22/06/2019

Unusual Optical Activity &

Stereochemistry

Ref. Books:
 Stereochemistry Conformation & Mechanism
- P. S. Kalsi
 Organic Chemistry - L. G. Wade
 Organic Chemistry - I. L. Finar Vol. 2
 Organic Chemistry Reactions & Reagents
- O.P. Agrawal
 Stereochemistry of Carbon Compounds
- E. L. Eliel

Optical activity
 Optical activity is an effect of an optical
isomer's interaction with plane-polarized light.

 Light restricted to pass through a plane is

plane polarized.
 Plane-polarized light that passes through
solutions of achiral compounds retains its
original plane of polarization.
 Solutions of chiral compounds rotate plane-
polarized light and the molecules are said to
be optically active.

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Polarimeter
A polarimeter measures the rotation of plane-
polarized light that has passed through a solution
For chiral compound, rotation, in degree is [],
optically active

For achiral compounds [] = 0, optically inactive

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Sign/symbol for optical compound

 Dextrorotatory (Latin: dextre means right) and is
indicated by (+) sign. new older

Dextrorotatory
(+) d
 Rotates the plane of plane-polarized light to the right.

 Laevorotatory (Latin: laeves mean left) and is indicated

by (-) sign. new older

Levorotatory (-) l
 Rotates the plane of plane-polarized light to the left.

 Those substance which do not rotate the plane of

polarised light are called optically inactive.

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Chirality
 An object which cannot be superimposed on its mirror-
image is said to be chiral [Greek : Chier 'Hand'] and the
property of non-superimposability is called chirality. Thus
our hands are chiral.


 The presence of a chirality centre usually leads to
molecular chirality. Such a molecule has no plane of
symmetry and exists as a pair of enantiomers.

Chirality - optical activity: discovery

 French chemist Louis Pasteur (1848) discovered that
crystalline optically inactive sodium ammonium
tartarate was a mixture of two types of crystals
which were mirror images of each other.
 Each type of crystals when dissolved in water was
optically active. The specific rotations of the two
solutions were exactly equal, but of opposite sign.

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Chirality - optical activity: discovery

A (50:50) racemic mixture of both crystal types
dissolved together was not optically active.
The optical rotations of equal concentrations of
these forms have opposite optical rotations.
In all other properties, the two substances were
identical.
As the rotation differs for the two samples in
solution in which shapes of crystals disappear,
Pasteur proposed that like the two sets of
crystals, the molecules making up the crystals
were themselves mirror-images of each other
and the difference in rotation was due to
'molecular dissymmetry'

Chiral (asymmetric) atom

The most common feature that leads to chirality

in organic compounds is the presence of a chiral
(or asymmetric) atom. (An atom that is bonded
to four different groups)

 In general:
 no asymmetric atom usually achiral
1 asymmetric atom always chiral
> 2 asymmetric atoms may or may not be chiral

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Chirality at nitrogen atom

 Attempts to resolve a tertiary amine molecule (Nabc),
have failed.

 Meisenheimer et al (1924) attempted to resolve, but failed.

 The non-resolvability gave raise to the belief that they are planar.
 Various studies showed that amine molecule is not planar, pyramidal

 Meisenheimer explained that at RT two enantiomeric

forms of the tertiary amines are rapidly interconvertible
into each other and hence an optically active form can
never be obtained.

Chirality at nitrogen atom

 The most common (but not the only) cause of
chirality in organic molecules is a tetrahedral
atom, most commonly carbon, bonded to four
different groups.
 Nitrogen is commonly found in organic
compounds, and can have chirality center.
 Trivalent nitrogen is tetrahedral/pyramidal

 Shape of a molecule is determined by the

number of -bonds and lone-pairs only.

 Charge on the central atom has no effect

on the configuration of the cation.

