Transcript lec-5-211(optical is..

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
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
Polarimeter



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)
CH3
H2N
C
H
COOH
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 models and space-filling models are
3D or spatial molecular models.
CHIRALITY
AND
CHIRAL
COMPOUNDS



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.



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 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.
S-ibuprofen


Many pharmaceuticals are chiral.
Often only one enantiomer is
clinically active.
O
a.
H
C
CH2CH3
b.
CH
HO
CH
CH2OH
c.
d.
Cl
CH3CCH2CH
Br
CHCH3
O
CH3CHCOH
NH2
SAMPLE EXERCISE
PRACTICE EXERCISE
How many chiral carbon atoms are there in the open-chain form
of fructose
Answer: three
PRACTICE EXERCISE
How many chiral carbon atoms are there in the open-chain form
of glucose
Solve: The carbon atoms numbered 2, 3, 4, and 5 each
have four different groups attached to them, as indicated
here:

Enantiomers have identical physical
and chemical properties except in two
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 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.
 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.
O
NH
O
O
O
H2C
NH
O
C
C
N
CH2
H
O
S thalidomide (effective drug)
The body racemises each
enantiomer, so even pure S is
dangerous as it converts to R in
the body.
O
N
H2C
CH2
H
O
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).
CH3
CH3
O
O
H
C
CH2
H3C
S carvone (caraway seed)
Caraway Seed has a warm, pungent,
slightly bitter flavour with aniseed overtones.
H2C
C
H
CH3
R carvone (spearmint)
CH3
CH3
CH2
C
H
H
C
CH2
CH3
H3C
S limonene (lemons)
R limonene (oranges)
Stereochemistry
Optical isomerism
Determination of Number of Enantiomers
[stereoisomers]
2n
where n = number of chiral carbins
n = zero
1
2
3
4
5
no possible stereoisomers
2 enantiomers are possible
4~ ~ ~
~ ~ ~ ~
8~ ~ ~ ~
~
~
16 ~
~ ~
~
~ ~
32 ~ ~
~
~
~
~
Optical isomerism
More than one chiral
carbon
Different chiral carbons
Same chiral carbons
CH3CH(Br)CH(Br)CH2CH3
CH3CH(Br)CH(Br)CH3
CH3CH(Br)CH(Br)CH2OH
CH3CH(OH)CH(OH)CH3
CH3CH(Br)CH(Cl)OH
CH3CH(Cl)CH(Br)NH2
CO2HCH(OH)CH(OH)CO2H
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 ………
Stereochemistry
Optical isomerism
(±)- Ethanolamine
CH3CH(OH)NH2
has one chiral carbon, so 2- enantiomers
H
H 2N
H
OH
H 2N
OH
CH3
CH3
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
H
OH
H 2N
CH3
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
OH > NH2 > CH3 > H
H 2N
1
2
3 CH3
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 2N
H
1
H 2N
OH
CH3
H 2N
H
OH
CH3
OH
2
CH3
H
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
H
(R)-ethanolamine
(+)- ethanolamine
Draw the formulas for the two enantiomers of each of the
following compunds
then assign each as Ror S
OH
Br
a-
C
H
CH3
b-
H3CH2C
C
H
CH3
Stereochemistry
(±)- CH3CH(Cl)CH(Br)NH2
n = 2 ….. So No. of stereoisomer 4
CH3 mirror
CH3
mirror
CH3
H
Cl
Cl
H
H
Cl
Cl
H
Br
Br
H
Br
H
H
NH2
CH3
H
Br
NH2
NH2
NH2
2
3
4
1
Enantiomers
1,3 and 1,4
2,3 and 2,4
Enantiomers
are diastereoisomers
Stereochemistry
Determination of ( AC ) in enatiomer 1
a. At C1 : Br > NH2 > C2 > H
Br
C2
2
Br
H
1
NH2
NH2
C2
H
AC at C1 is S
Stereochemistry
Optical isomerism
Determination of ( AC ) in enatiomer 1
a. At C2 : Cl > C1 > CH3 > H
C1
CH3
2
Cl
H
1
C1
CH3
Cl
H
AC at C2 is S
Stereochemistry
Optical isomerism
So for overall
1 ( 1S, 2S )
2 ( 1R, 2R )
similarly:
3 ( 1R, 2S )
4 ( 1S, 2R )
Enantiomers and diastereomers:
EXAMPLE:
2-Bromo-3-chlorobutane
Cont.
More than one chiral carbon

EXAMPLES:
A.
1,2-Dibromo-1-phenylpropane
B.
2,3,4-trihydroxybutanal
(erthyrose)

In the simplest case, they are compounds
which have internal plan of symmetry.

EXAMPLE:
 Tartaric acid
COOH
H
OH
H
OH
COOH
Stereochemistry
Optical isomerism COOHCH(OH)CH(OH)COOH
tartaric acid
Meso-compound are :
- superimposable mirror images
- only 3 stereoisomers
- optically inactive
COOHmirror
COOH mirror
COOH
HO
H
H
OH
HO
H
H
OH HO
COOH
1
COOH
2
Mesocompounds
H
COOH
OH HO
H
H
OH
COOH
H
COOH
4
3
Enantiomers
2R,3R-(+)
2S,3S-(-)
Cont.
Meso compounds

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.
Stereochemistry
Optical isomerism
Enantiomers
-Resolution : process that involves ……..
(±) ethanolamine
resolution
(+)-ehtanolamine
(-)-ethanolamine
Stereochemistry
Resolution of racemic mixture
1- treat the mixture with microorganism
H
H
N
Pseudomonas
Putida
N
CH3
N
CH3
N
(R,S) nicotine
(R)
2- using chiral reagent
( R) RCOOH
( S) RCOOH
+
( S) R’NH2
( R) RCOO - (S) R’NH3+
( S) RCOO - (S) R’NH3+
Examine the following structural formulas and select those that are chiral.