisomers]
2n where n = number of chiral carbins
n = zero no possible stereoisomers 1 2 enantiomers are possible 2 4 ~ ~ ~ ~ ~ ~ ~ 3 8 ~ ~ ~ ~ ~ ~ 4 16 ~ ~ ~ ~ ~ ~ 5 32 ~ ~ ~ ~ ~ ~
Optical isomerism
More than one chiral carbon
Different chiral carbons
CH3CH(Br)CH(Br)CH2CH3
CH3CH(Br)CH(Br)CH2OH
CH3CH(Br)CH(Cl)OH
CH3CH(Cl)CH(Br)NH2
Same chiral carbons
CH3CH(Br)CH(Br)CH3
CH3CH(OH)CH(OH)CH3
CO2HCH(OH)CH(OH)CO2H
Stereochemistry
Optical isomerismAbsolute Configuration ( AC )
Is the actual spatial arrangement of atoms or groups around a chiral carbon
In 1891 German chemist [ Emil Fisher ] introduce formula showing the spatial arrangement ………
StereochemistryOptical isomerism
(±)- Ethanolamine CH3CH(OH)NH2
has one chiral carbon, so 2- enantiomers
HH22NN
CHCH33
HH
OHOH HH22NNOHOH
HH
CHCH33
Mirror Fischer projection formula
Determination of ( AC ) by ( R ) and ( S ) system
Groups are assigned a priority ranking using the
same set of rules as are used in ( E ) and
( Z ) system
CH3CH(OH)NH2
1. Draw Fischer Projection formula 1. Draw Fischer Projection formula
HH22NN
CHCH33
OHOH
HH
Determination of ( AC ) by ( R ) and ( S ) system
Groups are assigned a priority ranking using the
same set of rules as are used in ( E ) and
( Z ) system
CH3CH(OH)NH2
2. Rank the substitution according to the priority order2. Rank the substitution according to the priority order
HH22NN
CHCH33
OHOH
HHOH > NHOH > NH22 > CH > CH33 > H > H
1 2
3
Determination of ( AC ) by ( R ) and ( S ) system
3. The group (atom) with lowest priority [H] should
be away from the observer , if not do an even
number of changes to get H away from the observer
HH22NN
CHCH33
OHOH
HH1
OHOH OHOH
CHCH33
CHCH33
HH22NN HH22NN
HH
HH
2
Determination of ( AC ) by ( R ) and ( S ) system
4. Draw an arrow from group with highest priority ( OH ) to second highest priority ( NH2 ) . if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S
HOHO
HH
NHNH22
CHCH33
(R)-ethanolamine(+)- ethanolamine
Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S
CH
Br
CH3
OH
CH
CH3H3CH2Ca- b-
Stereochemistry(±)- CH3CH(Cl)CH(Br)NH2
n = 2 ….. So No. of stereoisomer 4
CH3
H Cl
NH2
H Br
CH3
Cl H
NH2
Br H
CH3
H Cl
NH2
Br H
CH3
Cl H
NH2
H Br
1 2 3 4
Enantiomers Enantiomers
mirror mirror
1,3 and 1,4 2,3 and 2,4 are diastereoisomers
StereochemistryStereochemistry
Determination of ( AC ) in enatiomer 1
a. At C1 :a. At C1 :
HH
NHNH22
CC22
CC22NHNH22
HH
BrBr
BrBr
22
11
AC at C1 is SAC at C1 is S
Br > NHBr > NH22 > C > C22 > H > H
StereochemistryStereochemistry
Optical isomerismOptical isomerism
StereochemistryStereochemistry
Optical isomerismOptical isomerismDetermination of ( AC ) in enatiomer 1Determination of ( AC ) in enatiomer 1
a. At C2 :a. At C2 :
HH
CC11
CHCH33
ClClCHCH33
HH
ClCl
CC11
22
11
AC at C2 is SAC at C2 is S
Cl > CCl > C11 > CH > CH33 > > H H
StereochemistryStereochemistry
Optical isomerismOptical isomerism
So for overall So for overall
1 ( 1S, 2S ) 1 ( 1S, 2S ) 2 ( 1R, 2R )2 ( 1R, 2R )
similarly: similarly:
3 ( 1R, 2S )3 ( 1R, 2S ) 4 ( 1S, 2R ) 4 ( 1S, 2R )
Enantiomers and diastereomers:Enantiomers and diastereomers:
EXAMPLE:EXAMPLE:
2-Bromo-3-chlorobutane2-Bromo-3-chlorobutane
EXAMPLES:
A. 1,2-Dibromo-1-phenylpropane
B. 2,3,4-trihydroxybutanal (erthyrose)
Cont.More than one chiral carbon
In the simplest case, they are compounds which have internal plan of symmetryhave internal plan of symmetry.
EXAMPLE: Tartaric acid
COOH
H OH
COOH
H OH
StereochemistryOptical isomerismOptical isomerism
Meso-compound are : - superimposable mirror images - only 3 stereoisomers - optically inactive
COOHCH(OH)CH(OH)COOHCOOHCH(OH)CH(OH)COOH tartaric acidtartaric acid
COOH
HO H
COOH
HO H
COOH
H OH
COOH
H OH
COOH
H OH
COOH
HO H
COOH
HO H
COOH
H OH
1 2 3 4
Mesocompounds Enantiomers
mirror mirror
2R,3R-(+) 2S,3S-(-)
Important properties of meso compounds with 2 chiral centers:
1. They are optically inactive.
2. They must be (R,S) configuration.
3. They are diastereomers of the (R,R) and (S,S) isomer.
Cont. Meso compounds
Stereochemistry
Optical isomerism
-Resolution : process that involves ……..
Enantiomers
(±) ethanolamine
(+)-ehtanolamine (-)-ethanolamine
resolutionresolution
StereochemistryStereochemistry
Resolution of racemic mixture Resolution of racemic mixture
1- treat the mixture with microorganism1- treat the mixture with microorganism
N
N
H
CH3
N
N
H
CH3
(R,S) nicotine (R)
PseudomonasPutida
2- using chiral reagent 2- using chiral reagent
( R) RCOOH ( R) RCOO( R) RCOOH ( R) RCOO-- (S) R’NH (S) R’NH33++
+ ( S) R’NH+ ( S) R’NH22 ( S) RCOOH ( S) RCOO( S) RCOOH ( S) RCOO-- (S) R’NH (S) R’NH33
++
Examine the following structural formulas and select those that are chiral.
