1) Chiral molecules can undergo three types of reactions at the chiral center: inversion, retention, and racemization. Inversion changes the configuration, retention keeps it the same, and racemization converts an enantiomer to a racemic mixture. 2) Racemization is the process of converting an optically active compound into a racemic mixture. It can occur through mechanisms like anion formation, thermal reactions, or reversible intermediate formation. Racemic mixtures contain equal amounts of both enantiomers and are optically inactive. 3) Resolution is the separation of a racemic mixture into its pure enantiomers, often by converting them into diastereomers with different properties like crystallization or

1. REACTION OF
CHIRAL
MOLECULES
Lecture by
SOWMIYA PERINBARAJ, M.Pharm
Assistant Professor
Dept. of Pharmaceutical Chemistry
SVCP

2. Introduction
❖ Chiral molecules undergoes three major reactions
at the chiral centre.
1)Inversion
2)Retention
3)Racemisation
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3. 1. INVERSION
➢ A process in which the relative configuration of an atom is changed.
➢ It follows SN2 Mechanism
➢ R isomer S isomer
➢ S isomer R isomer.
➢ Eg: isobutyl chloride
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4. 2. RACEMISATION
❑ The process in which optically active compounds are converted
into optically inactive compounds with zero optical activity.
❑ R isomer RR, RS isomer
❑ S isomer RS , SS isomer
❑ Racemic mixture:
❑ A mixture containing equal amount of d/l enantiomers (50:50)
❑ They are optically inactive.
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5. Eg:
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6. 3. RETENTION
✓ It is the process in which configuration of substrate and product remains the
same.
✓ In this reaction, bonds of chiral atoms do not break.
➢ R isomer R isomer
➢ S isomer S isomer.
➢ Eg: isoheptylchloride and isoheptylbromide
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7. Racemic
Modification &
Resolution of
Racemic mixture
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8. Racemic modification
❑ Racemic modification is the process of mixing of equal amounts
of a pair of enantiomers and is optically inactive due to external
compensation.
❑ Such a mixture is called Racemic mixture represented as dl or (+-)
❑ When enantiomers are mixed together, the rotation caused by a
molecule of one isomer is exactly balanced by an equal and
opposite rotation caused by another molecule of its enantiomer.
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9. Preparation of Racemic modification
1) By Mixing
❖ This is done by mixing of exactly equal amounts of two
enantiomers (d/l or (+-).
❖ Louis Pasteur studied a sample of (+-) –sodium
ammonium tartrate (racemic mixture) which contains
50% (+) – enantiomers and 50% (-) –enantiomers.
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10. 2) By Synthesis
+ The synthesis of asymmetric compounds from symmetric
compounds in the absence of optically active catalyst or circulated
polarised light always produce a racemic modification.
+ Eg: Formation of lactonitrile from acetaldehyde
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11. 3) By Racemisation
➢ Racemisation is the process of converting an optically active (d/l)
compound into the racemic modification.
➢ Racemization is the process of production of racemic modification
starting with one of the pure enantiomers.
➢ Important mechanisms for racemisation are
A) Thermal racemisation
B) By anion formation
C) By cation formation
D) By reversible formation of stable inactive
intermediates
E) By walden inversion
F) By chemical transformation
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12. A) THERMAL RACEMISATION
o Heating at a higher temperature make homolytic splitting of one of the four
bonds attached to the asymmetric carbon atoms.
o Eg: The racemization of a α-phenethyl chloride on distillation at atmospheric
pressure may be of this type.
B) By Anion formation
o Since the carbanions are generally planar, they are optically inactive. The
formation of carbanion intermediates is the common practice of racemisation.
o The ease of racemisation depends upon the acidity of hydrogen atom
o The more liable and acidic the hydrogen atom , the greater is ease of
racemisation.
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13. c) By cation formation
✓ Formation of cation as intermediates results in racemisation.
✓ Eg: (+)-1-chloroethylbenzene racemises on treatment with antimony
pentasulphide.
D) By reversible formation of stable inactive
intermediates
✓ Mechanism is same as that of anion and cation formation, but here
symmetrical, non-ionic stable intermediate is formed.
✓ Eg: optically active 1-chloroethylbenzene racemises easily in liquid
SO2, By a dehydrohalogenation process.
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14. E) By Walden inversion
▪ Certain SN2 reactions involving symmetric centres proceed with
inversion of configuration and thus may cause racemisation of the
original optically active compound.
▪ Eg: The racemization of 2-iodooctane by potassium iodide in
refluxing acetone.
F) By Chemical transformation
▪ In this method, an enantiomer is converted into racemic modification
without breaking any of the bond.
▪ Eg: 5-methyl-2-cyclohexyl acid phthalate has been racemised in
aqueous acetone at 100 °C.
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15. Resolution of Racemic
modification
➢ The process of separating a racemic modification into its pure
enantiomers is known as resolution.
➢ The enantiomers of the racemate must be temporarily converted
into diastereomers.
➢ It is quantitative and sometimes only one isomer will be
isolated.
➢ Several methods have been developed and type of separation
will be selected depending upon the nature of compound.
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16. 16

