1. 1 כימיה אורגנית לתלמידי רפואה, מדעי הרפואה, ורפואת שיניים 69118 ד"ר עידית תשובה המחלקה לכימיה אי אורגנית בניין לוס-אנג'לס, חדר 213 02-6586084 tshuva@chem.ch.huji.ac.il האוניברסיטה העברית

2. 2 כימיה אורגנית לתלמידי רפואה, מדעי הרפואה ורפואת שיניים תוכן הקורס Organic Chemistry, 4 th Edition, Paula Yurkanis Bruice Organic Chemistry, 5 th Edition, Paula Yurkanis Bruice OR אתר הקורס: http://owl.huji.ac.il

3. 3 ChaptersTopic *** 1 *** *** Electronic structure and bonding acids and bases; Mandatory self reading *** 22An introduction to organic compounds; nomenclature, properties, structures 3-4 Alkenes; structure, nomenclature, reactivity 55Stereochemistry 66Alkynes 7-87Delocalization and resonance, Dienes 911Reactions of alkanes 10-128-10Substitutions and eliminations; alkyl halides, alcohols, ethers, epoxides, Griniard reactions 1514Aromaticity 1615Reactions of aromatic compounds 17-1916-18Carbonyl compounds 2019Oxidation-reduction 22,23,26,2721,22,26,27 Bioorganic compounds; carbohydrates, proteins, lipids, nucleic acids -*** 25 ****** The Chemistry of metabolism; Highly recommended self reading *** כימיה אורגנית לתלמידי רפואה, מדעי הרפואה ורפואת שיניים סילבוס 4th5th

4. 4 Organic Chemistry, 4 th Edition, Paula Yurkanis Bruice Chapter 5 Pg 182-237 Stereochemistry The Arrangement of Atoms in Space; The Stereochemistry of Addition Reactions Irene Lee Case Western Reserve University Cleveland, OH ©2004, Prentice Hall קריאה מלווה מחייבת Chapter 5 Pg 200-257 Stereochemistry The Arrangement of Atoms in Space; The Stereochemistry of Addition Reactions Organic Chemistry, 5 th Edition, Paula Yurkanis Bruice

5. 5 Isomers Nonidentical compounds having the same molecular formula Do not interconvert under ambient conditions

6. 6 Cis-Trans Isomers Caused by restricted rotation

7. 7 Achiral compounds have superimposable mirror images Chiral compounds have nonsuperimposable mirror images; they do not have a plane of symmetry SuperimposableNon-superimposable

8. 8 SuperimposableNon-superimposable

9. 9 Enantiomers

10. 10 Enantiomers nonsuperimposable mirror-image molecules

11. 11 Drawing Enantiomers Perspective formula Fischer projection

12. 12 A stereocenter (stereogenic center) is an atom at which the interchange of two groups produces a stereoisomer

13. 13 Naming Enantiomers Rank the groups (atoms) bonded to the chirality center The R,S system of nomenclature

14. 14 Orient the lowest priority (4) away from you Clockwise = R configuration Counterclockwise = S configuration

15. 15 Orient the lowest priority (4) away from you Clockwise = R configurationCounterclockwise = S configuration

16. 16 Naming from the Perspective Formula 1 2 3 4 1. Rank the groups bonded to the asymmetric carbon 2. If the group (or atom) with the lowest priority is bonded by hatched wedge,

17. 17 3. If necessary, rotate the molecule so that the lowest priority group (or atom) is bonded by a hatched wedge 4. You can draw group 1 to group 2, passing group 4, but never 3

18. 18 Naming from the Fischer Projection 1. Rank the groups (or atom) that are bonded to the asymmetric carbon and draw an arrow with the highest priority to the lowest priority (R)-3-chlorohexane 2. If the lowest priority is on a horizontal bond, the naming is opposite to the direction of the arrow (S)-2-butanol

19. 19 A Fischer projection can only be rotated 180 ° in the plane of the paper to yield the same molecule 3. The arrow can go from group 1 to 2, passing group 4, but not group 3 (S)-lactic acid

20. 20 Enantiomers share many physical properties. Chiral compounds are optically active; they rotate the plane of polarized light. Clockwise (+)Counterclockwise (-) Different from R,S configuration Achiral compounds do not rotate the plane of polarized light. They are optically inactive.

21. 21 Chiral compounds are optically active; they rotate the plane of polarized light. Clockwise (+)Counterclockwise (-) Different from R,S configuration Achiral compounds do not rotate the plane of polarized light. They are optically inactive.

22. 22 Chiral compounds are optically active; they rotate the plane of polarized light. Clockwise (+)Counterclockwise (-) Different from R,S configuration Achiral compounds do not rotate the plane of polarized light. They are optically inactive.

23. 23 Chiral compounds are optically active; they rotate the plane of polarized light. Clockwise (+,d)Counterclockwise (-,l) Different from R,S configuration Achiral compounds do not rotate the plane of polarized light. They are optically inactive.