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Chirality at nitrogen atom

 Amines, however, are not chiral, because they

rapidly invert, or turn ‘inside out’, at room
temperature.
 Does not form a chirality center since it rapidly
flips.
 Individual enantiomers cannot be isolated.
 Barrier to inversion is very low

Chiral cyclic amine

 Prelog and Wieland (1944)

 If the nitrogen atom is contained in a small ring, it is

prevented from attaining the 120 bond angle that
facilitates inversion.
 Such a compound has a higher activation energy for
inversion, the inversion is slow, and the enantiomers
may be resolved.
 1,2,2-trimethylaziridine has been resolved.

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Stereochemistry of quaternary ammonium salts

 Shape of a molecule is determined by the

number of -bonds and lone-pairs only.
 Quaternary ammonium salts, formula
[Nabcd]+X-
 Five-point system similar to carbon compounds
Cabde. (four valencies in ammonium ion are
equivalent).
 Charge on the central atom has no effect on
the configuration of the cation.

Quaternary ammonium salts

 Quaternary ammonium salts may have a chiral nitrogen

atom if the four substituents are different.
 Inversion of configuration is not possible because there
is no lone pair to undergo nitrogen inversion.
 Methyl ethyl isopropyl anilinium salts can be resolved
into enantiomers

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Stereochemistry of quaternary ammonium salts

 Quaternary ammonium salts, [Nabcd]+X-

 Three possible configuration for the cation
[Nabcd]+

planar pyramidal tetrahedral

Quaternary ammonium salts

 Le Bel (1891) claimed to have partially

resolved isobutylethylmethylpropylammonium
chloride, but later work apparently showed it
was wrong.

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Quaternary ammonium salts

 Pope and Peachey (1899) resolved
allylbenzylmethylphenylammonium iodide.
 This was the first optically active compound with center
atom other than carbon.

 Following this work, Jones (1905) resolved

benzylethylmethylphenylammonium iodide.
 Since ammonium ions were obtained as optically active,
so it’s structure is not plannar, but either pyramidal or
tetrahedral.

Quaternary ammonium salts

 Jones (1905) and Jones and Dunlop (1912) proposed
pyramidal structure on the basis of Bischoff (1890)
proposal.
 Werner (1911) had suggested the tetrahedral
configuration and it was supported by Neagi (1919).

 Mills and Warren (1925) gave the most conclusive

evidence that the configuration of nitrogen is tetrahedral.
 Compound of the type is resolvable
since carbon is tetrahedral.
 If nitrogen is also tetrahedral , then
should be resolvable.

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Quaternary ammonium salts

 Mills and Warren (1925) prepared 4-carbethoxy-4’-
phenylbispiperidinium-1,1-spiran bromide and resolved
it.
If the configuration is like
spiran (tetrahedral), then it
possesses no element of
symmetry, and resolvable.

If the configuration is
pyramidal then it possesses
vertical plane of symmetry,
hence optically inactive.

Since the structure was resolved, the configuration

must be tetrahedral

Diquaternary ammonium salts

Cis Trans

Diquaternary salts of dimethylpiperazine

exhibit geometrical isomerism, and this is
readily explained on the tetrahedral
configuration of the four nitrogen valencies.

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Tertiary amine oxide

 Tertiary amine oxide (abcNO)
 Nitrogen atom is joined to four different groups,
so the configuration is tetrahedral and
resolvable.
 Meisenheimer (1908) resolved the followings:

Chirality at phosphorus
Trivalent phosphorus compounds or phosphines

Electron configuration of P, [Ne] 3s2 3p3

 Phosphorus can exhibit covalencies of 3,4,5,6

 Have more possible configuration than nitrogen.
 Similar to tercovalent nitrogen, tercovalent
phosphorus compound is tetrahedral (sp3) and can
produce chiral structure.
 The inversion at phosphorus is substantially slower
than inversion at nitrogen.

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Tercovalent phosphorus compounds

 Oscillation phosphorus in phosphine is 5106, while
that of nitrogen in ammonium is 2.31010, in
deuterium ammonium, 6103
 Unlike tertiary amines, certain trivalent phosphines
have been resolved, because of slower frequency.
 Horner et al. (1961) resolved MePhPrP.

