1. 3 3-1 Organic Chemistry William H. Brown & Christopher S. Foote

2. 3 3-2 Chirality Chapter 3

3. 3 3-3 Isomers  Isomers:  Isomers: different compounds with the same molecular formula  Constitutional isomers:  Constitutional isomers: isomers with a different connectivity  Stereoisomers:  Stereoisomers: isomers with the same molecular formula and connectivity but a different orientation of their atoms in space

4. 3 3-4 Isomers

5. 3 3-5 Chirality  Mirror image:  Mirror image: the reflection of an object in a mirror  Chiral:  Chiral: an object that is not superposable on its mirror image; an object that shows handedness  Achiral:  Achiral: an object that lacks chirality; an object that has no handedness an achiral object has at least one element of symmetry

6. 3 3-6 Elements of Symmetry  Plane of symmetry:  Plane of symmetry: an imaginary plane passing through an object dividing it so that one half is the mirror image of the other half

7. 3 3-7 Elements of Symmetry  Plane of symmetry (contd.)

8. 3 3-8 Elements of Symmetry  Center of symmetry:  Center of symmetry: a point so situated that identical components of the object are located on opposite sides and equidistant from the point along any axis passing through it

9. 3 3-9 Stereocenter  The most common (but not the only) cause of chirality in organic molecules is a tetrahedral atom, most commonly carbon, bonded to four different groups stereocenter stereogenic center  A carbon with four different groups bonded to it is called a stereocenter or, alternatively, a stereogenic center

10. 3 3-10 Enantiomers  Enantiomers:  Enantiomers: stereoisomers that are nonsuperposable mirror images; refers to the relationship between pairs of objects  On the three following screens are examples chiral molecules. Each has one stereocenter and can exist as a pair of enantiomers.

11. 3 3-11 Enantiomers  Lactic acid

12. 3 3-12 Enantiomers  2-Chlorobutane

13. 3 3-13 Enantiomers  3-Chlorocyclohexene

14. 3 3-14 Enantiomers  A nitrogen stereocenter

15. 3 3-15 R,S Convention  Priority rules 1. Each atom bonded to the stereocenter is assigned a priority based on atomic number; the higher the atomic number, the higher the priority 2. If priority cannot be assigned per the atoms bonded to the stereocenter, look to the next set of atoms; priority is assigned at the first point of difference

16. 3 3-16 R,S Convention 3. Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds

17. 3 3-17 Naming Enantiomers 1. Locate the stereocenter, identify its four substituents, and assign priority from 1 (highest) to 4 (lowest) to each substituent 2. Orient the molecule so that the group of lowest priority (4) is directed away from you 3. Read the three groups projecting toward you in order from highest (1) to lowest priority (3) 4. If the groups are read clockwise, the configuration is R; if they are read counterclockwise, the configuration is S (S)-2-Chlorobutane

18. 3 3-18 R,S Configuration (R)-3-Chlorocyclohexene (R)-Mevalonic acid

19. 3 3-19 Enantiomers & Diastereomers  For a molecule with 1 stereocenter, 2 1 = 2 stereoisomers are possible  For a molecule with 2 stereocenters, a maximum of 2 2 = 4 stereoisomers are possible  For a molecule with n stereocenters, a maximum of 2 n stereoisomers are possible

20. 3 3-20 Enantiomers & Diastereomers  2,3,4-trihydroxybutanal two stereocenters; 2 2 = 4 stereoisomers exist

21. 3 3-21 Enantiomers & Diastereomers  2,3-dihydroxybutanedioic acid (tartaric acid) two stereocenters; 2 n = 4, but for this molecule, only three stereoisomers exist  Meso compound:  Meso compound: an achiral compound possessing two or more stereocenters

22. 3 3-22 Enantiomers & Diastereomers 2-methylcyclopentanol

23. 3 3-23 Enantiomers & Diastereomers 1,2-cyclopentanediol

24. 3 3-24 Enantiomers & Diastereomers cis-3-methylcyclohexanol

25. 3 3-25 Enantiomers & Diastereomers trans-3-methylcyclohexanol

26. 3 3-26 Properties of Stereoisomers  Enantiomers have identical physical and chemical properties in achiral environments  Diastereomers are different compounds and have different physical and chemical properties  Meso-tartaric acid, for example, has different physical and chemical properties from its enantiomers (see Table 3.1).

27. 3 3-27 Plane-Polarized Light  Ordinary light:  Ordinary light: light vibrating in all planes perpendicular to its direction of propagation  Plane-polarized light:  Plane-polarized light: light vibrating only in parallel planes plane polarized light is the vector sum of left and right circularly polarized light; these two forms of light are enantiomers because of their handedness, each component of circularly polarized light interacts in an opposite way with a chiral molecule.

