Subject Chemistry

Paper No and Title Paper 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No and Title Module 29; Stereoisomerism (Atropisomersim) of Biaryl

Module Tag CHE_P1_M29

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction

2.1 Atropisomerism

3. Summary

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

1. Learning Outcomes

After studying this module, you shall be able to

 To know the atropisomerism in biaryl compounds  Know the conditions for atropisomersim in non-bridged biaryl and bridged biaryl compounds  To identify axial chirality in biphenyls  To find out absolute configuration (R/S) nomenclature for biaryl compounds  Study some examples of atropisomerism to get a better insight into their stereochemistry.

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.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

C-C (sigma bond and also known as pivotal bond)

Symmteric - Achiral

Fig. 1. Structure of biphenyl

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.

NO2 O N O2N 2 NO2

COOH COOH HOOC HOOC

1 1'

Fig. 2. Enantiomers of the 6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid

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

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

more than 1000 seconds (16.7 min) at a given temperature”. The minimum free energy barrier (G) required to observe atropisomers varies with temperature. Atropisomerism is not a phenomenon restricted to biphenyls and other many systems from t-alkyl-tryptycyls to binaphthyls exhibiting atropisomerism. A classic example of an atropisomeric binaphthyl is the ligand BINAP (2), the development of which earned Noyori a share of the Nobel Prize for Chemistry in 2001. Once the atropisomers have been separated, BINAP can be used as a chiral catalyst for the asymmetric hydrogenation of C=C and C=O bonds (Figure 3).

PPh2 PPh2

2 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:

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

i. The combined steric demand of the substituent in the combined steric demand of the substituents in the proximity of the axis. ii. The existence, length and rigidity of bridges. iii. Atropisomerisation mechanism different from a merely physical rotation about the axis, e.g. photo chemically or chemically induced processes.

Biaryl Atropisomers classified into two categories is based upon the basic structure of the biaryl atropisomers.

Biaryl Atropisomers

Bridged Biaryls Nonbridged Biaryls

(I) Atropisomerism in Non-bridged Biphenyls

Biphenyl is an aromatic hydrocarbon with a molecular formula (C6H5)2. It is notable as a starting material for the production of polychlorinated biphenyls (PCBs), which were once widely used as dielectric fluids and heat transfer agents. Biphenyl is also used as an intermediate for the production of the organic compounds like emulsifiers, optical brighteners, crop protection products, and plastics. Biphenyl is insoluble in water, but soluble in typical organic solvents. The biphenyl molecule consists of two connected phenyl rings. Biphenyl’s ortho positions are substituted with two different bulky groups makes it chiral and resolvable due restricted rotation through pivotal bond.

(II) Stereochemistry of Biphenyls Biphenyl does not show geometrical isomerism, it shows conformational isomerism the rotation around the single bond is possible in biphenyls and especially their ortho- substituted derivatives are sterically hindered. For this reason, some substituted biphenyls CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

show atropisomerism that is the individual C2-symmetric-isomers are optically stable. Some derivatives, as well as related molecules such as BINAP, find application as ligands in asymmetric synthesis. In the case of unsubstituted biphenyl, the equilibrium torsional angle is 44.4° and the torsional barriers are quite small, 6.0 kJ/mol at 0° and 6.5 kJ/mol at 90°. Adding ortho substituents greatly increases the barrier: in the case of the 2, 2'-dimethyl derivative, the barrier is 17.4 kcal/mol (72.8 kJ/mol). The below given compound (3) can resolvable at room temperature (Figure 4).

COOH Br

Br HOOC

3

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.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

3. Ortho substituent increases the restricted rotation through pivotal bond (atropisomerism) in non-bridged biaryl compounds by their steric repulsion. If the Van der Walls radiuses of the substituents are more than hydrogen atom rotation through pivotal bond will be restricted and molecule will show the atropisomerism. The Van der

Walls radius I > Br > Cl > NO2 > COOH > OMe > F > H (Figure 6).

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 Fig. 7: No atropisomer formed at room temperature.

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.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

The buttressing effect of the some of the groups are in the following order: NO2>Br>Cl>Me

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).

NO2 MeO NO 2 NO2 MeO 3'

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

6a-c; R = D, NH2, Br, I Fig. 10: Less common chiral molecules.

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).