 R- and S-methypropylphenylphosphine are

configurationally stable at 100C.

Determination of configuration of MePhPrP

An enantiomer of an optically active phosphine is

treated with benzyl bromide, the phosphonium bromide
is obtained with the retention of configuration.
This salt on electrolytic reduction, regenerates the
original phosphine without loss of optical activity.
The absolute configuration of (+)-benzylmethylphenyl-
propylphosphonium bromide has been shown to be (S),
so configuration of phosphine is (S).

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Quinquevalent phosphorus compounds

 Many optically active compounds containing

pentavalent phosphorus of the type R3P=O have
been resolved:

 Meisenheimer et al. (1911) resolved

ethylmethylphenylphosphine oxide (I) and
benzylmethylphenylphosphine oxide (II)

 After these two, several phosphorus compounds of the

type R3P=X have been resolved

 Optically active phosphine oxides was prepared

from phosphines and hydrogen peroxide with the
retention of configuration

 Optically active phosphine oxides are recemised by

acid by the formation of symmetrical trigonal
bipyramid (Denney et al. 1946)

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Ethyl triphenylmethylpyrophosphonate

 If the two phosphorus atoms are asymmetric

then its structure corresponds to the molecule
Cabd.Cabd
 Hatt (1933) studied optical activity of the
compound and obtained meso and racemic
modification forms

Quaternary phosphonium compounds

 Generally phosphonium salts containing alkyl

groups tend to racemize in solution due to the
following type of dissociation-equilibrium.

 But compounds of the above two have been resolved

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Quaternary phosphonium compounds

 Phosphonium salts containing phosphorus atom in

the ring are much more optically stable and can be
easily resolved.

 Holliman and Mann (1947) prepared a salt in

which the phosphorus atom was in a ring, and
resolved it.

Stereochemistry of selenium compounds

Pope et al. (1902) resolved active platinichloride.

Mann et al. (1945) also resolved selenonium salt.

So far, attempts to resolve selenoxides have failed

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Chirality

R R J J FF
(Chiral objects)

A A M M O O
(Achiral objects)
 Chiral objects - human hand, gloves, shoes, etc.
 Achiral objects - a sphere, a cube, a button, socks
without thumb, etc.
 Chirality or molecular dissymmetry is the necessary
and sufficient condition for a molecule to be
optically active.

Asymmetry v/s Dissymmetry

 In general the term asymmetry is used for those
optically active compounds which have none of
the four elements of symmetry.
 In contrast the term dissymmetry is used for all
stereoisomeric compounds which are capable of
existing as pairs of non-superimposable mirror
images despite the presence of some elements
of symmetry.
 Dissymmetry is applicable to all stereoisomers,
which are related to each other as non-
superimposable mirror images, e.g. 2,3-
dibromobutane possesses a C2 axis of
symmetry in the molecule at right angle to the
plane of the paper.

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Since structures I and II are indistinguishable, the

molecule has C2 axis of symmetry. But it is non-
superimposable on its mirror image so it is dissymmetric
and not asymmetric and exhibits optical activity.

CH3 CH3 CH3

Br H H Br H Br
Rotation
Br H by 180o Br H
H Br
CH3 CH3
CH3
III I II
All asymmetric molecules are dissymmetric but all
dissymmetric molecules are not asymmetric. However,
both these types of molecules show optical activity and
are chiral. Hence, to avoid any confusion, in using these
terms, - asymmetry or dissymmetry - the term chirality is
used.

Stereogenic centre or chirality centre

 In 1996, the IUPAC recommended that a tetrahedral
carbon atom bearing four differnt atoms or groups may
be called a chirality centre. Several earlier terms
including asymmetric centre, asymmetric carbon, chiral
centre, stereogenic centre and stereocentre are still
widely used. H

1 2 3 4
CH 3 C C H 2CH 3

OH C hirality centre
2-B utanol

 In general it has been observed that compounds having

one or more chirality centre show enantiomerism and
therefore, optically active. However, this statement does
not hold good for all such molecules, e.g.

