Tribhuvan University
Institute of Science and Technology
Master of Science( M.Sc.)
M.Sc. 2nd Semester
Organic Chemistry
(Chem. 555)
Group B
Stereochemistry
____________________
Prof. Dr. A.D. Mishra,
Tribhuvan University,
Department of Chemistry, P.N. Campus, Pokhara, Nepal
Email: mishraad71@gmail.com
1
Stereochemistry
Day-1
• The word “stereo" has been derived from Greek language,
where it means “solid”.
• It is used with reference to three-dimensional structure of
compounds like solid objects.
• Stereochemistry is a branch of chemistry that deals with
the spatial arrangement of atoms and groups in molecules
and the effect of it on their physical and chemical
properties.
2
Contd…
• In stereochemistry, the molecules are considered as 3D solid objects.
• Objects can be categorized as 0D, 1d, 2D and 3D based on dimensions
0D
1D
2D
3D
Fig: Dimensions of objects
3
Molecular structures can be represented by three ways:
Fig: Fischer projection formula
Fig: Newman projection formula
Fig: Sawhorse projection formula
4
Molecular Symmetry
• The property of molecules by virtue of which it can be
divided into two identical parts is called molecular symmetry.
• Symmetry can be studied with different elements called
symmetry elements.
• Main symmetry elements are:
1. Plane of symmetry
2. Axis of symmetry
3. Centre of symmetry
4. Rotation symmetry
5. Reflection symmetry
5
1. Plane of symmetry (σ)
• A line by which a molecule can be divided into two identical
halves is called plane of symmetry.
• It is denoted with σ and called as σ operation.
• Plane of symmetry is also called as mirror plane
• Objects which can be divided into two identical halves are
called symmetric objects and others which can't be divided into
two identical halves are called asymmetric objects.
e.g., human hand is asymmetric, and a ball is symmetric objects.
6
Contd…
Fig: symmetric and asymmetric objects
7
Contd..
• Tartaric acid possesses a plane of symmetry
• It is optically inactive due to plane of symmetry.
Fig: Plane of symmetry in tartaric acid molecule
8
Contd…..
• All the planar molecules possess at least one plane of symmetry.
e.g., 1,2-dichloroethene possesses one plane of symmetry, water
molecule possesses two planes of symmetry and ammonia molecule
possesses three planes of symmetry.
• Angles between the planes of symmetry are called dihedral angles.
• Dihedral angle of water molecule is 90° and that of ammonia is 60°.
Fig: Plane of symmetry in water molecule
Fig: Plane of symmetry in ammonia molecule
9
2. Axis of Symmetry (Cn)
Day 2
• The imaginary line through which a molecule is rotated to
obtain two or more structures identical to the original
structure is called axis of symmetry.
• Different three-dimensional structures are formed on rotating
the molecule horizontally or vertically around this axis.
• Axis of symmetry is represented by Cn which may range up to
Cꝏ. where ‘n’ represents number of folds of symmetry and its
value can be obtained by 360/θ
• Axis of symmetry originates at the point of intersection of
plane of symmetry.
10
Contd…
For example, H2O molecule has two-fold axis of symmetry, NH3 and CHCl3
have three-fold axis of symmetry each i.e., C2 and C3 respectively.
• Sometimes, axis of symmetry and plane of symmetry are same.
For example, plane of symmetry in H20 is 2 and axis of symmetry also 2.
• Similarly, in NH3 molecule, plane of symmetry and axis of symmetry both
are 3.
Fig. axis of symmetry in water molecule
11
Contd…
• Axis of symmetry may be vertical as well as horizontal
• For example, Benzene has C6 axis of symmetry, i.e., vertical as well as
horizontal axis.
• This symmetry of benzene is called dihedral symmetry.
Fig. axis of symmetry in benzene molecule
12
Contd…
• Similarly, Cis 1,3-dimethyl cyclobutane has vertical C2 axis, and in trans
1,3-dimethyl cyclobutane the axis is horizontal.