24. 24 A polarizer measures the degree of optical rotation of a Compound, polarimeter The observed rotation (  ) T is the temp in °C is the wavelength  is the measured rotation in degrees l is the path length in decimeters c is the concentration in grams per mL Each optically active compound has a characteristic specific rotation

25. 25 A racemic mixture (  ), which contains an equal amount of the two enantiomers, is optically inactive optical purity = observed specific rotation specific rotation of the pure enantiomer enantiomeric excess = excess of a single enantiomer entire mixture

26. 26 Diastereomers are stereoisomers that are not enantiomers Unlike enantiomers, they have different physical properties, react differently with achiral compounds Isomers with more than one chiral carbon: a maximum of 2 n stereoisomers can be obtained

27. 27 Identification of Asymmetric Carbons in Cyclic Compounds these two groups are different cis-1-bromo-3-methylcyclohexane trans-1-bromo-3-methylcyclohexane

28. 28 Meso Compounds Have two or more asymmetric carbons and a plane of symmetry They are achiral molecules

29. 29

30. 30 As long as any one conformer of a compound has a plane of symmetry, the compound will be achiral plane of symmetry plane of symmetry Also true for acyclic, we usually check the eclipsed conformation

31. 31 The R,S nomenclature of isomers with more than one asymmetric carbon Enantiomers have opposite configurations at all asymmetric carbon atoms. Diastereomers have one similar configurationand opposite on the other.

32. 32 Reactions of compounds that contain an asymmetric carbon. No reaction at the asymmetric carbon; both the reagent and the product have the same relative configuration, not always the same absolute configuration. If a reaction breaks a bond at the asymmetric carbon, you need to know the reaction mechanism in order to predict the relative configuration of the product.

33. 33 Resolution of a Racemic Mixture (R)-acid (S)-acid enantiomers (S)-base (R,S)-salt(S,S)-salt diastereomers (R,S)-salt(S,S)-salt HCl (S)-baseH + + (R)-acid (S)-baseH + + (S)-acid

34. 34 1.Enantiomers react similarly with achiral compounds 2.Enantiomers react differently with chiral compounds 3.Diastereomers react differently with both chiral and achiral compounds 4.A reaction that involves non-optically active reactants, whether achiral or racemic, in which a new asymmetric carbon is formed, will necessarily lead to formation of racemic mixtures (optically inactive). 5.Only when one of the reactants, or a catalyst, are optically active (chiral with excess of one enantiomer over the other), a new chiral center that leads to optical activity may be formed (enantiomeric excess, ee). Some Rules to Remember

35. 35 Discrimination of Enantiomers by Biological Molecules An enzyme is an example of a stereospecific catalyst A receptor is a protein that binds a certain molecule.

36. 36 Discrimination of Enantiomers by Biological Molecules Enantiomers have different therapeutic properties. Both enantiomers need to be tested, preference for the use of the pure beneficial enantiomer מנטהקימל

37. 37 More Terminologies of Stereochemistry 1.Two hydrogen atoms bound to a single carbon atom, that upon replacement of each at a time with deuterium give identical compounds, are homotopic. 2.Two hydrogen atoms bound to a single carbon atom, that upon replacement of each at a time with deuterium give enantiomeric compounds, are enantiotopic. 3.Two hydrogen atoms bound to a single carbon atom, that upon replacement of each at a time with deuterium give diasteriomeric compounds, are diasteriotopic

38. 38 More Terminologies of Stereochemistry Enantiotopic hydrogens have the same chemical reactivity and cannot be distinguished by achiral agents, but they are not chemically equivalent toward chiral reagents. The ‘prochiral carbon’ of the ‘prochiral molecule’ may turn chiral upon changing an enantiotopic hydrogen with deuterium. Replacement of the pro-R hydrogen with deuterium will result in an R configuration. Diastereotopic hydrogens have different reactivity towards achiral compounds as well. pro-R-hydrogen pro-S-hydrogen

39. 39 Diastereotopic hydrogens do not have the same reactivity with achiral reagents

40. 40 Atoms other than carbon can be asymmetric

41. 41 Amine Inversion

42. 42 A regioselective reaction: preferential formation of one constitutional isomer A stereoselective reaction: preferential formation of a stereoisomer

43. 43 A stereospecific reaction: each stereoisomeric reactant produces a different stereoisomeric product or a different set of products All stereospecific reactions are stereoselective Not all stereoselective reactions are stereospecific

44. 44 Stereochemistry of Electrophilic Addition Reactions of Alkenes What is the absolute configuration of the product?

45. 45 Addition reactions that form one asymmetric carbon

46. 46

47. 47 Addition reactions that form an additional asymmetric carbon Diastereomers have different properties, stabilities, etc. One diastereomer may form in excess.

48. 48 A carbocation reaction intermediate Addition reactions that form two asymmetric carbons Two substituents added to the same side of the double bond: syn Two substituents added to opposite sides of the double bond: anti

49. 49 A radical reaction intermediate Addition reactions that form two asymmetric carbons

50. 50 Stereochemistry of Hydrogen Addition (Syn Addition) The reaction is stereoselective (not all possible isomers form) and stereospecific (cis and trans reactants yield different isomers. (Meso for identical groups on both carbons)

51. 51 Hydrogenation of Cyclic Alkenes Only cis isomers are obtained with alkenes containing fewer than eight ring atoms Both cis and trans isomers are possible for rings containing eight or more ring atoms

52. 52 Stereochemistry of Hydroboration– Oxidation Concerted reaction, syn addition.

53. 53 Addition reactions that form a bromonium ion intermediate (anti addition)

54. 54

55. 55