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Compounds having chirality centre(s) but

not enantiomeric
Meso-2,3-dibromobutane contains two chirality
centres (marked with *) but it does not exhibit
enantiomerism due to internal compensation
and hence is optically inactive.
CH3 CH3
H * Br Br * H
Plane of
* * Symmetry
H Br Br H
CH3 CH3
Mirror
Meso - 2,3-dibromobutane (optically inactive)

Chirality in molecules devoid of chiral centers

 A necessary and sufficient condition for a

molecule to be chiral is that the molecule is
non-superimposable with its mirror image.
 The presence of a (single, configurationally
stable) chiral center in the molecule (central
chirality) is a sufficient condition for the
existence of chirality but not a necessary one.
 Chiral molecules without a chiral center:
allenes, cumulenes, alkylidenecycloalkanes,
spiranes, biphenyls, etc.

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Elongated tetrahedron approach

 A regular tetrahedron with four distinguishable vertices
represents a three-dimensional chiral simplex.
 If the centre is replaced by a linear grouping such as C-C
or C=C=C, the tetrahedron becomes elongated
(extended) along the axis and this axis is called chiral
axis or the stereoaxis.

Molecules with axial chirality

 Axial chirality is the chirality resulting from the

nonplanar arrangement of four groups about an
axis. This axis is called a chiral axis.
 The axis along which the tetrahedron is
elongated is called chiral axis or the stereoaxis.
 With proper substitution, the long axis of this
framework constitutes the chiral axis.
 A necessary and sufficient condition for chiral
axis is that a≠b and c ≠d.

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Molecules with chiral axes

 Allenes, alkylidenecycloalkanes, biphenyls, and so
on, are said to possess a ‘chiral axis’.

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Atropisomers
Atropisomers are stereoisomers resulting from
hindered rotation about single bonds where the
steric strain barrier to rotation is high enough to
allow for the isolation of the conformers (from
Greek, a = not and tropos = turn).
 The name was introduced by Kuhn in 1933, but
atropisomerism was first detected in 6,6’-
dinitro-2,2’-diphenic acid by Cristie in 1922.

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Atropisomers (non-coplanar)
 Conformers that cannot interconvert (due to steric
hindrance) can be enantiomers

Conditions for atropisomerism

 Two necessary preconditions for axial chirality

are:
1. A rotationally stable axis
2. Presence of different substituents on both
sides of the axis

Atropisomers are recognized as physical

separable species when, at a given
temperature, they have a half life of at least
1000 s (16.7 min).

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Conditions for atropisomerism

 The minimum required free energy barriers at different
temperatures are as bellow:
o ΔG200 K = 61.6 kJ mol-1
o Δ G300 K = 93.5 kJ mol-1
o Δ G350 K = 109 kJ mol-1

 The configurational stability of axially chiral biphenyl

compounds is mainly determined by three following
factors:
o The combined steric demand of the substituents in the
proximity of the axis.
o The existence, length, and rigidity of bridges.
o The involvement of atropisomerization mechanisms
different from a merely physical rotation about the axis,
e.g. photo chemically or chemically induced processes.

Nomenclature of atropisomers
Orientation of biphenyl compounds

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Configurational nomenclature of atropisomers

 Notations used for atropisomers:
o aR (axially Rectus) or aS (axially Sinister)
o or P (plus) or M (minus)
 Priority of the substituents are determined by the CIP rule
 Here it is assumed that priority of A>B and A >B

Assigning configurations of atropisomers (Ra & Sa)

1 1
NO2 NO2

3 3
CO2H NO2 NO2 CO2H

CO2H CO2H
2 2
Sa Ra

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Assigning configurations of atropisomers (P & M)

A
A NO2
NO2
A
A NO2 CO2H
CO2H NO2
CO2H
CO2H
P M

Absolute configuration of biphenyls

(R,S-nomenclature of biphenyls)

 Since biphenyls do not owe their asymmetry to the

presence of asymmetric carbon atoms, the criterion now
is the presence of a chiral axis.

