Biphenyl derivatives & Atropisomerism

Biphenyl derivatives & Atropisomerism:Optical activity in Biphenyls, Stereochemistry of biphenyl derivatives, rules and assigning RS configuration to biphenyls

1. DOS&R IN ORGANIC CHEMISTRY TUMKUR UNIVERSITY By PRUTHVIRAJ K Faculty DOS&R in Organic Chemistry KPR. DOS&R in ORGANIC CHEMISTRY TUT Optical activity in Biphenyls

2. Biphenyls are in which two phenyl groups are joined by single bond (sp 2 -sp 2 ), called pivotal bond The distance b/w the ortho H’s in adjacent rings in the planar conformation is appreciably greater (0.29nm) than twice the vander Waals radius of hydrogen(0.12nm) hence rotation around pivotal bond is not impeded by steric factor. A phenyl group which is dissymetrically substituted does not have a vertical plane of symmetry is two-dimensionally chiral and a planar combination of two such groups would lead to two ( cis and trans) diastereomers and belonging to point groups c 2v and C 2h respectively. KPR. DOS&R in ORGANIC CHEMISTRY TUT

3. A non-planar combination would give to two enantiomers of C 2 symmetry, such combination of substituents leads molecule to be axially chiral with the line joining C-1 and C-1’ as the chiral axis so which leads to the additional condition for the biphenyls to be enantiomeric that planes of the two aryl groups must be kept non-coincidence KPR. DOS&R in ORGANIC CHEMISTRY TUT

4. Introduce of bulky groups in the ortho position leads to destabilization of planar conformations due to steric repulsion. The Bulkier the ortho substituents are, the higher is the energy barrier separating the enantiomers and when it exceeds 80-100 kJ mol -1 these stereoisomers are separable at RT. The kind of isomerism which owes its existence to restricted rotation around a single bond is known as atropisomerism and the isomers are called atropisomers and are actually torsional isomers about single bond. “ A tropisomers can be regarded as physically separable species when they interconvert with a half-life of more than 1000 seconds (16.7 min) at a given temperature”. The minimum free energy barrier (G) required to observe atropisomers varies with temperature. KPR. DOS&R in ORGANIC CHEMISTRY TUT

5. The characteristic of atropisomers is that they cannot be represented by any type formula as in the case of allenes , spiranes and centrally chirally compounds since the stereochemistry depends upon the bulks of the ortho substituents which restricts the rotation about the double bond. KPR. DOS&R in ORGANIC CHEMISTRY TUT

6. 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) [ ≥ 1000 s]. 3. The minimum required free energy barriers at different temperature are as below. Δ G 200K = 61.6 kJmol-1 Δ G 300K = 93.5 kJmol-1 Δ G 350K = 109 kJmol-1. 4. The configurational stability of axially chiral biaryl compounds is mainly determined 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. KPR. DOS&R in ORGANIC CHEMISTRY TUT

7. 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 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 KPR. DOS&R in ORGANIC CHEMISTRY TUT

8. 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 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 . 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 . KPR. DOS&R in ORGANIC CHEMISTRY TUT

9. 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. 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) KPR. DOS&R in ORGANIC CHEMISTRY TUT

10. 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. 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) KPR. DOS&R in ORGANIC CHEMISTRY TUT

11. 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. 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 KPR. DOS&R in ORGANIC CHEMISTRY TUT

12. 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 KPR. DOS&R in ORGANIC CHEMISTRY TUT

13. The R/S nomenclature can be given either by viewing a molecule from left hand side or right hand side. CIP Rule: If we will consider the carbon C2 and carbon C6 in this example, the extrapolation of 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’. C C-Br C-H C-C C C-COOH C-H C-C Note: In biaryl compounds if meta is not substituted than we can decide the preference by ortho substituents using CIP rule KPR. DOS&R in ORGANIC CHEMISTRY TUT

14. The R/S nomenclature can be given either by viewing a molecule from left hand side or right hand side KPR. DOS&R in ORGANIC CHEMISTRY TUT

15. The R/S nomenclature can be given either by viewing a molecule from left hand side or right hand side KPR. DOS&R in ORGANIC CHEMISTRY TUT

16. The R/S nomenclature can be given either by viewing a molecule from left hand side or right hand side KPR. DOS&R in ORGANIC CHEMISTRY TUT

17. 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 Always write bold line as vertical line 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. 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. KPR. DOS&R in ORGANIC CHEMISTRY TUT

18. P. S. Kalsi method for determining R/S descriptor Write 3 and 4 as it is on horizontal line (as it is marked to the ortho carbons of the biaryl ) 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 ’) KPR. DOS&R in ORGANIC CHEMISTRY TUT

19. 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 . 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 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 KPR. DOS&R in ORGANIC CHEMISTRY TUT

20. The bridging is seven-membered or more than it and ortho substituent are bulkier. These types of molecules ( 12-14 ) also show the atropisomerism KPR. DOS&R in ORGANIC CHEMISTRY TUT

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