• Trans dichlorothene has C2 axis and cyclopropane has C3 axis.
Fig. axis of symmetry in cis-1,3- dimethyl cyclobutane
13
Cont.….
• Some molecules do not have axis of symmetry as it can’t give identical
structures on rotating by 360°.
• For example, Nitrosyl chloride
• Linear molecules with a vertical plane of symmetry show Cꝏ axis.
• For example, hydrogen molecule has infinite fold of axis of symmetry
• This molecule possesses cylindrical symmetry with Cꝏ axis
Fig. lack of axis of symmetry
Fig. cylindrical symmetry in molecules
14
Contd….
• Similarly, acetylene, oxygen, carbon dioxide, etc. molecules also
have Cꝏ axis of symmetry
• These molecules possess many Cꝏ axis of symmetry
Fig. cylindrical symmetry in some linear molecules
15
Contd…
• Some other linear molecules like HCl, HCN, COS, etc do not have
cylindrical axis as the atoms are not same on the either side of the
bond.
• These molecules show conical symmetry with Cꝏ axis like in
cylindrical symmetry.
• These molecules possess only one Cꝏ axis of symmetry.
O=C=S
H-C≡N
H-Cl
Carbonyl sulphide
hydrogen cyanide
hydrogen chloride
• On the other hand, some molecules with spherical shape show
spherical symmetry because they possess many Cꝏ axis.
16
Contd…
Fig. conical symmetry in some linear molecules
Fig. spherical
symmetry in spheres
17
3. Centre of symmetry
Day 3
• The point at which all the axis of planes are intersected is called
Centre of symmetry.
• The initial conformer is obtained when the molecule is rotated by 360
vertically or horizontally.
e.g., 2,4–dimethylcyclobutane–1,3 –dicarboxylic acid
18
4. Rotation symmetry
• The symmetry which involves formation of identical molecule when it
is rotated by certain angle is called rotation symmetry.
• Thus, formed molecule is the reflection of one half over the next.
• One half is supposed to put on the other side of the next half like in
mirror image
e.g., 3,3’–dichloro–3,3’–dimethylhexane shows rotation symmetry.
19
5. Reflection symmetry
• The symmetry which involves formation of mirror image when
reflected is called reflection symmetry.
• The initial molecule is superimposable to its mirror image.
e.g., methane, water, ammonia, benzene, bromochlorofluoromethane,
etc. show reflection symmetry.
20
Symmetry operators and symmetry point groups
Day 4
• An operation of a molecule that carries it into a position
indistinguishable from the original position is called
symmetry operation.
• The operation can be brought about by different symmetry
elements, e.g., plane of symmetry, axis of symmetry, Centre
of symmetry, reflection and rotation symmetry.
• These elements are called symmetry operators.
21
Contd…
• For example, operation of C2 and C4 axis in following compounds:
Fig. operation of C2 and C4 axis in cyclobutanes
22
Contd…
• Rotation of this molecule about its axis gives rise to 3 additional
superimposable species by 90°, 180°, 270°, respectively and rotation by
360° leads back to original position.
• Altogether 4 identical species are obtained for the rotation of the
compound about its axis and thus the symmetry is denoted with C4.
• These symmetry operations so performed are called E, C14, C24 and C34,
where E is identity operation.
• The sum of possible operation is called symmetry point groups and the
number of possible species obtained is called order of group.
• In the case of C4 , there are 4 operations: E, C14, C24 and C34 . So, the
order of group in this operation is also 4, i.e., n.
23
Point groups containing chiral molecules
• Chiral molecules necessarily belong to point groups: C1, Cn or
Dn
1. Point group C1
• This point group has lowest degree of symmetry or no
symmetry at all.
• It implies in the case of asymmetric molecules.
• The symmetry in these molecules is only one-fold axis, C1 and
this point group is denoted as C1 , its order is 1.