 To apply the sequence rule to axial chirality, with respect

to an external point on the chiral axis, groups at the
near end of the axis are given precedence over
groups at the far end.
A
a a
a b
b
z b
a
b b
a b
a
B

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a b 1 1
2 1
4
3 2
3 2
b 4
a 4
3

b 2
a 2 1

4 1
a 3
b 4 3

1
(2 interchanges)

3 2

4
R

b a 4 3

a 1
b
2

1
4

(2 interchanges)
3 2 2 3

4 1
R

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R,S-nomenclature of biphenyls
 In biphenyl the two rings are perpendicular along the
axis of the bond joining the rings, projection of four
ortho substitutents on a plane at right angles to this
bond is very similar to a Fisher projection formula.

 Near groups precede far groups

3
NO2
2 1
HOOC NO2

COOH

Rotate 180

1 1 2

3 2
4
4 3
R

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COOH
1 2
Br NO2

OCH3
3
R
3
Br
1 2
Br H

H
S

3 NO2
2 1
m-H OMe-m

COOH
R
If there is a substituent at position 3, the 3,5 substituents
rather than 2,6 substituents determine the sequence

3COOH

2 1
H COOH

H
R

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Synthesis of biphenyl (C6H5-C6H5)

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Resolution of biphenyl derivative

When n=3, the molecules are highly optically stable

Resolution of biphenyl derivative

1,1-Binapththyl-8,8-
dicarboxylic acid was
resolved by Stanley
(1931)

Bianthryl derivatives
was resolved by Bell et
al(1949)

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Allenes
An allene is a compound in which one carbon
atom has double bonds with each of its two
adjacent carbon centres.

General structure

 The central carbon of allene forms two sigma

bond and two -bonds. The central carbon is
sp-hybridized and the two terminal carbons are
sp2-hybridized.

Allenes
 The two -bonds attached to the central
carbon are perpendicular to each other.

 The geometry of the -bonds causes the

groups attached to the end carbon atoms to lie
perpendicular planes.
 The bond angle formed by the three carbons is
180, indicating linear geometry for the
carbons of allene.

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Asymmetric synthesis of allene

 Mills and Maitland carried out a catalytic
asymmetric dehydration on (I), to give (II)
[1935].

(I) (II)
1,3-di-1-naphthyl-1,3-diphenylprop-2-enol dinaphthyldiphenylallene

 (+) and (-) allene was obtained by boiling with 1% benzene

solution of (+) and (-) camphorsulphonic acid, respectively.

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Asymmetric synthesis of allene

 Another asymmetric synthesis of an 1-3-

diphenylallene was carried out by Jacobs et
al. (1957) by adsorption on alumina
impregnated with brucine or quinine.
 Brucine gave (-) allene and quinine gave (+)
allene.

Resolution of allene derivative

 The first successful resolution of an allene
derivative was carried out by Kohler et al.
(1935) by converting 3-1-naphthyl-1,3-
diphenylallene-1-carboxylic acid (III) into
glycolic acid ester (IV).

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Axially chiral systems (chirality of allenes)

 Since the geometry of the cumulated -bonds causes
the groups at the terminal carbons to lie in
perpendicular planes, allenes that are unsymmetrically
substituted on both ends are chiral.

 Different substituents attached to the end carbons form

non-superimposable mirror images, they are optically
active.

 Cumulated polyene with an odd number of

double bonds
 The atoms connected to the terminal carbons
lie in the same plane
 They are like an ordinary alkene.

