Racemisation is the process where a pure enantiomer is converted into a 50/50 mixture of both enantiomers, called a racemate. This can occur through various chemical reactions or physical changes that allow for inversion or interchange of chiral centres. Resolution is the separation of the enantiomers in a racemate. Several methods can be used to induce and monitor racemisation, such as changes in pH, temperature, catalysts, or conformational changes. Resolution techniques include forming diastereomeric salts, molecular complexes, or exploiting kinetic or thermodynamic differences in reactions.

2. •Racemisation is the process when the enantiomer is converted into
racemic modification (i.e. chemical reactions) or when one pure form
of an enantiomer is converted into equal proportion of both
enantiomers, forming a racemate.
•Resolution is the process when a racemic modification is separated
into its constituent enantiomers.
•Racemisation is a thermodynamically favorable process and it
proceed spontaneously if a convenient pathway is available for the
interconversion of the enantiomers.
•It is reversible process because any mechanism of racemisation must
operate from either of the enantiomers.

3. •If a molecule contains more than one chiral centre and configurational
inversion takes place at one centre, the product formed is a diasteriomer
i.e epimer, the process is called as epimerization.
•Due to the free energy difference, the two epimers exists in unequal
amounts in equilibrium.
•Racemisation is usually monitored by observing the gradual zeroing of
optical rotation. 13C-NMR also gives a good probe for monitoring
epimerization of both optically active and inactive stereoisomers.

4. •If a ligand at a tetrahedral chiral centre is removed by heterolytic
cleavage leaving behind on anionic species, the latter undergoes
rapid inversion so that when the ligand recombines.
•An acidic proton is removed using mild to strong bases such as
Sodium Hydroxide and Sodium Alkoxides.

5. Example-
OH
Ph-C -C H (M e)C H 2 M e Ph-C -C (M e)C H 2 M e Ph-C -C (M e)C H 2 M e
O H 2O O O ------- (1)
Phenyl S-butyl ketone
OH O
P h -C H -C O 2 H P h -C -C O 2 P h -C = C
OH H 2O OH OH O
------- (2)
Mandelic acid

6. •When the concerned proton is very acidic as in the disulphone, the
carbanion may form in appropriate solvents without any base and
racemisation takes place spontaneously.
------- (3)
• Mineral acid also effect racemisation of a ketone containing an α-H.
------- (4)

7. •Electron withdrawing group may be detached from a chiral centre
with an electron pair leaving behind a cationic species.
•Racemisation occurs when the substrate is capable of giving rise to
a stable carbocation.
------- (5)
------- (6)

8. •Free radical having a near planar structure and if a chiral centre is
converted into a free radical pair by homolytic cleavage of a bond the
recombination of pair leads to racemic product.
•Example-
Benzylic allylic, tertiary stable radicals undergo racemisation under
the influence of heat or light.

9. •Enantiomers are interconverted through stable achiral intermediates
and get racemised.
•Example-
Secondary alcohol in the form of its aluminium derivative heated with
ketone (acetone), reversible oxidation- reduction done and an
equilibrium is established between enantiomers or diastereomers.

10. ------- (7)
M= dialkoxyaluminium
•Acid chloride of an optically active carboxylic acid, in presence
of tertiary amine undergoes racemisation through a ketone.
------- (8)

11. •Racemisation takes place through rotation around a single bond or
bonds and the interconversion usually takes place readily via an achiral
conformation.
•Most of these enantiomeric atropisomers racemise by application of
heat leads to bond stretching or bond behind and helps the non-polar
enantiomers to cross the planar transition state.
•Cyclic compounds which exist in enantiomeric conformations undergo
racemisation through ring inversion.
•Example-
cis-1,2-dimethylcyclohexane and cis-decalin

12. Fig: Racemisation through rotation around single bond
In above structural features i.e. a biphenyl derivative [(+)-methyl (-)-
methyl 2,6,2l,6l-tetranitrobiphenyl-4,4l-dicarboxylate] prepared by
Mislow and Bolstad.

13. •In SN2 reaction, the reaction of optically active 2-iodooctane with
Sodium iodide, the reaction becomes reversible and an equilibrium
between the two enantiomers leading to racemisation.
Fig: Conformational inversion in SN 2 reaction

14. •In SN 1 reaction, a rate determining step leaving behind a carbonium
ion and has a planar structure and so extensive racemisation occurs.
Fig: Retension of configuration: SN 1 mechanism

15. •A compound with a labile chiral centre can undergo configurational
change in solution at equilibrium. If there exists a chiral element in the
environment one or other of the enantiomers would predominate in
equilibrium and shows complete racemisation known as asymmetric
transformation.
•The change in the optical rotation is known as Mutarotaion.
Mutarotation is an experimental observation-phenomenological in
nature and does not have any mechanical implication.