• The compounds can be considered as mirror images.
24
Contd…
Fig. C1 operation in bromochlorofluoro methane
25
2. Point groups Cn
• In the Cn point groups, the only symmetry element is the Cn axis,
where ‘n’ denotes the number of axis, e.g., n may be 2, 3, 4, 5, 6, etc.
• Based on the value of n, point groups Cn may be specified as C2, C3, C4,
C5, C6, etc.
• C2, C3, C4, C5, C6 divides the molecule into 2, 3, 4, 5 and 6 identical
fragments respectively through certain axes.
• Point group C2 is of fairly common occurrence
• Point group C3 is quite rare.
26
Contd..
Fig. (+) or (-) tartaric acid.
Fig. Biphenyls
27
Contd…
Fig. Trans-3,7,11- trimethyl cyclododeca- 1,5,9- triene
Fig. Tri-o-thymotide
28
3. Point groups Dn
• These are called dihedral point groups.
• These point groups are characterized by nC2 axes perpendicular
to the main Cn axis.
• The symmetry of these point groups is quite high.
• The axis of highest multiplicity is taken as the main axis.
• The Dn point group may be D2, D3 , D4 , etc. based on the
diagonal number of axes: 2, 3, 4, etc. respectively.
• The order of Dn point groups is 2n.
29
For example,
Fig. D2 point groups in twistane
Fig. D3 point groups in triphenylene
30
Point groups containing only achiral molecules
Day 5
• Point groups other than Cn and Dn generally have planes, a Centre or an
alternating axis of symmetry, and thus are achiral.
• These point groups increase the number of symmetry elements.
• Some point groups in achiral molecules are:
1. Point group Cs
• This point group has a symmetry plane σ only.
• Different conformational structures are possible due to this point
group.
31
For example,
Chloroethene
Metabromochloro Benzene
32
2. Point group Sn
• This point group has Centre of symmetry with an n-fold alternating
axis of symmetry.
• The molecules possess axis of rotation as well.
• n may have odd or even values ranging from 1.
• The order of point group Sn is n.
For example, meso-2,3- dichlorobutane
Meso-2,3-dichlorobutane
33
3. Point group Cnv
• This point group has a single Cn axis and n symmetry planes vertically
σv.
• Symmetry planes intersect at the centre of symmetry.
• The plane of symmetry lies right angle to each other .
• n may have 2, 3, 4, 5, etc. values.
• The order of Cnv is 2n.
For example, if C2v is there, the point order will be 4.
Cis-1,2-dichloethene
meta-dichloro Benzene
34
4. Point groups Cnh
• This point group has a Cn axis but only a single symmetry plane in
horizontal manner σh.
• The plane of symmetry is perpendicular to the axis.
• n may have values 2, 3, 4, 5, 6, etc.
glyoxal
1,4-dichloro-2,5-dibromobenzene
Phloroglucinol
35
5. Point groups Dnd
• This point group has dihedral symmetry with a Cn axis and nC2 axes
perpendicular to it.
• There are n symmetry planes intersecting in the principal axis.
• The symmetry planes are diagonal σd.
• n may have values 2, 3, 4, 5, 6, etc.
• The order of point group is 2n.
Spiranes
Biphenyls
36
6. Point group Dnh
• This symmetry point group has dihedral Cn axis and horizontal plane
of symmetry σh.
• It is like Dnd and more common than it.
• The values of n ranges from 2, 3, 4, 5, 6, etc.
For examples,
Ethene
1,4-dichlorobenzene
37
Point groups corresponding to the platonic solids: Td, Oh, Ih
day 6
• Highly symmetric bodies like tetrahedron, cube, octahedron,
dodecahedron, and icosahedron are known as platonic solids for they have
been mentioned by plato.
• These bodies are nowadays represented by certain molecular structures.
• Among platonic solids, some commonly used molecular structures are
mentioned below:
1. The tetrahedral point group(Td):
• The point group of the regular tetrahedron is denoted with the symbol Td.