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Nomenclature of allenes
 Notations used for allenes:
o aR (axially Rectus) or M (minus)
o aS (axially Sinister) or P (plus)
 Priority of the substituents are determined by the CIP rule
 The near groups have a higher precedence over far groups
2
H H
3 2 1
CH3 H H CH3
CH3 CH3
1
3
Sa Sa

Assigning configurations of allenes (P & M)

H
H
A
CH3 H
A
H CH3
Clockwise=P
A CH3
CH3 A
P
P

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a b 1 2

a 3
b 4

2
1

(2 interchanges)
3 1 4 2

4 3
S

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Synthesis of allenes
Anti-elimination

Asymmetric deprotonation-protonation

Synthesis of allenes
Syn or anti-halogenation

Sigmatropic rearrangement

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Cyclic allenes

 The smallest cyclic allene so far isolated is

1-tert-butyl-1,2-cyclooctadiene.
 The parent 1,2-cyclooctadiene has not been
isolated.
 The presence of tert-butyl group prevent
dimerization.

1-tert-butyl-1,2-cyclooctadiene

Alkylidenecycloalkane
 Allenes were successfully resolved in 1935, but
alkylidenecycloalkane having the similar configuration
of allene was resolved by Pope et al. in 1909.

4-methylcyclohexylidene-1-acetic acid

 One of the double bonds of allene has been replaced

by a six-membered ring, and the general shape of the
allene is retained.

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R,S-nomenclature of alkylidenecycloalkane

a b 1 2

b 4
a 3

3 2

Spiranes
 If both double bonds in allene are replaced by
ring systems, the resulting molecules are
called spiranes.
 A spiro compound is a bicyclic compound with
rings connected through just one atom.

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Nomenclature of spiranes
 Prefix ‘spiro’ with number in square brackets
indicating the number of carbon atoms joined the
‘junction’ carbon is used.
 The position of substituents are indicated by
numbers, the numbering beginning with the
smaller ring and ending on the junction carbon.

Spiro-[2,2]-pentane 1-Chlorospiro-[5,3]-nonane

 Mills et al. (1920, 1921) resolved dilactone of

benzophenone-2,2,4,4-tetracarboxylic acid.
 Treating with NaOH, the lactone rings opens and
yields optically inactive compounds.

NaOH

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Some spiro compounds those have been resolved

R,S-nomenclature of spiro compounds

a b 1 2

b 4
a 3

3 2

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R,S-nomenclature of spiro compounds

b a 2 1

b 4
a 3

3 1

4
S

Chirality plane
 Planar chirality appears when a planar
molecule loses its symmetry plane by bridging
with short tether or forming π-complex.

Plane of symmetry No plane of symmetry

Optically inactive Optically active
 Resolvable when n=8
 Racemises easily when n=9
 Non-resolvable when n=10

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Configurational nomenclature
Pilot atom

 Pilot atom: directly bonded to an atom in the chiral plane

but itself is not in the plane

Stereochemistry of tricovalent carbon

 Carbon usually forms four covalent bond
involving four bond orbital containing two
electrons each. When one of the orbital is not
engaged in a bond, the carbon atom is
tricovalent.
Depending on the number of non-bonding electron,
it may form:
o Carbonium ions RRRC+ (no non-bonding electron),
positively charged.
o Carbon free radicals RRRC (contain one electron),
neutral.
o Carbanions RRRC (contain two non-bonding
electron), negatively charged.

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Stereochemistry of tricovalent carbon

 Tricovalent carbon compounds are usually very

fleeting stability and are found only as short-
lived reaction intermediates.

Carbocation (carbonium ion or carbenium ion)

 A carbocation is a species that contains a
carbon atom bearing a positive charge and has
no nonbonding electrons.
 It is sp2 hybridized, with a planar structure and
bond angles of about 120°.

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Carbocations

 The carbocations being reactive intermediates

have short life and so they are unstable.
 The greater the resonance and hyper-
conjugation the greater is the stability of
carbocation.