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

O O

7 Fig. 11: Diether forms showing chirality. 6. Heteroaromatic system provides chirality even though their ortho substituents are same. In this molecule (8) both phenyl rings A and B are perpendicular to each other (Figure 12).

A A

N

HOOC COOH HOOC COOH

N

B

B

8

Fig. 12: Perpendicular A and B rings.

(III) How to write R/S nomenclature for the Biphenyls

Example 1: 6, 6'-dibromobiphenyl-2,2'-dicarboxylic acid (3’)

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' 1. Viewing from left hand side

A 2 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 6 groups will be given 1 2 Near our eyes will and 2 according CIP be on bold line rule than vertical line 3 (Vertical line) and 4 according CIP. Clock wise = R Converted in to Rotate 1-2-3, clock Newman Projection wise R

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

2. Viewing from right hand side

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 C-H C-H C2 = and C6 = . 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 according CIP rule than C6' (HOOC) C2'(Br) 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

Example 2: R/S nomenclature for the BINOL (9) CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

1. Viewing from left hand side

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. Viewing from right hand side

2 D B D OH View 3 A B OH A OH HO C C1

Newman Projection anti clock wise Absolute configuration 'S'

3. P. S. Kalsi method for determining R/S descriptor

This type way of nomenclature writing we should always view molecule from the bottom side of axis

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

4 3 1 OH 4 3 2 OH 1 2

Newman Projection anti clock wise Absolute configuration 'S' View

1. Always write bold line as vertical line

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’)

If we rotate same molecule and assign R/S nomenclature

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

3 4 2 HO 3 4 HO (S) 1 2 1

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.

(IV) Bridged Biphenyls

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

Fig. 13: Restricted rotation prevents isomerism.

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

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

demand of ortho substituent. Ortho substituent R = H, OMe, Me, Et their half-life at room temperature is less than 1 min but if R = iPr its half-life is 28 min (Figure 14).

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).

R H Me O S Me H N

S H N O H R 12 13 14

Fig. 15: Seven-membered bridging.

(V) Atropisomerism other than Biphenyls

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

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

pivotal bond is restricted. The atoms joined through the pivotal bond are usually sp2 hybridized.

[1] One or both of the phenyl groups are replaced by other heteroaromatic or aromatic rings. Appropriately substituted molecules (15) are resolvable (Figure 16).

C2 will have 1st priority because its neghibouring carbon is connected with COOH 1 CH COOH C (CH , C,C-COOH) 3 3 2 3 HOOC 2 2' C (C-H,C, C-H) View N C2'(H-C,C,HOOC-C) 6' 6 6' C6 (CH3, C, C-H) CH3 H 2 15 R configuration

Fig. 16: Appropriately substituted molecules (15) are resolvable.

[2] 3,3’-bipyridyl (16) can also resolved and it exits in two enantiomer due to atropisomerism (Figure 17).

2 C (C, C, C) COOH COOH 6 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'

Fig. 17: 3,3’-bipyridyl (16) showing atropisomerism.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

[3] Two phenyl groups (A and B) are introduced on p-substitution at biphenyls to form para terphenyl derivative and restricted rotation may arise around two pivotal bonds so two terminal phenyl rings (A and B) are co-planar as well as co-axial (Figure 18).

Br Br OH Br

CH H3C A B 3 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

CH H3C A B 3 A B Br HO Br H

18; Trans

Fig. 19: Trans form of molecule 17.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

[4] If one of the planar ring is replaced by an acyclic grouping (substituted alkene) which is two dimensionally. This type of molecules 19 may give atropisomerism if sufficient steric hindrance is created around the pivotal bond. (Figure 20).

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

PhH C Me CH2Ph 2 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.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl

3. Summary

In this module we have discussed that

 Atropisomerism in nonbridged and bridged biaryl compounds due to restricted rotation through pivotal bond.  Biaryl compound with appropriate different ortho susbsituent on each aryl ring will so the atropisomerism. The bulkier groups on ortho position of the biaryl ring restrict the rotation through C-C bond gives two enantiomers and resolvable at room temperature.  In bridged biaryls effect of bridging on the restricted rotation of biaryl system is depends on the ring size. Some of the molecules which different than biphenyl also show the atropisomerism.  The sp3-sp3 single bond is restricted through various extents and triptycene type molecules the barrier to rotation around may be quite high and these atropisomers can be isolate at room temperature.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 29: Stereoisomerism (Atropisomersim) of Biaryl