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2.1 Atropisomerism 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.
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