An alkyl group stabilizes an electron-deficient

carbocation in two ways:
1. through an inductive effect, and
2. through the partial overlap of filled orbitals
with empty ones.

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 Unsaturated carbocations are also stabilized

by resonance stabilization.

 Highly substituted alkyl halides can ionize

when they are heated in a polar solvent.

 The triphenylmethyl cation is so stable that

some of its salts can be stored for months.
The triphenylmethyl carbocation shows its
stability because the positive charge on the
carbon is distributed uniformly over a number of
structures.

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Free radicals
Like carbocations, free radicals are sp2
hybridized and planar (or nearly planar).
Unlike carbocations, the p orbital perpendicular
to the plane of the bonds of the radical is not
empty; it contains the odd electron.

Carbanions
 A carbanion has a trivalent carbon atom that
bears a negative charge.
 There are three bonds and one lone pair
electrons around the carbon atom.
 Electronic structure is like ammonia or an
amine.

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Both the methyl anion and ammonia have an sp3

hybridized central atom, with a nonbonding pair of
electrons occupying one of the tetrahedral positions.

The tetrahedron can undergo inversion or

retain its stereochemistry depending on the
attached substituents.

Tetrahedral carbanion

R = H; barrier = 2 kcal/mole
R = F; barrier = 120 kcal/mole

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 Carbanions that occur as intermediates in

organic reactions are almost always stabilized
by neighboring groups.
 They can be stabilized either by inductive
effects or by resonance.

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Homotopic atoms or groups : Aliphatic

atoms/groups which are interconvertable by a
rotational axis and chemically & magnetically
equivalent are termed homotopic.
homotopic

Homotopic groups are always equivalent, they give a

single NMR absorption. Homotopic groups are
interchangeable by rotational symmetry. The simplest
way to recognize homotopic groups is by means of a
substitution test.

Homotopic face: If a transformation at opposite

faces of a trigonal center generates two Identical
compounds, the faces are homotopic.

Identical compound

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Enantiotopic atoms or groups:

 Two atoms or groups that upon replacement

with a third group give enantiomers

 Two compounds upon replacement of H by Z

are not identical but enantiomeric, the
hydrogens are not equivalent and are called
enantiotopic hydrogens

Prochiral: There is a special term for molecules

that are achiral but which can be converted to
molecules with chiral centers by a single
chemical substitution or addition reaction is
called prochiral.
Chiral center

These two products

are enantiomers.

Chiral center
In general, both enantiomers are formed in equal amount

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 An sp3 carbon with two groups same is also a

prochiral center
 The two identical groups are distinguished by
considering either and seeing if it was increased in
priority in comparison with the other
 If the center becomes R the group is pro-R and pro-S
if the center becomes S

pro-R pro-S
(R)

Chiral
(S)
Prochiral
Chiral

Enantiotopic faces: Flat molecules (trigonal) have two

faces and are not stereochemically equivalent.
Attachment of a ligand to one or the other of them gives
rise to one or other of a pair of enantiomers.

Re face (clockwise)
Enantiomer

1 (S)-2-butanol

3
2

Si face (counterclockwise)
(R)-2-butanol

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re, rectus
si, sinister

Decreasing priority Decreasing priority

re face si face

Maleic acid
si-re re-si

Fumeric acid

si-si re-re

Diastereotopic atoms or groups: Two atoms or

groups in a molecule are in such positions that
replacing each of them with a group Z gives rise
to diastereomers, the atoms or groups are called
diastereotopic.

diastereomers

2-dichlorobutane

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Diastereotopic face: If a transformation at

opposite faces of a trigonal center generates two
different diastereomers, the faces are
diastereotopic.

Diastereomers

Resolution of racemic mixtures

 The separation of a racemic mixture into the

individual enantiomerically pure enantiomers is
called resolution.
 Enantiomers have identical physical properties, can
not be resolved by common physical techniques.
 Diastereomers have different physical properties,
can be separated by conventional physical
techniques.
 This difference is exploited in resolution by placing
a mixture in a chiral environment to initiate
diastereomeric interactions.

