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Chapter 5 Stereoisomerism Organic Chemistry Second Edition David Klein Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry.

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Presentation on theme: "Chapter 5 Stereoisomerism Organic Chemistry Second Edition David Klein Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry."— Presentation transcript:

1 Chapter 5 Stereoisomerism Organic Chemistry Second Edition David Klein Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

2 Chapter 5: Stereochemistry The three-dimensional structure of a molecule can greatly affect its physical and chemical properties. Can you give some examples? Three dimensional structure is critical in biochemistry. HOW? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-2

3 Chapter 5: Stereochemistry For pharmaceuticals, slight differences in 3D spatial arrangement can make the difference between targeted treatment and undesired side-effects. WHY? Isomers that have the same connectivity between atoms but different 3D, spatial arrangement of their atoms are called STEREOisomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-3

4 5.1 Isomers Isomers are NONidentical molecules that have the same formula There are two classifications of isomers Draw a pair of molecules that are constitutional isomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-4

5 5.1 Isomers C-C bonds that are constrained in a cyclic structure can not freely rotate Although the two molecules below have the same connectivity, they are NOT identical. The naming system we have learned thus far would give them the same name, but they are NOT identical, so we need to learn additional nomenclature rules…to be continued Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-5

6 5.1 Isomers To maintain orbital overlap in the pi bond, C=C double bonds can not freely rotate. Although the two molecules below have the same connectivity, they are NOT identical Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-6

7 Identify the following pairs as either constitutional isomers, stereoisomers, or identical. EXPLAIN Isomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-7

8 5.1 Isomers With rings and with C=C double bonds, cis-trans notation is used to distinguish between stereoisomers Cis – identical groups are positioned on the SAME side of a ring Trans – identical groups are positioned on OPPOSITE sides of a ring Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-8

9 Cis – identical groups are positioned on the SAME side of a C=C double bond Trans – identical groups are positioned on OPPOSITE sides of a C=C double bond Practice with SkillBuilder 5.1 trans because of the H's 5.1 Isomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-9

10 Identify the following as either cis, trans, or neither. EXPLAIN Isomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-10

11 5.2 Stereoisomers Beyond cis-trans isomers, there are many other important stereoisomers To identify such stereoisomers, we must be able to identify chiral molecules A chiral object is NOT identical to its mirror image You are a chiral object. Look in a mirror and raise your right hand. Your mirror image raises his or her left hand. You can test whether two objects are identical by seeing if they are superimposable. Can you be superimposed upon your mirror image? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-11

12 5.2 Stereoisomers Some other chiral objects include gloves. HOW? Think of some other examples of chiral everyday objects Chirality is important in molecules. – Because two chiral molecules are mirror images, they will have many identical properties, but because they are not identical, their pharmacology may be very different Visualizing mirror images of molecules and manipulating them in 3D space to see if they are superimposable can be VERY challenging It is highly recommended that you use handheld models as visual aids until you get more experience Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-12

13 5.2 Stereoisomers Chirality most often results when a carbon atom is bonded to 4 unique groups of atoms. Make a handheld model to prove to yourself that they are NOT superimposable Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-13

14 5.2 Stereoisomers When an atom such as carbon forms a tetrahedral center with 4 different groups attached to it, it is called a chirality center (aka stereocenter or stereogenic center) Analyze the attachments for each chirality center below Practice with SkillBuilder 5.2 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-14

15 5.2 Stereoisomers Identify all of the chirality centers (if any) in the following molecules Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-15

16 5.2 Enantiomers Some stereoisomers can also be classified as enantiomers Enantiomers are TWO molecules that are MIRROR IMAGES but are NONidentical and NONsuperimposable For the pair below, draw in the missing enantiomer Make handheld models for both structures to verify that they are NONidentical mirror images Practice with SkillBuilder 5.3 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-16

17 What is the relationship between the two molecules below? Given that the molecules are so similar, how is it possible that our noses can distinguish between them? 5.2 Enantiomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-17

18 5.3 Designating Configurations Enantiomers are NOT identical, so they must not have identical names How would you name these molecules? Their names must be different, so we use the Cahn- Ingold-Prelog system to designate each molecule as either R or S. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-18

19 5.3 Designating Configurations The Cahn, Ingold and Prelog system 1.Using atomic numbers, prioritize the 4 groups attached to the chirality center 2.Arrange the molecule in space so the lowest priority group faces away from you 3.Count the group priorities 1…2…3 to determine whether the order progresses in a clockwise or counterclockwise direction 4.Clockwise = R and Counterclockwise = S A handheld model can be very helpful visual aid for this process Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-19

20 The Cahn, Ingold and Prelog system 1.Using atomic numbers, prioritize the 4 groups attached to the chirality center. The higher the atomic number, the higher the priority – Prioritize the groups on this molecule 5.3 Designating Configurations Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-20

21 5.3 Designating Configurations The Cahn, Ingold and Prelog system 2.Arrange the molecule in space so the lowest priority group faces away from you – This is the step where it is most helpful to have a handheld model Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-21