28. 3 3-28 Plane-Polarized Light

29. 3 3-29 Plane-Polarized Light because of its handedness, circularly polarized light reacts one way with an R stereocenter, and in an opposite with its enantiomer the net effect of the interaction of plane polarized light with a chiral compound is that the plane of polarization is rotated  Polarimeter:  Polarimeter: a device for measuring the extent of rotation of plane polarized light

30. 3 3-30 Optical Activity  Observed rotation:  Observed rotation: the number of degrees, , through which a compound rotates the plane of polarized light  Dextrorotatory (+):  Dextrorotatory (+): refers to a compound that rotates the plane of polarized light to the right  Levorotatory (-):  Levorotatory (-): refers to a compound that rotates of the plane of polarized light to the left

31. 3 3-31 Optical Activity  Specific rotation:  Specific rotation: observed rotation of the plane of polarized light when a sample is placed in a tube 1.0 dm in length and at a concentration of 1g/mL

32. 3 3-32 Optical Activity  For a pair of enantiomers, the value of the specific rotation of each is the same, but opposite in sign

33. 3 3-33 Enantiomeric Excess  When dealing with a mixture of enantiomers, it is essential to describe the composition of the mixture and the degree to which one enantiomer is in excess  The most common designation is enantiomeric excess (ee)

34. 3 3-34 Enantiomeric Excess Example: a commercial synthesis of naproxen, a nonsteroidal antiinflammatory drug (NSAID), gives this enantiomer in 97% ee. Assign an R or S configuration to its stereocenter, and calculate the % R and S enantiomers in the mixture.

35. 3 3-35 Resolution  Racemic mixture:  Racemic mixture: an equimolar mixture of two enantiomers because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific activity is zero.  Resolution:  Resolution: the separation of a racemic mixture into its enantiomers

36. 3 3-36 Resolution  One means of resolution is to convert the pair of enantiomers into two diastereomers diastereomers are different compounds and have different physical properties  A common reaction for chemical resolution is salt formation after separation of the diastereomers, the enantiomerically pure acids are recovered

37. 3 3-37 Resolution Examples of enantiomerically pure bases

38. 3 3-38

39. 3 3-39 Resolution  Enzymes as resolving agents

40. 3 3-40 Chirality in the Biological World  Except for inorganic salts and a few low- molecular-weight organic substances, the molecules of living systems are chiral  Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system  It’s a chiral world!

41. 3 3-41 Chirality in the Biological World  Consider chymotrypsin, a protein-digesting enzyme in the digestive system of animals chymotrypsin contains 251 stereocenters the maximum number of stereoisomers possible is 2 251 there are only 2 38 stars in our galaxy!

42. 3 3-42 Chirality in the Biological World  Enzymes are like hands in a handshake the substrate fits into a binding site on the enzyme surface a left-handed molecule will only fit into a left-handed binding site and a right-handed molecule will only fit into a right- handed binding site enantiomers have different physiological properties because of their handedness of their interactions with other chiral molecules in living systems

43. 3 3-43 Chirality in the Biological World

44. 3 3-44 Prob 3.15 Draw mirror images for each molecule.

45. 3 3-45 Prob 3.16 Which are identical with (a) and which are mirror images of (a)?

46. 3 3-46 Prob 3.17 Mark all stereocenters in each molecule.

47. 3 3-47 Prob 3.20 Assign an R or S configuration to the stereocenter in each enantiomer.

48. 3 3-48 Prob 3.21 Assign an R or S configuration to this enantiomer of 2- butanol. Also draw a Newman production viewed along the bond between carbons 2 and 3.

49. 3 3-49 Prob 3.22 Assign an R or S configuration to each stereocenter in this enantiomer of ephedrine.

50. 3 3-50 Prob 3.23 Assign an R or S configuration to this enantiomer of carbon-14 labeled citric acid.

51. 3 3-51 Prob 3.24 Draw all stereoisomers possible for this compound. Label which are meso and which are pairs of enantiomers.

52. 3 3-52 Prob 3.25 Mark are stereocenters in each molecule. How many stereoisomers are possible for each molecule?

53. 3 3-53 Prob 3.26 Label the eight stereocenters in cholesterol.

54. 3 3-54 Prob 3.27 Label the four stereocenters in amoxicillin.

55. 3 3-55 Prob 3.29 Are the formulas in each set identical, enantiomers, or diastereomers?

56. 3 3-56 Prob 3.30 Which are meso compounds?

57. 3 3-57 Prob 3.31 Oxidation of this bicyclic alkene gives a dicarboxylic acid. Is the product of this oxidation one enantiomer, a racemic mixture, or a meso compound?

58. 3 3-58 Prob 3.35 Verify that although, this molecule has no stereocenter, it is chiral.

59. 3 3-59 Prob 3.36 Verify that, although this substituted allene has no stereocenter, it is chiral.

60. 3 3-60 Chirality End of Chapter 3