• A tetrahedron has four axes passing through a center and six σd planes.
Example,
38
Methane
Tetrahedrane
39
2. The cubic point group (Oh):
• The cube and the octahedron belong to the octahedral point group
denoted as Oh.
• This group has three axes and nine σ planes passing through a Centre.
Examples:
Cubane(C8H8)
Sulphurhexafluoride
40
3. The Icosahedral point group (Ih)
• These are point groups in regular polyhedral molecular structures
denoted with Ih.
• Dodecahedron and icosahedron are prominent structures in this
category.
• Dodecahedron has 12 faces in the shape of regular pentagon and
icosahedron has 20 faces in the shape of equilateral traingles.
• These are polyaxes and polyplanar structures with polymeric order.
• For example,
41
Racemization and methods of resolution
Day 7
Isomerism
• The phenomenon which involves formation of different structures from
same molecular formula is called isomerism and the compounds thus
formed as isomers.
• The isomers differ in their physical and chemical properties.
• Isomerism can be classified into two classes:
1. Structural isomerism
• The isomerism which involves different structures is called structural
isomerism.
• Structural isomers possess entirely different physical and chemical
properties.
• Structural isomerism may be of following types.
Chain isomerism, positional isomerism, functional isomerism and metamerism.
42
2. Stereoisomerism
• It involves same molecular structure but different arrangement of atoms or
groups with respect to space.
• The compounds are called stereoisomers.
• Stereoisomerism is three dimensional study of molecules.
• Stereoisomerism is of two types:
a. Geometrical isomerism
• The isomers generated due to different arrangement of atoms or groups
with respect to double bond are called geometrical isomers.
• Free rotation is restricted due to double bonds in between two atoms,
generally carbon atoms in case of organic compounds.
• Geometrical isomerism may be of two types:
i. Cis-isomerism (z-isomerism)
ii. Trans-isomerism (E-isomerism)
43
• Same atoms or same groups lie on the same side of double bond in
cis-isomers.
• Same atoms or groups lie on the opposite side of double bond in
trans-isomers.
• If the atoms or groups are not same, then the heavier atoms or
groups are considered to be on the same side to specify the isomer
with z (z=zusamen, means same side in German language) and they
are considered to be on the opposite side to specify the isomers with
E (E=entgegen, means opposite side in German language)
44
• For example,
Cis-1,2-dichloroethene
Z-bromochlorodeuteroethene
Trans-1,2-dichloroethene
E-bromochlorodeuteroethene
45
b. Optical isomerism
• The isomers which show their action on plane polarized light are
optical isomers.
• The light which vibrate only in one direction is called plane polarized
light.
• Optically active compounds possess at least one chiral center.
• They may rotate plane polarized light to right or left, i.e., these
compounds may be dextrorotatory (d or +) or laevorotatory (l or -)
• A compound containing chiral Centre forms 2n stereoisomers.
• Stereoisomers may be enantiomers and diastereomers.
46
• Mirror image stereoisomers are called enantiomers and non-mirror
image stereoisomers as diastereomers.
• Enantiomers possess equal and opposite optical rotation but
diastereomers may or may not possess equal and opposite rotation.
• Optical rotation is measured with Polari meter.
47
For example, stereoisomers of one chiral Centre and two chiral centers
Stereoisomers of lactic acid
Stereoisomers of tartaric acid
48
• If the molecule possess plane of symmetry which divides
molecules into two halves, i.e., one half is mirror image to
next half, it is called meso isomers.
• Meso isomer is denoted with (±)specification.
• A meso compound is optically inactive because the optical
rotation caused by one half is equal and opposite to the
rotation caused by next half.
• E.g., meso-tartaric acid.
Mesotartaric acid
49
Racemization and Methods of Resolution
Day 8
• The process of converting an optically active compound into a
mixture of two enantiomers with equal amount is called
racemisation.