17. 1) Mechanical separation
❖ Introduced by Pasteur and also known as spontaneous resolution by
crytallisation.
❖ Applicable only for the racemic mixtures where the crystal forms of
enantiomers are enantiomorphous – which are separated by hand.
❖ Pasteur separated sodium ammonium tartrate racemate in this way
❖ He crystallized sodium ammonium tartrate racemate from a
concentrated solution at room temperature below 28 0C and separated
mechanically.
❖ The crystals of two forms have different shapes, can be separated
using magnifying lens and a small forceps.
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18. 2) Preferential crystallization by inoculation
+ This method involve seeding of a saturated solution of the racemic
mixture with a pure crystal of one of the two enantiomers.
+ The solution now become supersaturated with respect to the added
enantiomers.
+ It begins to crystallise out.
+ Eg. Resolution of free α-amino acid by adding corresponding d/l
isomers of amino acid.
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19. 3) Biochemical separation
+ It was introduced by Pasteur in 1858.
+ This method is based on fact that when certain micro
organisms like bacteria, fungi, yeast, moulds, etc are grown in
dilute solution of racemic mixture, they eat up one
enantiomer rapidly than other.
+ Example: the mould Penicillium glaucum preferentially
destroys the (+) isomer of racemic ammonium tartarate
leaving (-) ammonium tartarate in solution.9
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20. 4) Chromatographic separation
+ The racemic mixture can be separated by chromatography on
an optically active support.
+ The diastereomeric adsorbates which are formed have
different stabilities.
+ Thus one enantiomer will be held more tightly than the other
and would be eluted first.10
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21. 5) Kinetic method
+ This method is based on the fact that one of the enantiomer of
racemic mixture reacts faster than other with optically active
compound.
+ Eg: Menthol reacts faster with (+) mandelic acid than with (-)
mandelic acid.
+ Thus with difference in kinetics of reaction, racemic mixture
can be separated.
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22. 6) Precipitation
+ This method is based on formation of precipitate
by reaction between any reagent and racemic
mixture.
+ Example: (+) & (-) Narcotine when dissolved in
HCl, precipitates (+) Narcotine.
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23. 7) By Diastereomers
+ When racemic mixture is allowed to interact with optically
active material, it give a diastereomeric derivatives.
+ Diastereomer have different physical properties and hence
can easily separated into two component by fractional
crystallization.
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24. Asymmetric
Synthesis:
Partial &
Absolute
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25. Asymmetric Synthesis
+ The direct synthesis of an optically active compound from a
symmetric compound (optically inactive) with or without the
use of optically active reagent is known as asymmetric
synthesis.
The major approaches of asymmetric synthesis:
+ These are of two types
1) Partial asymmetric synthesis
2) Absolute asymmetric synthesis
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26. A) Partial Asymmetric synthesis
+ An optically active compound synthesised directly from
symmetric (achiral) compound by the intermediate use of semi
optically active compound is known as partial asymmetric
synthesis.
+ Examples:
1) Preparation of valeric acid from methyl ethyl malonic acid
with the aid of brucine.
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28. 2) Reduction of benzoyl formic acid to mandelic acid in
the presence of (-) menthol
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29. 3) Reduction of 3,3- dimethylbutane-2-one into (+)-
3,3-dimethylbutan-2-ol in presence of (+)-2-
methylbutylmagnesium chloride
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30. 4) Reduction of butan-2-one with LiAlH4 in presence of (+)-
camphor to (+)-isoborneol and (+)-butan-2-ol.
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5) Reformatsky reaction between acetophenone, (-)-
methylbromoacetate and Zinc to form (+)-β-hydroxy β-phenyl
butyric acid.

31. B) Absolute asymmetric synthesis
+ Absolue configuration is the synthesis of optically active products
from achiral substrate without the use of optically active reagents .
+ In this type of synthesis a physical presence of chirality is necessary .
+ Examples:
1) Addition of bromine to 2,4,6-trinitrostilbene give a dextrorotatory
product.
+ Here there is the use of circularly polarized light for the induction of
chirality.
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32. 2) Substituted tartaric acid having very small optical rotation can
be synthesised from ethyl fumarate and H2O2 under the influence
of dextro - circularly polarised light.
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33. The way to get
started is to quit
talking and
begin doing.
Walt Disney
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