1 Stereochemistry

2 Handedness Some things have a “handedness,” that is look at your right and left hand. They look alike, but are not the same. They are mirror images.

3 Nobel Prize Their research deals with the fact that many molecules appear in two forms that are mirror images of each other, just like the left and right hands.

4 The mirror image of a chiral object is different and will not superimpose on the original object. Objects which are chiral have a sense of “handedness” and exist in two forms. Chirality

5 Mirror Image

6 Are these two structures identical? mirror

7 Stereoisomers

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10 Stereoisomers

11 Stereoisomers

12 Stereoisomers

13 enantiomers enantiomers. Stereoisomers that are nonidentical mirror images are called enantiomers. Stereoisomers

14 Visualize, visualize ….

15 Visualize, visualize …

16 C CH 3 Br F H C CH 3 F Br H enantiomer …etc interchanges = enantiomer etc interchanges = original compound ODD: EVEN: Visualize, visualize …

17 CC CH 3 Br F H CH 3 H F Br CC C C CH 3 Br F H CH 3 Br F H CH 3 H Br F H CH 3 Br F ENANTIOMER SAME YOU CAN USE INTERCHANGES Are these identical or are they enantiomers?

18 Isomers Isomers: different compounds with the same molecular formula Constitutional isomers: isomers with a different connectivity Stereoisomers: isomers with the same molecular formula, the same connectivity but a different orientation of their atoms in space that cannot be interconverted by rotation about a single bond

19 Chirality Mirror image: the reflection of an object in a mirror Objects that are not superposable on their mirror images are said to be chiral, that is, they show handedness Objects that are superposable on their mirror images are said to be achiral, that is, they do not show handedness. An achiral object has at least one element of symmetry

20 Chirality A molecule cannot be chiral if it has a plane of symmetry.

21 Chirality A plane of symmetry is a plane that cuts through an object in such a way that one half of the object is an exact mirror image of the other half. A molecule that has a plane of symmetry must be identical to its mirror image and therefore must be nonchiral, or achiral.

22 stereocenter This is one type of …. …. others are possible A stereogenic carbon is tetrahedral and has four different groups attached. Stereogenic Carbons

23 C l Cl Br F F B r ClCl Elements of Symmetry Plane of symmetry: an imaginary plane passing through an object dividing it such that one half is the mirror image of the other half

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

25 Two identical groups renders a tetrahedral carbon achiral. The plane of the paper is a plane of symmetry Achiral

26 Cl Cl Br F F Br ClCl plane of symmetry side viewedge view Two Views of the Plane of Symmetry

27 Symmetry Plane

28 CONSTITUTIONAL ISOMERS Isomers with a different order of attachment of the atoms in their molecules STEREOISOMERS Isomers with the same order of attachment, but a different configuration (3D arrangement) of groups on one or more of the atoms ISOMERS Different compounds with the same molecular formula cis/trans ISOMERS ENANTIOMERS Stereoisomers whose molecules are non- superimposible mirror images of each other DIASTEREOMERS Stereoisomers whose molecules are not mirror images of each other each isomer could double bond or ring both can apply have stereoisomers with a ring TYPES OF ISOMERISM (geometric)

29 Enantiomers Enantiomers: stereoisomers that are nonsuperposable mirror images; refers to the relationship between pairs of objects

30 rotate this molecule is chiral note that the fluorine and bromine have been interchanged in the enantiomer do interchanges in class Enantiomers

31 Enantiomers Lactic acid

32 Enantiomers 1,2-propanediol

33 Enantiomers 3-Chlorocyclohexene

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37 Carvone

38 Limonene

39 Chiral Drugs Most pharmaceutical drugs are chiral thalidomide

40 Optically Active Refers to molecules that interact with plane-polarized light Jean Baptiste Biot French Physicist He discovered that some natural substances (glucose, nicotine, sucrose) rotate the plane of plane-polarized light and that others did not.

