i upload racemic modification and resolution

1. WELCOME

2. Mr. DILIP R. DAVHARE
M.Pharm. IInd Sem. (Pharmaceutical Chemistry)
UNIVERSITY DEPARTMENT OF PHARMACEUTICAL SCIENCES,
RASHTRASANT TUKADOJI MAHARAJ
NAGPUR UNIVERSITY, NAGPUR

3. Contents.
 Defination
 History
 Method of racemic modification
 Properties of racemic modification
 Resolution of racemic modification

4. Defination
RACEMIC MODIFICATION
 A mixture of enantiomers is called a racemic modification.
 Racemic modification is optically inactive if the mixture is
50:50.
 When enantiomers are mixed together, the rotation caused
by a molecule of one isomer is exactly cancelled by an equal
and opposite rotation caused by a molecule of its
enantiomer.
 (dl) or (±) – lactic acid.

5. OPTICAL ISOMERS
The two forms are called optical isomers. Mirror
image non superimposable. Optical isomers also
called enantiomers.
C
C
CH3
OH
H OH
O
C
C
CH3
O
OH H
OH
(d) or (+) Lactic acid (l) or (-) Lactic acid
The phenomenon is called optical isomerism.
5

6. ENANTIOMERS
 Enantiomers Greek word enantio =
opposite
 Isomers that are mirror image of each
other are called enantiomers.
 Two stereoisomers that are not
superimposable mirror image of each
other.
2,3-Dichloropentane
CH3
C
C
C2
H5
H Cl
Cl H
CH3
C
C
C2
H5
Cl H
H Cl
6

7. Nomenclature
 A racemic mixture is denoted by the prefix (±)- or dl- ,
indicating an equal (1:1) mixture of dextro and levo
isomers. Also the prefix rac- (or racem-) or the
symbols RS and SR (all in italic letters) are used.
 If the ratio is not 1:1 (or is not known), the
prefix (+)/(−), D/L- or d/l- (with a slash) is used
instead.
 The usage of d and l is strongly discouraged by IUPAC.
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8. Racemic Mixtures
 Equal quantities of d- and l-enantiomers.
 Notation: (d,l) or ()
 No optical activity.
 The mixture may have different boiling point (b. p.) and
melting point (m. p.) from the enantiomers!
8

9. Racemic Products
If optically inactive reagents combine to form a chiral
molecule, a racemic mixture is formed.
9

10. Racemic Mixture
o
(g/mL) 1.7598 1.7598 1.7723
m.p. C 168-170 168-170 210-212
[] (degrees) - 12 + 12 0
(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid
Racemic Mixture (Racemate): 50/50 mixture of enantiomers
CO2H
CO2H
H OH
HO H H OH
HO H
CO2H
CO2H
R,R S,S
10

11. Figure 1. Classification of racemic modifications
11

12. 12
1. Conglomerate
If the molecules of the substance have a greater affinity
for the same enantiomer than for the opposite one, a
mechanical mixture of enantiomerically pure crystals will
result.
The melting point of the racemic conglomerate is always
lower than that of the pure enantiomer. Addition of a
small amount of one enantiomer to the conglomerate
increases the melting point.

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2. Pseudoracemate (sometimes racemic solid
solution)
 When there is no big difference in affinity between the
same and opposite enantiomers, then in contrast to the
racemic compound and the conglomerate, the two
enantiomers will coexist in an unordered manner in the
crystal lattice. Addition of a small amount of one
enantiomer changes the melting point just little bit or
not at all.

14. Formation of Racemic Modification
I. By Mixing:-
Racemic modification is by intimate mixing of
exactly equal amounts of dextorotatory (+) and
levorotatory (-) isomers. This process is associated
with an entropy mixing, since the racemic
modification represents a more random state of
affairs than the separate enantiomers.
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15. 2. By synthesis
Any synthesis of dissymmetric molecules, starting from
either symmetric molecules or a racemic modification
and using active reagent or catalysts and no asymmetric
physical influence always produces a racemic
modification.
The first method is exemplified by the bromination of
propionic acid to alpha bromopropionic ace by the Hell-
Volhard-Zelinsky (H-V-Z) Method.
two alpha hydrogen bears the same relationship to the other
and to the rest of the molecule each is replaced at the
15

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Rate as the other and equal numbers of (+) and (-) molecule
of alpha bromopropionic acid result.
Bromination of propionic acid
H C
COOH
CH3
H
H-V-Z H-V-ZBr C
COOH
H
CH3
H C
COOH
CH3
Br
Propionic Acid 2 Bromo Propionic Acid2 Bromo Propionic Acid
(-) (+)

17. 3. Epimerization, Mutarotation and
Asymmetric Transformation.
a) Epimerization :- Change in configuration
(arrangement of the group) at one asymmetric atom
in a compound having more than one such atom.
Epimerization of an optically active compound does
not involve racemization.
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b) Mutarotation and first-order asymmetric Transformation. :-
In 1846 Dubrunfaut discovered that, When glucose is
dissolved in water and the optical activity of the solution
observed, there is a gradual change in roatation from an
initial value corresponding to [a]20 D of +1110 to an
equilibrium value of [a]20 D +52.50
In the case of (+) glucose mutarotation involves a change of
configuration at the No. 1 carbon ( called anomeric center)
owing to an opeining and reclosing of the hemiacetal ring.

