Alpha axial haloketone rule and octant rule

This presentation discusses the use of alpha axial halo ketone rule and Octant rule for determination of absolute configuration

1. Determination of Absolute Configuration using α -a xial haloketone and Octant Rule Prepared by Dr. Krishna swamy G Faculty DOS & R in Organic Chemistry Tumkur University

2. Elucidation of configuration of chiral compounds will be done based on ORD and CD spectrum by using Semi empirical rules as follows There are two types of rule Sector rule applied for achiral chromophores for example saturated ketones α -Axial halo ketone rule Quadrant/ Octant rule (2) Helicity rule applied for chiral chromphores such as Helicenes and biaryls . Whenever atoms or groups are present in a molecule containing an achiral chromophore, perturbation of the electronic transitions of the chromophore will be sufficient to generate chiroptical properties i.e. a Cotton effect.

3. In sector rule the symmetric chromophore is divided into sectors by nodal planes as well as nodal surfaces. Such sectors are designed to assess the contributions of perturbing group to the cotton effect according to their position in one or other sector that surrounds the chromophore. Sector rules are widely used in the assignment of configuration by inspection of homologous and analogous compounds that have identical chromophores . Sector rule

4. This rule is applied for ketosteroid that are axially substituted with a halogen atom at the α -carbon. Axial substitution is preferred because of dipole-dipole repulsion in equatorial isomer. α -Axial halo ketone rule The position of the halogen (- Cl , -Br) was observed to influence the sign of the cotton effect and similar effects were found for other substituents such as NR 2 , SR, SO 2 R etc.

5. Assignment of configuration based on this rule is carried out by viewing the carbonyl carbon at the head of the chair. If the axial α -halogen is found on the right side in the compound it shows positive cotton effect. If the axial α -halogen is found on the left side in the compound it exhibits negative cotton effect.

6. Axial α -halogen – right side +CE

7. Axial α -halogen – left side -CE

8. Applications Determination of Absolute Configuration 12-ketosteroid undergoes bromination to form 11-bromo-12-ketosteroid product. The configuration of the product will be decided by the sign of cotton effect. The product formed shows negative cotton effect. Hence deduced to be (R) configuration.

9. In this enantiomer –Br is on the left side it makes – ve contribution to CE In this enantiomer –Br is on the right side it makes + ve contribution to CE

10. (-)-trans-2-decalone undergoes bromination to form (+)-trans-2-bromo-1-decalone and two enantiomeric products are possible. Since it gives positive cotton effect curve and based on the rule enantiomer with –Br on right side makes + ve contribution and Hence , its configuration is (S).

11. Determination of position of halogen substitution The position of halogen substitution can be determined based on the sign of CE of cyclic fused ring ketones .

12. Octant rule This rule is applied for substituted cyclohexanones . For assigning configuration based on this rule is to divide the space around the carbonyl group into eight sectors (Octant). Viewing will be through the carbonyl carbon and this octant has two sectors i.e. front sector and rear sector. Rear sector signs contribute to the CE hence they are more important.

13. Contributions from hydrogens are usually ignored. Substituents at 4 th position will have no effect on the CE, since equatorial or axial groups are in nodal plane. Contribution of the substituent in different sector towards cotton effect

14. Like wise equatorial groups at 2 nd and 6 th position will make only small contribution to CE because proximity to the XY nodal plane. 2 nd and 6 th axial group contribute more to the CE .

15. Substituent at 5 th position and 2 nd position make + ve contribution whereas substituent at 3 rd and 6 th position make – ve contribution to CE. Axial and equatorial substituents at 5 th position and 3 rd position contributes equally.

16. Determination of conformation of known configuration The compound (R)-(+)- methylcyclohexanone exhibit a positive cotton effect. From the application of the octant rule indicated that preferred conformation is equatorial.

17. Determination of configuration When applying the octant rule to determine configuration of ketosteroids , the sector with most carbons in it will make the major contribution to the sign of the cotton effect. For example consider the determination of absolute configuration of trans-10-methyl-2-decalone. The absolute configuration of (+)- enantiomer shows positive cotton effect and it also indicated by octant rule. Other enantiomer shows negative cotton effect and also according to octant rule there is negative contribution.

18. + CE - CE