• Equimolar mixture of the enantiomers is called racemic mixture or
racemic modification.
• Racemic modification is optically inactive because of equal
proportions of (+) and (-) isomers.
• Racemization is accompanied by symmetrical intermediate where
inversion and retention are equal.
50
For example,
51
Mechanism of Racemization
• Racemization may take place by following processes:
1. Thermal racemization
• In this process one of the bond in asymmetric carbon atom is broken
down by the action of heat to give symmetric intermediate.
• Thus obtained symmetric intermediate undergoes reaction with the
reactants to give equimolar mixture of (+) and (-) enantiomers.
e.g., distillation of α-phenylethyl chloride gives (+) and (-)
α-phenylethyl chloride in equal amount.
52
Racemisation of alpa-phenylethylchloride
53
2. Anion formation process (Base catalyzed process)
• In this process, a base abstracts hydrogen ion from an optically active
compound and forms an anion (carbanion)
• Carbanion thus formed gives rise to racemic mixture.
For example, a carbonyl compound gives carbanion by attack of alkali,
which then forms enol followed by conversion into (+) and (-)
enantiomers by hydrogen transfer.
54
Example, 3-methyl-2-pentanone gives (+) and (-) 3-methyl-2pentanones.
55
3. Cation formation process
• In this process, a cation is formed from optically active compound by
the action of a Lewis acid.
• Cation is a symmetrical species and thus gives racemic mixture by the
action of a nucleophile.
56
For example, reaction between phenylethyl chloride with
antimony pentachloride gives enantiomeric mixture with equal
amount.
(-)
Racemisation by cation formation process
57
4. Walden inversion process
• A substitution reaction which leads by SN2 mechanism, follows
inversion of configuration.
• The product possesses opposite rotation to the initial compound.
• The process is called Walden inversion.
• The reaction is carried out till the concentration of product and the
reactant becomes equal.
• A transition state, stereo chemically symmetrical is formed.
For example, Nucleophilic substitution in alkyl halide.
58
SN2 mechanism: Walden inversion
59
5. Rotation process
• Rotation about single bond also causes racemization.
• It is possible in case of configurational isomers i.e., cis-trans
isomerization.
• Cis and trans isomers have got opposite optical rotation.
• This isomerization may be caused by the action of heat on an isomer,
i.e., trans or cis isomers.
• Non-planar isomers are optically active which are obtained from
planar isomers on heating.
For example, substituted biphenyls.
60
Rotational racemerisation in biphenyls
61
6. Epimerisation
• Optically active compounds which differ in configuration about C-2
position are called epimers and the process as epimerization.
• It is vary common in the lengthening carbon chain of aldoses by
Kiliani-Fischer synthesis.
• Here addition of HCN on an aldose gives epimeric cyano-hydrins, i.e.,
-OH on C-2 lies on left in one product and on right in other product.
• in this way 50:50 mixture of (+) and (-) isomers is obtained.
62
For example,
Synthesis of cyanohydrins from aldoses
63
7. Racemisation of Amino acids
• Amino acids are bifunctional compounds and can be racemised under
the catalytic action of an acid or a base.
• Amino acid may form carboxylate or carbanion in the process.
• These ions are then subjected to substitution reactions to obtain
racemic mixture based on the composition or nature of the
substituent.
• Reaction is carried out until equimolar mixtures of either isomers is
obtained.
64
Racemisation in amino acids
65
Mutarotation
Day 9
• Some optically active compounds undergo change in the structure to
form equilibrium state.
• One of such compounds is D(+) glucose which exists in two isomeric
forms, i.e., α ̶ D(+) and β ̶ D(+) glucose in cyclic structure.
• Optical isomers which differ in configuration at C ̶ 1 atom are called
anomers.
• The anomer with higher optical rotation is called α and that with
lower rotation is called β isomer.
• α ̶ D(+)glucose is changed into β ̶ D(+) glucose through open-chain
structure.
