1. Pharmaceutical Organic Chemistry Lec 3

2. Stereochemistry Optical isomerism Absolute Configuration ( AC ) Is the actual spatial arrangement of atoms or groups around a chiral carbon In 1891 German chemist [ Emil Fisher ] introduce formula showing the spatial arrangement ………

3. configuration – the arrangement in space of the four different groups about a chiral center. How do we show configurations? “wedge” formulasFischer projections “cross structures” use only for chiral centers!

4. Rules for Fischer projections Arrange the molecule so that horizontal bonds at chiral carbon point toward you and vertical bonds point away from you.

5. H F ClBr Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.

6. Stereochemistry Optical isomerism (±)- Ethanolamine CH 3 CH(OH)NH 2 has one chiral carbon, so 2- enantiomers H2NH2NH2NH2N CH 3 H OH H2NH2NH2NH2N OH H Mirror Fischer projection formula

7. Determination of ( AC ) by ( R ) and ( S ) system Groups are assigned a priority ranking using the same set of rules as are used in ( E ) and ( Z ) system CH 3 CH(OH)NH 2 1. Draw Fischer Projection formula H2NH2NH2NH2N CH 3 OH H

8. Determination of ( AC ) by ( R ) and ( S ) system Groups are assigned a priority ranking using the same set of rules as are used in ( E ) and ( Z ) system CH 3 CH(OH)NH 2 2. Rank the substitution according to the priority order H2NH2NH2NH2N CH 3 OH H OH > NH 2 > CH 3 > H 1 2 3

9. Determination of ( AC ) by ( R ) and ( S ) system 3. The group (atom) with lowest priority [H] should be away from the observer, if not do an even number of changes to get H away from the observer H2NH2NH2NH2N CH 3 OH H 1 OH OH H2NH2NH2NH2N H2NH2NH2NH2N H H 2

10. Determination of ( AC ) by ( R ) and ( S ) system 4. Draw an arrow from group with highest priority ( OH ) to second highest priority ( NH 2 ). if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S HO H NH 2 CH 3 (R)-ethanolamine (+)- ethanolamine

11. The viewing rule

12. Switching Substituents on a Fischer Projection 1)Any single (odd #) exchange of 2 substituents gives the other enantiomer 2)Any two (even #) of exchanges gives the same enantiomer R R S

13. Draw the formulas for the two enantiomers of each of the following compunds then assign each as R or S

14. a) Analyze compounds A, B, and C. Which are identical Which are enantiomers

15. b) How are the following pairs of compounds related

17. Stereochemistry (±)- CH 3 CH(Cl)CH(Br)NH 2 n = 2 ….. So No. of stereoisomer 4 1,3 and 1,4 2,3 and 2,4 are diastereoisomers

18. Stereochemistry Determination of ( AC ) in enatiomer 1 a. At C1 : H NH 2 C2C2C2C2 C2C2C2C2 H Br Br 2 1 AC at C1 is S Br > NH 2 > C 2 > H

19. Stereochemistry Optical isomerism Stereochemistry Determination of ( AC ) in enatiomer 1 a. At C2 : H C1C1C1C1 CH 3 Cl H Cl C1C1C1C1 2 1 AC at C2 is S Cl > C 1 > CH 3 > H

20. Enantiomers and diastereomers: EXAMPLE: 2-Bromo-3-chlorobutane

21. Meso compounds have internal plan of symmetry  In the simplest case, they are compounds which have internal plan of symmetry.  EXAMPLE:  Tartaric acid

22. Stereochemistry Optical isomerism Meso-compound are : - superimposable mirror images - only 3 stereoisomers - optically inactive COOHCH(OH)CH(OH)COOH tartaric acid tartaric acid

24. Racemic Mixture

25. A racemic mixture dose not rotate the plane of polarization of plane-polarized light because the rotation by each enantiomer is cancelled by the equal and opposite rotation by the other. A solution of either a racemic mixture or of achiral compound said to be optically inactive Many drugs are optically active, with one enantiomer only having the beneficial effect. In the case of some drugs, the other enantiomer can even be harmful, e.g. thalidomide.

26. In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness. This led to many disabilities in babies and early deaths in many cases.

27. Thalidomide was banned worldwide when the effects were discovered. However, it is starting to be used again to treat leprosy and HIV. Its use is restricted though and patients have to have a pregnancy test first (women!) and use two forms of contraception.

28. Stereochemistry Resolution of racemic mixture 1- treat the mixture with microorganism 2- using chiral reagent 2- using chiral reagent ( R) RCOOH ( R) RCOO - (S) R’NH 3 + ( R) RCOOH ( R) RCOO - (S) R’NH 3 + + ( S) R’NH 2 + ( S) R’NH 2 ( S) RCOOH ( S) RCOO - (S) R’NH 3 + ( S) RCOOH ( S) RCOO - (S) R’NH 3 +

29. Resolution of Enantiomers React a racemic mixture with a chiral compound to form diastereomers, which can be separated. =>

30. Examine the following structural formulas and select those that are chiral.