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Atropisomerism PDF
Atropisomerism PDF
2.1 Atropisomerism
3. Summary
2. Introduction
2.1 Atropisomerism
Atropisomers can be defined as isomers that can be isolated due to prevention or
restriction of rotation about a given single bond, usually between two planar moieties.
The term atropisomerism comes from the words a, Greek for not, and tropos, Greek for
turn.1 If bulky group on ortho position of bi-phenyl or strained ring structural features.
Bulky substituents or strained rings may enhance the barrier to rotation between two
distinct conformations to such an extent as to allow observation of atropisomers.
Atropisomerism is also called axial chirality and the chirality is not simply a centre or a
plane but an axis. As the phenomenon of axial chirality relies on the rotational stability
about a single bond, the important preconditions for this stability will be discussed in this
Section. Simple biphenyl can easily rotate by C-C bond and it is symmetric so simple
biphenyl is achiral (Figure 1). C-C sigma bond is known as pivotal bond.
Symmteric - Achiral
Biphenyl substituted on ortho position in molecule 1 (Figure 2), which contains a chiral
axis along the biphenyl linkage. The biphenyl rings are perpendicular to each other in
order to minimize steric clashes between the four ortho substituents meaning that rotation
about the biphenyl bond through pivotal bond is restricted. The interconversion between
the two isomers is restricted (slow) therefore two isomers are separate entities, and can
resolved to its separate enantiomers. The first chirality due to restricted rotation about a
single bond was described by Christie and Kenner in 1922, they successfully resolved the
enantiomers of 6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid.
COOH
COOH HOOC HOOC
1 1'
Another useful definition of atropisomers was given by Oki who said that “atropisomers
can be regarded as physically separable species when they interconvert with a half-life of
PPh2
PPh2
Fig. 3: BINAP
Conditions of Atropisomerism:
1. Two necessary preconditions for axial chirality are:
(a) A rotationally stable axis
(b) Presence of different substituents on both sides of the axis
2. Atropisomers are recognized as physically separable species when, at a given
temperature, they have a half-life of at least 1000 s (16.7 min) [
3. The minimum required free energy barriers at different temperature are as below.
∆G200K = 61.6 kJmol-1 ∆G300K = 93.5 kJmol-1 ∆G350K = 109 kJmol-1.
4. The configurational stability of axially chiral biaryl compounds is mainly determined
by three following factors:
Biaryl Atropisomers classified into two categories is based upon the basic structure of the
biaryl atropisomers.
Biaryl Atropisomers
Bridged Biaryls
Nonbridged Biaryls
COOH Br
Br HOOC
Fig. 4: Adding ortho substituents greatly increases the barrier: in the case of the 2, 2'-
dimethyl derivative.
Conditions for biphenyls to be enantiomeric or resolvable:
1. The planes of two aryl groups must be non-planar. This can be done by introducing
bulky groups in the ortho positions so that the planar conformations are destabilized due
to steric repulsion (Figure 5).
A C
B D
Fig. 5: Non planarity can be introduced by placing bulky groups in the ortho positions.
2. Most of tetra substituted biphenyls (A, B, C, D ≠ H) can be resolved and quite stable to
racemization at least two of the groups are fluorine or methoxy.
H R
R' H
Fig. 6: Ortho substituent increases the restricted rotation through pivotal bond
(atropisomerism) in non-bridged biaryl compounds by their steric repulsion.
3. Mono ortho substituted biaryl compounds do not form stable atropisomer at room
temperature. This type (4 and 5) of compound show atropisomerism if both substituents
are bulky (Figure 7).
F3C
CF3
4 5
4. In addition to the bulk of the ortho substituents, the nature and position of other
substituents in the ring play some role in configuration stability of the atropisomers. The
bulky groups adjacent to the ortho substituents exert a buttressing effect.
The rate of racemization is much lower in compound (I) than the compound (II). In
compound (I) the bulkier group (NO2) is adjacent to methoxy but in case of compound
(II) the bulkier group is adjacent to hydrogen. Compound (I) is having more buttressing
effect and racemization is slow compared to the compound (II) (Figure 8).
5'
COOH H
COOH H NO2
I
II
Fig. 8: Rate of racemization is affected by the nature of groups attached.
5. If two substituents on ortho position are similar but on meta position substituents are
different then these type of molecules (6a-c) are less common and it is chiral (Figure 9).
R Me Me H
Me Me
H Me Me R
5. In a biaryl compounds (7) where four ortho substituents are equal if these are
connected pairwise through two bridges as the D2-symmetric diether also show the axial
chirality (Figure 11).
A A
HOOC COOH
HOOC COOH
The R/S nomenclature can be given either by viewing a molecule from left hand side or
right hand side
CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding
and Stereochemistry)
MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl
Br Br
chiralaxis
COOH
HOOC
3D view of the molecule
3'
A2 6'
View B A B
2'
6
Rotate
Rotate right hand
right hand 3D view of the molecule side
side
1
C2 (C-Br, C,C-H)
3 2
B
(H-C,C ,Br-C)C2' C6' (C-COOH), C,C-H 6'
2' A
Bold line (Vertical line) C6 (C-COOH), C,C-H
groups will be given 1 6
2 Near our eyes will
and 2 according CIP be on bold line
rule than vertical line 3 (Vertical line)
and 4 according CIP. Converted in to
Clock wise = R
Rotate 1-2-3, clock Newman Projection
wise R
CIP Rule: If we will consider the carbon C2 and carbon C6 in this example, the extrapolation of
C-Br C-COOH
C C-C C C-C
C2 = C-H and C6 = C-H . Carbon C2 is connected with C-Br, C-C and C-H and
carbon C6 is connected with C-COOH, C-C, C-H, Br having higher atomic number than the C
hence C2 will have preference over the C6. If we follow same rule for C2’ and C6 therefore C2’
will have preference over C6’.