66
Contd..
• Interconversion of α into β isomer establishes an equilibrium with
open-chain structure.
• When α ̶ D(+) glucose is dissolved in water, its specific rotation
changes from +112° to 52.7° and when β-form is dissolved in water,
its specific rotation gradually changes from +19° to 52.7°.
• This change in optical rotation due to change in the structure is called
mutarotation.
Mutarotation in glucose
67
Mutarotation of Glucose
68
Racemates
Day 10
• Optically active compounds exist in the form of racemic mixture or
racemic modification.
• The compounds which exist in racemic mixture may form racemates,
i.e.,new combined product.
• Racemates may exist in liquid, solid or gaseous states.
• They may exist in binary phases as well.
• The temperature which causes binary phase is called transition
temperature.
• The properties of racemates may differ from that of pure enantiomers
in isolation.
69
• Racemates in crystalline form are called conglomerates.
• H-bonding, unit cell inclusion, molecular affinity, molecular disaffinity,
etc are reasons for difference in properties of racemates and
enantiomerically pure forms, i.e., enantiomers.
• Some properties like m.p, solubility, density, vapour pressure, etc. can
be studied for racemates and enantiomers.
70
1. Melting point
• At ordinary conditions, the proportions of either of enantiomers is
equal in a racemic mixture , however it is changed beyond transition
temperature.
• This causes difference in melting point of racemic mixture in
comparison to pure enantiomers.
• Generally mp of racemic mixtures is less than that of pure enantiomer
as it is considered to be impure mixture of two compounds.
• Melting point of (+) and (-) enantiomer coincided at certain
temperature which is called as eutectic point.
• For example, m.p. of sodium ammonium tartrate.
71
Melting point of racemic mixture
72
• Interaction of enantiomers may give rise to new compound called
racemate.
• Racemate differ from racemic mixture in the sense of interaction and
isolation.
• Racemate is formed above transition temperature and below this
racemic mixture is formed.
For example,
Sodium ammonium tartrate gives racemic mixture below 27°C and
above this it gives racemate.
• Melting point of a racemate generally is higher than that of
enantiomer.
73
Melting point of racemate
74
2. Solubility
• Solubility is dissolution power of solute with solvent.
• Solubility of racemic mixture is higher than that of pure enantiomer
because both (+) and (-) isomers interact with the solvent separately.
• But the solubility of racemate is generally lower than that of pure
enantiomer because of blockade of free solvent interacting sites of
enantiomers during compound formation.
75
Solubility of racemic mixture
Solubility of racemate
76
3. Density
• Density is mass of matter per unit volume and thus depends upon
molecular mass.
• It also depends upon intermolecular distance.
• Intermolecular forces cause aggregation of molecules, e.g., Hbonding, dipole-dipole interaction, dimerisation, etc.
• Normally density of racemates is higher than that of pure
enantiomers due to coupling of molecules to form mew compounds.
• However, the density of cage-crystallites is less than enantiomers in
liquid state.
For example, density of a dimer is higher than that of monomer
77
4. Vapour pressure
• Some liquid and solid sublimates have got vapour pressure at certain
temperature.
• Racemates with low boiling point or sublimation temperature possess
high vapour pressure.
• Low heat of vaporization increases vapour pressure of racemates.
• Vapour pressure of pure enantiomers is higher than that of racemates
as racemates block the reactive sites of enantiomers to form
compounds.
For example, vapour pressure of amino acids is higher than that of
peptides.
78
5. Infrared spectra
Day 11
• IR spectra give the information about functional groups due to bond
stretching and bending frequencies.
• IR absorption frequencies differ based on the nature of bonding in the
molecules.
• IR absorption frequencies of recemate and corresponding enantiomers
differ due to molecular structures.
• Racemates possess H-bonding and dimerization which alters absorption of
IR radiation.
• For example, lactic acid, tartaric acid, amino acids, phthalic acid, aldoses,
etc.