16. •Conformational changes which occur in solution (involving a single
phase) is known as first order asymmetric transformation.
•Example-
All reducing sugars (excepting a few ketoses) and many of their
undergo first order asymmetric transformation and exhibit mutarotation.
•In glucose, equilibrium (in water) corresponds to 38% of the α- and
62% of the β-form.

17. Fig: First order asymmetric transformation in glucose
•Mechanism involves protonation of the oxide ring, depolarisation of
1-OH by base followed by ring opening to the aldehyde form.
•Its subsequent ring close to the original hemiacital or its epimer by
acid catalysts.

18. •Mutarotation due a structural change given with gluconolactone a
solution of which in water establishes between δ-glucono and
γ-gloconolactone through the intermediate gluconic acid.
Fig: Mutarotation due to saturated change

19. •In an asymmetric transformation one of the enantiomer or diasteriomers
crosses the phase boundry i.e. comes out of the solution as crystals or
immisible liquids known as second order asymmetric transformation.
•100% conversion of a racemic mixture into a pure enatiomer.
•Example-
A solution of glucose in ethanol is concentrated, the less soluble α-form
crystallises first and after equilibrium only α-form of glucose is obtained.
Crystallisation of glucose from pyridine gives the β-form only.

21. •Three types of crystalline forms,
i. Conglomerate with homochiral assemblies of enantiomers in a
single crystal.
ii. Racemic compounds containing equal number of (+) and (-)
isomers in the unit cell of crystal.
iii. Pseudoracemates with no preference for enantiomers in the crystal
structure.
•In the case of conglomerate, the two enantiomorphous crystals are
distinguishable visually and can be separated by hand-sorting with
the help of a magnifying glass and a pair of tweezers.
•The preferential crystallisation depends on the principle that the
solubility of the enantiomer is less than that of the racemic form.

22. • Pasteur developed method for the formation of diastereomeric salts
and their fractional crystallisation is the best method for resolution.
• Example-
Resolution of a racemic acid (±)-A with an optically pure base
(+)-B which combines with racemic acid gives two diastereomeric
salts respectively.
(±)-A + (+)-B (+)-A. (+)-B + (-)-A. (+)-B
•Two salts differ in properties such as solubility, boiling point and
adsorption coefficient.
•Diposition of the salt with mineral acid would furnish (+)-A in
enantiomerically pure form.

23. •Instead of forming stable salts or covalent compound with the
substrates and the resolving agents, have molecular complexes which
form easily and decompose easily which are suitable for resolution.
•Example-
Digitonin a steroidal saponin forms addition complexes with various
alcohols ex. Α-terpineol, isocarvomenthal and phenolic compounds
gives (+) 2- Naphthylcamphylamine.

24. Digitonin (+)-2-Nphthylcamphylamine
Fig: Some chiral complexing reagent

25. •Gas chromatography use for analysis as well as separation of
enantiomers.
•Trifluroacetyl derivatives of optically active amino acid have been
used for gas chromatographic resolution of racemic alcohols with
esters.
•Paper chromatography effects partial resolution of camphorsulphonic
acid.

26. •Rsolution based on two steps,
i. Epimerisation of a diatereomeric species.
Example-
Treatment 2-(p-carboxybenzyl)-1-hydrindanone with brucine in
acetone solution, diastereomers precipitates in over 90% yield.
O
OH
O
2-(p-carb ox y b en zy l)-1 -hy d rin d an o n e

27. ii. Precipitation of the predominant epimer .
Example-
(-)-menthyl ester of racemic phenylchloroacetic acid treated with base,
it epimerises and gives equilibrium mixture of esters with 57%
(-)- acid and 43%(+)- acid.
HO
O
Cl
p hen y lch lo ro acetic acid

28. i. Kinetic method of resolution:
.........thermodynamically controlled condition
.........kinetically controlled condition

29. •Racemic substrate i.e. (±)-A is react with an optically active reagent
i.e. (+)-B, shows two diastereomeric transition states , p* leading to
the p-diastereomer, (+)-A.(+)-B and n*leading to the n-diastereomer,
(-)-A.(+)-B.
ii. Kinetic method using diastereomeric substrate:
•A mixture of diastereomers used in a reaction with an achiral reagent.
•The two diastereomers are react at different rates and a partial
separation of diastereomers may be effected.
•Example-
Hydrolysis of mandelic acid and menthol shows partial resolution
and partial separation of diastereomeic esters.

30. •Biochemical method having important application in the resolution
of (±)-amino acids.
•Acetylated (±)-amino acid is treated with an enzyme ‘acylase I’ till
the half of the acetyl groups hydrolysed i.e. L-amino acid and
unhydrolysed group i.e. D-amino acid.