Note: In biaryl compounds if meta is not substituted than we can decide the preference
by ortho substituents using CIP rule
2 6'
B A
A B View
2'
6
Rotate left
Rotate left
hand side
hand side
3D view of the molecule
A
3 Bold line (Horizontal
C2 (Br) line) groups will be
B 2 1 given 1 and 2
C6' (HOOC) C2'(Br) according CIP rule than
B
A vertical line 3 and 4
according CIP. Rotate
Near our eyes will C6 (COOH)
1-2-3, clock wise R
be on bold line
(Horizontal line)
Converted in to Clock wise = R
Newman Projection
D
B D
OH B A
View 2 1
OH
A C
OH HO C 3
Newman Projection
anti clock wise
Absolute configuration 'S'
2
D D
B
OH View 3A B
OH
A
OH HO C C1
Newman Projection
anti clock wise
Absolute configuration 'S'
This type way of nomenclature writing we should always view molecule from the bottom
side of axis
Newman Projection
anti clock wise
Absolute configuration 'S'
View
2. Assign priority according CIP on both ortho carbons of the biaryl and near groups to
our eyes should be given preference 1 and 2 according to CIP.
3. Always put ortho carbon having CIP numbering which belong to the above the plane
on the top of the vertical bold line and rest CIP number is on the bottom of the vertical
line. (In this example the priority 1 is on the above the plane so 1 should be put on the top
of the vertical bold line and 2 is on the bottom.
4. Write 3 and 4 as it is on horizontal line (as it is marked to the ortho carbons of the
biaryl)
5. CIP 1-2-3 rotates in clockwise than it will be ‘R’, If it is anti-clockwise than ‘S’ (In
this molecule 9, it is anti-clockwise so it configuration is ‘S’)
Newman Projection
anti clock wise
Absolute configuration 'S'
View
In this molecule the CIP numbering 2 is on above the plane than it should be writing on
top of the bold vertical line and 1 should be on bottom of the line. 3 and 4 should be
writing on the horizontal line as it.
In biaryl system two ortho substituents are replaced by a single bridging atom (five-
membered ring is formed) rotation is restricted at room temperature and disubstituted
fluorine (10) which is planar does not show optical isomerism (Figure 13).
OH CH3
10
The effect of bridging on the restricted rotation of biaryl system is depends on the ring
size. If the ring size is six–membered bridge still considerably facilitate rotation but lesser
extent. In benzonaphthopyranones (11) exist as racemic mixture of their helically
distorted atrop-enantiomers S (M) and R (P). The restricted rotation increases with steric
O O
O R O
R
R1 R1
R2 R2
11 (S) 11 (R)
Fig. 14: Benzonaphthopyranones (11) exist as racemic mixture of their helically distorted
atrop-enantiomers S (M) and R (P).
The bridging is seven-membered or more than it and ortho substituent are bulkier. These
types of molecules (12-14) also show the atropisomerism (Figure 15).
H Me O R
S Me H
N
S
H N
O H
12 13 14 R
Some of the molecules which different than biphenyl also show the atropisomerism.
These molecules are linked together through a pivotal bond and rotation around the
[1] One or both of the phenyl groups are replaced by other heteroaromatic or aromatic
rings. Appropriately substituted molecules (15) are resolvable (Figure 16).
[2] 3,3’-bipyridyl (16) can also resolved and it exits in two enantiomer due to
atropisomerism (Figure 17).
2
C6 (C, C, C)
COOH COOH
6 6' 3
View Ph Ph C6' (C, C, C) C2' (C,N,N)
N N
2 2'
COOH COOH C2 (C,N,N)
1
16 Clcokwise
Configuration is 'R'
Br Br OH Br
H3C A B CH3
A B
H HO Br H
C2
17; Cis
Fig. 18: Introduction of two co-planar and co-axial phenyl rings A and B
Molecule 17 is Cis, where both bromide on phenyl ring A and ring B are on same side.
The molecule is C2 symmetric and also resolvable and chiral axis is passing through ring
A and middle ring of the biaryl and another chiral axis is passing through ring B and
middle ring of the biphenyl. The cis molecule has two chiral axes so it will have
enantiomers as well as diasetreromers. If molecule B is trans than it will possess the
inversion center and Ci point group and compound will be meso (same like in two chiral
centre tartaric acid) (Figure 19).
H Br OH Br
H3C A B CH3
A B
Br HO Br H
18; Trans
Pivotal bond
CH3 Cl
CH3
COOH
H3C CH3
Br
19
Fig. 20: Creation of steric strain around pivotal bond introduces atropisomerism.
[5] We have learned that the atropisomerism is due to restricted rotation around sp2-sp2
single bond. The sp3-sp3 single bond is restricted through various extents but the energy
barrier is too low so such type of molecules cannot be isolated. In the triptycene type
molecules, however the barrier to rotation around a 9-substituted bond may be quite high
and these atropisomers (20 and 20’) can be isolate at room temperature (Figure 21).
COOH COOH
MeO2C MeO2C
Me CH2Ph PhH2C Me
Me Me
20 20'
C1 symmetric
Fig. 21: In the triptycene type molecules, however the barrier to rotation around a 9-
substituted bond may be quite high and these atropisomers (20 and 20’) can be isolate at
room temperature.