22 5.3 Designating Configurations 1.Using atomic numbers, prioritize the 4 groups attached to the chirality center 2.Arrange the molecule in space so the lowest priority group faces away from you Complete steps 1 and 2 for the following molecule Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-22

23 5.3 Designating Configurations The Cahn, Ingold and Prelog system 3.Counting the other group priorities, 1…2…3, determine whether the order progresses in a clockwise or counterclockwise direction 4.Clockwise = R and Counterclockwise = S Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-23

24 5.3 Designating Configurations Designate each chirality center below as either R or S. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-24

25 5.3 Designating Configurations When the groups attached to a chirality center are similar, it can be tricky to prioritize them Analyze the atomic numbers one layer of atoms at a time First layer Second layer 1 4 Tie 2 3 Is this molecule R or S? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-25

26 Analyze the atomic numbers one layer of atoms at a time First layer Second layer 5.3 Designating Configurations 1 4 Tie 2 3 The priority is based on the first point of difference, NOT the sum of the atomic numbers Is this molecule R or S? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-26

27 5.3 Designating Configurations When prioritizing for the Cahn, Ingold and Prelog system, double bonds count as two single bonds Determine R or S for the following molecule Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-27

28 5.3 Designating Configurations Handheld molecular models can be very helpful when arranging the molecule in space so the lowest priority group faces away from you Here are some other tricks that can use – Switching two groups on a chirality center will produce its opposite configuration Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-28

29 5.3 Designating Configurations Switching two groups on a chirality center will produce its opposite configuration You can use this trick to adjust a molecule so that the lowest priority group faces away from you With the 4 th priority group facing away, you can designate the configuration as R Work backwards to show how the original structure’s configuration is also R Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-29

30 5.3 Designating Configurations Practice with SkillBuilder 5.4 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-30

31 5.3 Designating Configurations The R or S configuration is used in the IUPAC name for a molecule to distinguish it from its enantiomer Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-31

32 5.4 Optical Activity Because the structures of enantiomers are so similar, many of their properties are identical. If you have a sample of a chiral compound, imagine how can its enantiomeric purity be assessed? In other words, how can one enantiomer be distinguished from another? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-32

33 5.4 Optical Activity Enantiomers have opposite configurations (R vs. S), so they will rotate plane-polarized light in opposite directions What is plane-polarized light? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-33

34 5.4 Optical Activity To get light waves that travel in only one plane, light travels through a filter When plane polarized light is directed through a sample of a pure chiral compound, the plane that the light travels on will rotate. Compounds that can rotate the plane or plane- polarized light are called optically active Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-34

35 5.4 Optical Activity Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-35

36 5.4 Optical Activity Enantiomers will rotate the plane of the light to equal degrees but in opposite directions The degree to which light is rotated depends on the sample concentration and the pathlength of the light Standard optical rotation measurements are taken with 1 gram of compound dissolved in 1 mL of solution, and with a pathlength of 1 dm for the light Temperature and the wavelength of light can also affect rotation and must be reported with measurements that are taken Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-36

37 5.4 Optical Activity Consider the enantiomers of 2-bromobutane R and S refer to the configuration of the chirality center (+) and (-) signs refer to the direction that the plane of light is rotated The optical activity was measured at 589 nm, which is the Sodium D line wavelength Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-37

38 5.4 Optical Activity There is no relationship between the R/S configuration and the direction of light rotation (+/-) Should the chirality center below be designated R or S? As long as its bonds are not rearranged, its configuration CANNOT change It is levorotatory (-) at 20°C, while at 100°C, it is dextrorotatory (+) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-38

39 5.4 Optical Activity The magnitude and direction of optical rotation can not be predicted from a chiral molecule’s structure or configuration. It can ONLY be determined experimentally Predict the optical rotation for a racemic mixture (a sample with equal amounts of two enantiomers) Can you predict the optical rotation for a sample of 2- methylbutane Practice with SkillBuilder 5.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-39

40 5.4 Optical Activity For unequal amounts of enantiomers, the enantiomeric excess (% ee) can be determined from the optical rotation For a mixture of 70% (R) and 30% (S), what is the % ee? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-40

41 5.4 Optical Activity If the mixture has an optical rotation of +4.6, use the formula to calculate the % ee and the ratio of R/S Practice with SkillBuilder 5.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-41

42 5.5 Stereoisomeric Relationships Categories of isomers Are cis/trans isomers enantiomers or diastereomers? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-42

43 5.5 Stereoisomeric Relationships Draw each of the four possible stereoisomers for the following compound. It might be helpful to also make a handheld model for each isomer Pair up the isomers in every possible combination and label the pairs as either enantiomers or diastereomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-43

44 Consider a cyclohexane with three substituents What patterns do you notice? 5.5 Stereoisomeric Relationships Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-44

45 5.5 Stereoisomeric Relationships The number of possible stereoisomers for a compound depends on the number of chirality centers (n) in the compound What is the maximum number of possible cholesterol isomers? Practice with SkillBuilder 5.7 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-45

46 5.6 Symmetry and Chirality Any compound with only ONE chirality center will be chiral and have an optical rotation However, compounds with an even number (2,4,6, etc.) of chirality centers may or may not be chiral Identify each chirality center for both molecules below Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-46