41 Optical Activity incident polarized light transmitted light (rotated) sample cell angle of rotation,  (usually quartz) a solution of the substance to be examined is placed inside the cell 

42 Plane Polarized Light Ordinary light: consists of waves vibrating in all planes perpendicular to its direction of propagation Plane polarized light: consists of waves vibrating only in one plane Plane polarized light is an equal mixture of left and right-circularly polarized light. These two forms are nonsuperposable mirror images and, therefore, enantiomers.

43 Plane-Polarized Light Beam. unpolarized beam wavelength = c frequency ( n ) c = speed of light polarized beam Sine waves are not aligned in the same plane. NOT PLANE-POLARIZED END VIEW SIDE VIEW

44 Plane Polarized Light Because of its handedness, circularly polarized light reacts one way with a stereocenter with R-handedness, and differently 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: a device for measuring the extent of rotation of plane polarized light

45 Optical Activity optical activity - ability of certain molecules to rotate plane polarized light detected using a polarimeter

46 Polarimeter

47  l (dam) sample cell Na vapor lamp polarizer analyzer Polarimeter

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

49 Optical Activity Specific rotation: Observed rotation of the plane of polarized light when a sample is placed in a tube 1.0 dam in length and at a concentration of 1g/mL.  = observed rotation c = concentration ( g/mL ) l = length of cell ( dm ) D = yellow light from sodium lamp T = temperature ( Celsius )

50 Optical Activity For a pair of enantiomers, the value of the specific rotation of each is the same, but opposite in sign

51 Discovery of Enantiomers Louis Pasteur Recrystallized tartaric acid Two different kinds of crystals that were mirror images. Each type of crystal rotated light in opposite directions.

52 Discovery of Enantiomers “There is no doubt that in dextro tartaric acid there exists an assymetric arrangement having a nonsuperimposible image.”

53 (as a minor component) ALSO FOUND more about this compound later (+)-tartaric acid(-)-tartaric acid [  ] D = 0 meso -tartaric acid Tartaric Acid

54 R,S Convention Priority rules (Cahn, Ingold, Prelog) Each atom bonded to the stereocenter is assigned a priority, based on atomic number. The higher the atomic number, the higher the priority Increasing Priority

55 R,S Convention If priority cannot be assigned on the basis of the atoms bonded to the stereocenter, look to the next set of atoms. Priority is assigned at the first point of difference. Increasing Priority

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

57 Naming Enantiomers 1. Locate the stereocenter 2. Assign a priority to each substituent from 1 (highest) to 4 (lowest) 3. Orient the molecule so that the group of lowest priority (4) is directed away from you

58 Naming Enantiomers 4. Read the three groups projecting toward you in order from highest (1) to lowest priority (3) 5. If reading is clockwise, configuration is R (from the Latin rectus). If it is counterclockwise, configuration is S (from the Latin sinister).

59 2 clockwise counter clockwise (rectus)(sinister) view with substituent of lowest priority in back C C RS R, S Convention

RS Enantiomers Bromochlorofluoroiodomethane

61 Priorities 1. -OH 2. -COOH 3. -CH H

62 You try it! 1. Br 2. COOH 3. CH 3 4. H

63 Diastereoisomer Enantiomers: opposite configurations at all stereogenic centers. Diastereomers: Stereoisomers that are not mirror images of each other. Different configuration at some locations.

64 Diastereoisomer Stereoisomers that are not mirror images of each other. Different configuration at some locations.

65 Two Stereocenters

66 Diastereomers Threonine: 2 pairs of enantiomers 2R,3R2S,3S2R,3S & 2S,3R 2S,3S2R,3R2R,3S & 2S,3R 2R,3S2S,3R2R,3R & 2S,3S 2S,3R2R,3S2R,3R & 2S,3S

67 Enantiomers & Diastereomers For a molecule with 1 stereocenter, 2 stereoisomers are possible For a molecule with 2 stereocenters, a maximum of 4 stereoisomers are possible For a molecule with n stereocenters, a maximum of 2 n stereoisomers are possible 2 n-1 pairs of enantiomers

68 Enantiomers & Diastereomers For tartaric acid, the three possible stereoisomers are one meso compound and a pair of enantiomers. Meso compound: an achiral compound possessing two or more stereocenters.