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 The intermediate open-chain aldegyde form is present in
negligbly small concentration. Equilibrium corresponds to
38% of the alpha and 62% of the beta form.
H C OH
C
C
OHH
C
C
CH2OH
HHO
OHH
OH
H C
C
C
OHH
C
C
CH2OH
HHO
OHH
OHH
O HO C
C
C
C
C
CH2OH
H
OHH
HHO
OHH
OH
D Glucose
D GlucoseFructose
+1110
+19.20Equilibrium mixture +52.50

20. Properties of Racemic Modification
1. Physical properties
 Racemate may have different physical properties from
either of the pure enantiomers because of the differential
intermolecular interactions . The change from a pure
enantiomer to a racemate can change its density, melting
point, solubility, heat of fusion, refractive index, and its
various spectra. Crystallization of a racemate can result in
separate (+) and (−) forms, or a single racemic compound.
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a) Racemic Mixture :- In a crystal each enatatiomers
has a greater affinity for molecule of the same kind
than for molecule of the other enantiomer. In that
case once molecule of the (+) form is laid down in
the crystal, only (+) molecule will grow on it. And
similarly (-).
eg. Solubility and Melting Point of racemic
mixture.

22. Resolution
The separation of a racemate into its components, the
pure enantiomers, is called resolution.
22

23. used for resolution of racemic mixtures
1. Mechanical Separation or Spontaneous Resolution:-
It was the first method used by Pasteur (1884) for the resolution
of sodium ammonium tartarate which crystallizes out in the
form of racemic mixtures below 270C.
In this method crystals of the two forms have different shapes,
being mirror image of each other. They can be separated with
the help of magnifying lens and small forceps. This method is
laborious and is applicable to onlu those isomers having
different crystal. 23

24. 2. Preferential crystallization by inoculation
(Gernez-1866)
This method involves the seeding of a saturated solution of the
racemic mixture with a pure crystal of one of the two enantiomers.
The solution now becomes supersaturated with respect to the
added enantiomers and after sometimes cooling it begins to
crystallize out.
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 Example:-
 1.Harda (1865) obtained total optical resolution of free alpha-
amino acids with the aid of ‘/” or d-isomers of the
ccorresponding amino acid.
 Sometimes seeds with a a crystal of optically active form of
another molecule re also possible.
 Crystal of (-) asparagines crystallizes out (±) sodium
ammonium tartarate from solution of racemic modification.

26.  3. Biochemical separation:
 This method is based on the fact that when certain micro-
organisms (e.g. bacteria yeast, mould, fungi) are grown in
dilute solution of racemic modification they assimilate on one
enantiomers rapidly than the others.
 e.g. The mould penicillin glaucum preferentially destroys the
(+) isomers of racemic ammonium tartarate and thus leaves
the (-) ammonium tartarate in solution.
 Thia method has certain disadvantage viz.
 One isomer is always destroyed and sometimes some of the
other isomer is also destroyed.
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 Sometimes it is impracticable to find a
microorganism ( Enzyme) applicable to given
racemic form.
 Sometimes the racemic modification may be toxic
for the micro-organism and may destroy the enzyme
or may not be attacked by either ot them.

28. 4. By diastereomerism ( Pasteur-1858)
 This method converting the eanantiomers of a racemic
modification to diastereomers with the aid of a pure
enantiomers of other compound. Diastereomers are non-
identical, they have different physical properties and hence
easily be separated its two compounds by fractional
crystallization. After complete separation of the two
diastereomers.
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 Hence success depend upon:-
 Diastereomers- easily formed in crystalline form.
 Easy to convert back into parent compound.
 Resolving agent should be cheaper or readily
prepared and recoverable.

30. Biological significance
Additionally, many psychotropic drugs show differing
activity or efficacy between isomers,
e.g. amphetamine is often dispensed as racemic salts
while the more active dextro amphetamine is reserved
for refractory cases or more severe indications.
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31. Biological Discrimination

32. References:-
E.L.Eliel and S.H. Wilen, Stereochemistry of organic
compounds, A Wiley-Interscience Publication , John
Wiley & Sons, New York.
E.L. Eliel Stereochemistry of carbon compounds, Tata
McGraw-Hill Publishing Company Ltd, New Delhi.
R.T. Morrison, R.N. Boyd, Textbook of Organic
Chemistry, Sixth Edition, Prentice Hall Of India Pvt.
Ltd. , New Delhi.

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