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Methods of resolving racemic mixtures

There are five general strategies to separate a
racemic mixture.
1. Mechanical separation: crystallization method.
2. Formation of diastereomeric salts with an
enantiopure resolving agent.
3. Formation of diastereomeric compounds with an
enantiopure resolving agent.
4. Use of chiral stationary phases for chromatographic
resolution of racemic mixtures.
5. Enzymatic resolution.

Resolution of racemic mixtures

Mechanical seperation
Louis Pasteur, was able to isolate the
stereoisomers of tartaric acid from solution as
crystals with differing symmetry and shape.

But such cases are very rare.

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Resolution of racemic mixtures

Strategy of diastereomeric salt formation

Enantiomers C(+)
C(+) C(-) P(+)

2P(+) C(+)P(+)

C(-)P(+)

C(+)P(+) C(-)P(+) P(+)

Diastereomers
C(-)

Resolution of racemic mixtures

Diastereomeric salt formation
 (S)-1-Phenylethylamine combines with a racemic
mixture of lactic acid to form diastereomeric salts.
 The diastereomers are separated by fractional
crystallization.

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Resolution of racemic mixtures

Diastereomeric salt formation

After separation, each of the diastereomers is

treated with a strong acid to regenerate the
corresponding enantiomer of lactic acid.

Note that the lactic acid would be soluble in the

organic layer, while the ammonium salt would be
in the water layer.

Resolution of racemic mixtures

 (S)-1-phenylethyl ammonium chloride is recover

using base.

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Resolution of racemic mixtures

Formation of diastereomeric compounds
 An equally effective strategy of resolving racemic mixtures is by
formation of covalently bonded diastereomeric compounds.
 (-)-Menthol, can be readily used as a chiral resolving agent.

Resolution of racemic mixtures

Chromatography on chiral stationary phases
 Resolving a racemic mixture is through the use of
chromatography on chiral stationary phases.

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Resolution of racemic mixtures

Chiral stationary phase

Chiral chromatography
exploits the development of
transient, diastereomeric
interactions between the
enantiomers and the chiral
stationary phase.

Resolution of racemic mixtures

Enzymatic resolution

 In enzymatic or kinetic resolution, there is preferential

reaction of just one enantiomer resulting in an
enantioenriched sample of the less reactive enantiomer.

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Pseudo-asymmetric carbon atom

The traditional name for a tetrahedrally coordinated
carbon atom bonded to four different entities, two
and only two of which have the same constitution
but opposite chirality sense.
According to Freudenberg, the configuration of
pseudo-asymmetric carbon is designated as r/s.

Pseudo-asymmetric

Characteristics of pseudo-asymmetric atom

The pseudo-asymmetric atom is bonded to two

different atoms/groups and the other two
atoms/groups are constitutionally same and
enantiomers.
The r/s descriptors of pseudo-asymmetric
carbon atoms are invariant on reflection in a
mirror (i.e. r remains r, and s remains s).
The r/s descriptors are reversed by the
exchange of any two entities (i.e. r becomes s,
and s becomes r).

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Freudenberg’s simplified method

of determining R/S configuration:

 Priorities are assigned to the groups as is usual in

CIP.
 Group of the lowest priority is neglected.
 Other groups around the chiral atom move from the
lower priority towards higher one.
 A clockwise movement implies R and anticlockwise
movement S configuration.
 In case groups with same constitution but opposite
chirality sense chiral R is given preference over S.

Pseudo-asymmetric carbon atom

(1) (2) (3) (4)
S R R

S R S S
Enantiomers
Diastereomers

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Pseudo-asymmetric carbon atom

(1) (2) (3) (4)
Trihydroxyglutaric acid

Diastereomers Enantiomers
S S Active
R R Active
R r S Meso
R s S Meso
Pseudo-asymmetric

Pseudo-asymmetric carbon atom

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