• -C=O, O-H, N-H, C-O, etc absorption frequencies differ in their racemates
and corresponding enantiomers.
79
6. Nuclear Magnetic Resonance Spectra
• NMR spectra gives idea of environment of H atoms, C atoms and
other atoms like P, S, X, etc.in the molecules.
• Since racemates are dimers or conglomerates of enantiomers, their
structure and environment of H and C atoms mainly differ and thus
NMR peak differ in position, multiplication and intensities from their
corresponding enantiomers and diastereomers.
• Change in electronic density, bond length, and additional bond
formation in racemates are main causes of difference in NMR signals.
For example, Mesotartaric acid, dimethyl succinic acid, etc. may form
conglomerate (crystallite) and thus account for change in NMR signals.
80
7. Chromatography
• Chromatography is used to identify and separate the component of a
mixture, due to difference in relative flow rate on stationary phase.
• Mobile phase separates the components at different distances which
can be isolated and identified.
• Rf value of racemates differ from the corresponding enantiomers or
diastereomers because recemate is new compound formed by the
union of enantiomers.
• For example, nicotine, amino acids, naphthol, etc. may form dimers
and thus show different Rf value as compared to pure enantiomer.
81
8. Biological properties
• Racemates differ in some biological properties due to interaction with
various cellular, tissues and body organs compared to corresponding
enantiomers or diastereomers.
• This difference is due to molecular compositions.
• Odour, sweetness, biodegradation, etc. differ for racemates and
enantiomers.
• For example, monosaccaride is very sweet whereas disaccharide and
polysaccharides are less sweet in taste.
• Similarly, asparagine is sweet whereas its dimer is almost tasteless.
82
Determination of enantiomer and diastereomer
composition
Day 12
• An optically active compound may contain one or more chiral centers
and thus posses different enantiomers and diastereomers.
• Total number of stereoisomers is equal to 2n, where ‘n’ is the number
of chiral centers.
• The amount of a particular enantiomer or diastereomer can be
determined in the racemic mixture by different method:
83
1. Isotopic dilution method
• This method includes the isolation of a particular enantiomer from a
mixture of stereoisomers by using external isotopically labelled
enantiomer.
• Certain amount of known enantiomer labelled isotopically is added to
enantiomeric mixture with unknown concentration followed by
crystallization to obtain the isotopic enantiomer back.
• Initial and retrieved amount of isotopic enantiomer differs.
• Isolation of a pure enantiomer leads to loss in amount which is
calculated by comparing initial and retrieved amount of isotopic
enantiomer.
• The same loss takes place to the enantiomer of our interest.
84
• Making a sum of retrieved and lost amount of that enantiomer, one can
find the composition of that stereomeric mixture.
• The composition of this particular enantiomer can be calculated as
percentage amount for our convenience.
For example,
• Wt. of stereomixture = W1 gm
• Wt. of isotopic enantiomer added = W2 gm
• Wt. of retrieved isotopic enantiomer = W3 gm
• Wt. of lost isotopic enantiomer = (W2 - W3) gm
(W2 − W3)
• Percentage loss of isotopic enantiomer =
x 100 gm
W2
• This loss account for W1 gm of stereomixture
• The same calculation is done for non-isotopic enantiomer in W1 gm of
stereomixture or racemic mixture.
85
2. Kinetic method
• Rate of reaction of enantiomers differ considerably which can be used
to find out its concentration in the mixture.
• The amount of desired product is determined so as to determine the
concentration of that enantiomer in the stereomixture.
• The higher the amount of product obtained, the higher will
concentration of that enantiomer in racemic mixture.
• Non-racemic chiral reagent are reacted with the mixture in this
method.
• The reagent should be stereoselective, i.e., it reacts with only one
enantiomer leaving behind the another.
86
• For example,
• Enzyme specific reactions like oxidation of α-hydroxy acids with
nicotinamide adenine dinucleotide (NAD) can be used to determine
concentration of the acid in a racemic mixture.
