Pharmaceutical ORGANIC CHEMISTRY

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Pharmaceutical ORGANIC CHEMISTRY

• Pharmaceutical ORGANIC CHEMISTRY

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Lecture contents

• Optical Isomerism
• Polarimeter
• Chirality
• Chiral compounds
• Enantiomers and diastereomers
• Racemate

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Lecture contents

• More Than One Chiral Carbon
• Enantiomers and Diastereomers
• Meso Compounds

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Optical Isomerism
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Isomerism (stereoisomerism ) A phenomenon
resulting from molecules having the same
molecular formula but different arrangement
In space
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• Isomerism
• Structural Isomerism
• 1. Chain isomerism
• 2. Position isomerism
• 3. Functional isomerism
• Stereoisomerism
• Optical active isomers.
• Geometrical isomers.
• Conformational isomers.

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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
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Stereochemistry
Optical isomerism
An isomerism resulting from ability of certain
molecules to rotate plane of polarized light
-- the light is rotated either to the right or
left right ( clockwise )
d ( dexter ) dextro left ( anticlockwise
) - l ( laevous ) levo
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Polarimeter
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Optical Isomerism

• 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
• Alanine
• (amino acid)

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The Two Optical Isomers of Alanine (space-filling
models)
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• 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.

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Ball-and-stick models and space-filling models
are 3D or spatial molecular models.
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CHIRALITY AND CHIRAL COMPOUNDS
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What is chirality?

• Chirality (cheir, Greek for hand).
• The property of nonsuperimposability of an object
  on its mirror image is called chirality.
• If a molecule is not superimposable on its mirror
  image, it is chiral. If it is superimposable on
  its mirror image, it is achiral.

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Chirality

• 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.

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CHIRAL COMPOUNDS

• Compounds which contain 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.

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Chirality
S-ibuprofen

• Many pharmaceuticals are chiral.
• Often only one enantiomer is clinically active.

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Q Decide the chiral carbons in the following
formulas?
a.
b.
c.
d.
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SAMPLE EXERCISE
PRACTICE EXERCISE How many chiral carbon atoms
are there in the open-chain form of fructose
Answer three
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PRACTICE EXERCISE How many chiral carbon atoms
are there in the open-chain form of glucose
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• Enantiomers have identical physical and chemical
  properties except in two important respects
• 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 ().

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• 2. They react at different rates with other
  chiral compounds.
• This is the reason that many compounds are
  biologically active while their enantiomers are
  not.
• They react at the same rates with achiral
  compounds.

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• 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

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• 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.

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• In the 1960s 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.

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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)
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• 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).

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S carvone (caraway seed)
R carvone (spearmint)
Caraway Seed has a warm, pungent, slightly bitter
flavour with aniseed overtones.
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S limonene (lemons)
R limonene (oranges)
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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
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4 16
5 32

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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
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Stereochemistry
Optical isomerism
Absolute 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
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Stereochemistry
Optical isomerism
()- Ethanolamine CH3CH(OH)NH2 has one
chiral carbon, so 2- enantiomers
H
H
H2N
OH
H2N
OH
CH3
CH3
Mirror Fischer projection formula
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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
H
OH
H2N
CH3
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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 order
H
OH gt NH2 gt CH3 gt H
OH
H2N
1
2
3
CH3
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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
H
H2N
H2N
1
H2N
OH
H
OH
CH3
OH
2
CH3
H
CH3
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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
NH2
HO
CH3
(R)-ethanolamine ()- ethanolamine
H
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Draw the formulas for the two enantiomers of each
of the following compunds then assign each as
Ror S
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Stereochemistry
()- CH3CH(Cl)CH(Br)NH2 n 2 .. So No. of
stereoisomer 4
1,3 and 1,4 2,3 and 2,4
are diastereoisomers
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Stereochemistry
Determination of ( AC ) in enatiomer 1
a. At C1
Br gt NH2 gt C2 gt H
Br
C2
2
H
C2
NH2
Br
1
NH2
H
AC at C1 is S
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Stereochemistry
Stereochemistry
Optical isomerism
Optical isomerism
Determination of ( AC ) in enatiomer 1
a. At C2
Cl gt C1 gt CH3 gt H
C1
CH3
2
H
Cl
CH3
Cl
1
C1
H
AC at C2 is S
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Stereochemistry
Optical isomerism
So for overall 1 ( 1S, 2S ) 2 ( 1R,
2R ) similarly 3 ( 1R, 2S ) 4 (
1S, 2R )
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Enantiomers and diastereomers EXAMPLE
2-Bromo-3-chlorobutane
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(R) And (S) system for a compound with two chiral
carbon atoms
Cont.More than one chiral carbon

• EXAMPLES
• 1,2-Dibromo-1-phenylpropane
• 2,3,4-trihydroxybutanal
• (erthyrose)

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Meso compounds

• In the simplest case, they are compounds which
  have internal plan of symmetry.
• EXAMPLE
• Tartaric acid

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Stereochemistry
Optical isomerism
COOHCH(OH)CH(OH)COOH tartaric acid
Meso-compound are - superimposable mirror
images - only 3 stereoisomers -
optically inactive
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Cont. Meso compounds

• Important properties of meso compounds with 2
  chiral centers 
• They are optically inactive.
• They must be (R,S) configuration.
• They are diastereomers of the (R,R)
• and (S,S) isomer.

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Stereochemistry
Optical isomerism
Enantiomers

• Resolution process that involves ..

() ethanolamine
()-ehtanolamine
(-)-ethanolamine
resolution
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Stereochemistry
Resolution of racemic mixture
1- treat the mixture with microorganism
2- using chiral reagent ( R)
RCOOH (
R) RCOO- (S) RNH3
( S) RNH2 ( S)
RCOOH (
S) RCOO- (S) RNH3
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Examine the following structural formulas and
select those that are chiral.