47 5.6 Symmetry and Chirality Both molecules have 2 chirality centers, but only one is a chiral molecule, and the other is achiral If a molecule has a plane of symmetry, it will be achiral Half of the molecule reflects the other half Its optical activity will be canceled out within the molecule, similar to how a pair or mirror image enantiomers cancel out each others optical rotation Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-47

48 5.6 Symmetry and Chirality Draw the mirror image of the cis isomer and show that it can be superimposed on its mirror image By definition, when a compound is identical to its mirror image, it is NOT chiral. It is achiral Molecules with an even number of chirality centers that have a plane of symmetry are called meso compounds Another way to test if a compound is a meso compound is to see if it is identical to its mirror image Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-48

49 5.6 Symmetry and Chirality In another example, the plane of symmetry identifies it as a meso compound meso compounds also have less than the predicted number of stereoisomers based on the 2 (n) formula Draw all four expected isomers and show how two of them are identical. A handheld model might be helpful Practice with SkillBuilder 5.8 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-49

50 5.6 Symmetry and Chirality Determine the relationship between the two compounds below Analyze both molecules to see if either of them are meso compounds Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-50

51 5.6 Symmetry and Chirality Draw the mirror image of the molecule above and show that it can be superimposed on its mirror image Having handheld models to work with can simplify this challenging task Practice with conceptual checkpoint 5.23 Some compounds do NOT have a plane of symmetry and yet are still achiral The molecule to the right has chirality centers, yet because it is identical to its mirror image, it is not chiral Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-51

52 5.7 Fischer Projections Fischer projections can also be used to represent molecules with chirality centers Horizontal lines represent attachments coming out of the page Vertical lines represent attachments going back into the page Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-52

53 5.7 Fischer Projections Fischer projections can be used to quickly draw molecules with multiple chirality centers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-53

54 5.7 Fischer Projections Fischer projections can also be used to quickly assess stereoisomeric relationships Practice with SkillBuilder 5.9 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-54

55 5.8 Interconverting Enantiomers Molecules can rotate around single bonds. Recall the gauche rotational conformation of butane Is the gauche conformation of butane chiral? Draw its mirror image. Is it superimposable on its mirror image? Why is butane’s optical rotation equal to zero? To be chiral, a compound cannot be a rotational conformer of its mirror image Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-55

56 5.8 Interconverting Enantiomers Compare the (cis)-1,2-dimethylcyclohexane chair with the Haworth projection The Haworth image can be used to quickly identify the compound as an achiral meso compound. However, a plane of symmetry can NOT be found in the chair conformation Which conformation better represents the molecule’s actual structure? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-56

57 5.8 Interconverting Enantiomers Should the (cis)-1,2-dimethylcyclohexane chair conformation be chiral or achiral? – It is not superimposable on its chair mirror image – Is has two chirality centers and no plane of symmetry Recall that chairs can flip their conformation by rotating single bonds and interconvert readily at room temperature If the chair could interconvert with its mirror image, would it be chiral? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-57

58 5.8 Interconverting Enantiomers The freely interconverting mirror images cancel out their optical rotation, so it is achiral This analysis is much easier to do with a handheld models than in your mind If the Haworth image has a mirror plane, then the chair will be able to interconvert with its enantiomer, and it will be achiral. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-58

59 5.9 Resolution of Enantiomers Most methods of separating compounds from one another take advantages of the compounds’ different physical properties – Distillation – separates compounds with different boiling points – Recrystallization – separates compounds with different solubilities – Can you think of more methods of separation or purification? Such methods often don’t work to separate one enantiomer from its partner. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-59

60 5.9 Resolution of Enantiomers In 1847, Pasteur performed the first resolution of enantiomers from a racemic mixture of tartaric acid salts The different enantiomers formed different shaped crystals that were separated by hand using tweezers This method doesn’t work for most pairs of enantiomers. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-60

61 5.9 Resolution of Enantiomers Another method is to use a chiral resolving agent The differing physical properties of diastereomers allow them to be more easily separated Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-61

62 5.9 Resolution of Enantiomers Affinity chromatography is often used to separate compounds For example, a glass column or tube can be packed with particles of a polar solid substance If a mixture of two compounds with different polarities are passed through the column, what will happen? A pair of enantiomers will not have different polarities, so how might such chromatography be modified to resolve the enantiomers in a racemic mixture? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-62

63 Draw a pair of constitutional isomers. EXPLAIN Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-63

64 Draw a pair of cis-trans isomers. EXPLAIN Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-64

65 Draw a pair of diastereomers that are not cis-trans isomers. EXPLAIN Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-65

66 Draw a pair of enantiomers. Explain Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-66

67 Draw a molecule with 3 chiral centers. Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-67

68 For the molecule below, label each chiral center. Additional Practice Problems Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-68

69 Additional Practice Problems Designate each chirality center below as either R or S. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-69

70 Additional Practice Problems If pure R enantiomer has a specific rotation of +33 degrees, what will the rotation be when you have a mixture with a R/S ratio = 44/56? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-70

71 Additional Practice Problems Determine the relationship between the pairs below. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e 5-71


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