69 Symmetry Plane 2R, 3S and 2S, 3R are identical Molecule has a plane of symmetry perpendicular to C-C and is therefore achira

70 Symmetry Plane 2R, 3S and 2S, 3R are identical Molecule has a plane of symmetry perpendicular to C-C and is therefore achira One meso compound and a pair of enantiomers Mirror image is identical

71 enantiomers 1 enantiomers 2 diastereomers SR RS SS RR mirror 2-Bromo-3-chlorobutane

72 meso enantiomers diastereomers SR S S RR mirror image is identical 2,3-Dichlorobutane

73 Meso Meso compounds are achiral by virtue of a symmetry plane, but contain a stereogenic center.

74 Racemic Mixture Racemic mixture (d,l;  ): an equimolar mixture (50:50) of two enantiomers because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific activity is zero.

75 Properties of Stereoisomers Enantiomers have identical physical (except for  ) and chemical properties. 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

76 Tartaric Acid (-) - tartaric acid [  ] D = o mp o solubility of 1 g 0.75 mL H 2 O 1.7 mL methanol 250 mL ether insoluble CHCl 3 d = g/mL (+) - tartaric acid [  ] D = o mp o solubility of 1 g 0.75 mL H 2 O 1.7 mL methanol 250 mL ether insoluble CHCl 3 d = g/mL meso - tartaric acid [  ] D = 0 o solubility of 1 g mp 140 o 0.94 mL H 2 O d = g/mLinsoluble CHCl 3

77 HOH CH Fischer Projections Fischer projection: a two-dimensional representation showing the configuration of a stereocenter horizontal lines represent bonds projecting forward vertical lines represent bonds projecting to the rear the only atom in the plane of the paper is the stereocenter

78 Fischer Projections (R)-lactic acid How?

79 Fischer Projections

80 Fischer Projections

81 Fischer Projections 1. Orient the stereocenter so that bonds projecting away from you are vertical and bonds projecting toward you are horizontal 2. Flatten it to two dimensions

82 Assigning R,S Configuration Lowest priority group goes to the top. View rest of projection. A curved arrow from highest to lowest priority groups. Clockwise - R (rectus) Counterclockwise - S (sinister)

83 Assigning R,S Configuration s-lactic acid

84 Rules of Motion  Can rotate 180°, but not 90° because 90° disobeys the Fischer projection. Same groups go in and out of plane

85 Rules of Motion  Can rotate 180°, but not 90° because 90° disobeys the Fischer projection. Different groups go in and out of plane This generates an enantiomeric structure

86 Rules of Motion  One group can be held steady and the others rotated.

87 Rules of Motion To determine if two Fischer projections represent the same enantiomer carry out allowed motions.

88 Rules of Motion By performing two allowed movements on B, we are able to generate projection A. Therefore, they are identical.

89 Rules of Motion Perform one of the two allowed motions to place the group with lowest priority at the top of the Fischer projection.

90 Priorities 1. NH 2 2. COOH 3. CH 3 4. H

91 Stereochemistry of Reactions

92 Addition of HBr

93 Addition of Br 2 Cis Racemic mixture Achiral bromonium ion

94 Addition of Br 2 Trans Symmetry plane, therefore meso Models are superimposible

95 Addition of Br 2

96 Addition of HBr to a Chiral Alkene

97 Addition of HBr to a Chiral Alkene Chiral intermediate is not attacked equally from top and bottom because of steric reasons. Therefore, a mixture of product is formed in unequal amounts.

98 Chirality in Substituted Cyclohexanes Symmetry plane No stereogenic centers 1,4-disubstituted Only cis & trans diastereomers

99 1,3-disubstituted Cis Symmetry plane Meso compound

100 1,3-disubstituted Trans No symmetry plane Therefore enantiomers

101 1,2-disubstituted Trans Enantiomers

102 1,2-disubstituted Cis Meso

103 enantiomers diastereomers cis trans 1-Bromo-2-chlorocyclohexane

104 enantiomers cis trans diastereomers RSSR RRSS 1-Bromo-2-chlorocyclopropane

105 Br Br Br Br Br mirror image identical meso enantiomers diastereomers cis trans 1,2-Dibromocyclopropane

106 (S)-ibuprofen