• The reactions may be non- enzymatic as well, where comparison of
rate constants of either enantiomers gives their concentration in the
mixture.
• E.g., comparative reactivity of isomeric hydrocarbons may determine
their concentration in the mixtures.
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Resolution of Racemic Mixture
Day 13
• Separation of a racemic mixture into pure enantiomers is called
resolution.
• Generally it can be done by physical methods, chemical methods and
enzymatic methods.
• Physical method involves mechanical separation of crystals of
enantiomers as their crystals are visible distinctly. It is less applicable
because separation of crystals is difficult
• Chemical and enzymatic methods are more considerable for
separation purpose.
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1. Chemical method
• In this method, racemic mixture is reacted with an external agent to form
adduct.
• The adduct is separated by dissolving in suitable solvent as the salts formed
possess different solubility in a particular solvent.
• Recrystallization of solution gives back to pure enantiomers.
• For example,
a) Resolution of racemic mixture of tartaric acid
• a racemic mixture of tartaric acid can be resolved by reacting it with
resolving agents like (+) Cinchotoxine or (+) Quinotoxine.
• The adduct may be (+) tartaric and salt and (-) tartaric acid salts.
• Both the salts are separated easily and the enantiomers are regenerated
from it in pure state.
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Racemic tartaric acid
90
b) Resolution of α, β– unsaturated ketones
• α-β unsaturated ketones are reacted with a thiol in presence of an
amine.
• Here ketone is acceptor, thiol is addendum and amine is catalyst.
• Isomeric adducts are formed and one adduct gets crystallized out
leaving behind another.
• Thus obtained pure crystal is treated with silica gel to obtain pure
enantiomer.
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Resolution of alpha-beta unsaturated ketones
92
c) Optical activation of Menthone
• Resolution of racemic mixture of menthone can be done by reacting it
with a thiol to obtain thiolane.
• Thus obtained thiolane is crystallized out to get mixture of
diastereomeric salts, which are separated based on their melting
point into pure enantiomers.
Optical activity of menthone
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2. Enzymatic method
Day 14
• It is a biochemical method which involves the assimilation of one of the
enantiomer from racemic mixture by an enzyme.
• In this method enzyme is added to a racemic mixture and left for biochemical
reaction.
• The enzyme is highly enantiospecific in action, it may assimilate (+) or (-) form
leaving behind any one of them in the reaction bath.
• Unconsumed (+) or (-) enantiomer is then separated from reaction bath in pure
state.
• For example, when racemic tartaric acid is fermented in presence of yeast, (+)
enantiomer is consumed and (-) enantiomer remains unaffected.
• The disadvantage of this method is that it causes destruction of one form and
gives low yield of another form as well.
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3. Diastereomer formation method
• In this method racemic mixture is reacted with suitable resolving
agent which converts one of the enantiomer into diastereomer by
chemical reaction enantiospecifically.
• The diastereomers differ in mp, solubility, crystallization point, etc.
and thus can be separated easily by fractional crystallization.
• Thus separated diastereomers are then converted into corresponding
enantiomers by removing the resolving agent.
• For example,
dibenzoyl tartaric acid can be used for the resolution of amines from
their racemic mixture.
95
Resolution by diastereomer formation method
96
4. Asymmetric transformation of diastereomers
Day 15
• Some compounds containing asymmetric centre may undergo
configuration change in their solutions.
• Optically active compounds with different configuration possess
different physical and chemical properties because they behave as
diastereomers.
• This change in configuration is called asymmetric transformation.
• An equilibrium is established in between two diastereomers which
can be separated based on difference in properties like mp, optical
rotation, solubility, crystallization point, etc.
• For example,
D(+) glucose exists in α–D(+) glucose and β–D(+) glucose in solution
which can be separated by fractional crystallization easily.
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Resolution by asymmetric transformation method
98