1. Organic Chemistry Second Edition Chapter 5 David Klein Stereoisomerism
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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?
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

7. 5.1 Isomers
Identify the following pairs as either constitutional isomers, stereoisomers, or identical. EXPLAIN
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

9. 5.1 Isomers
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
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Klein, Organic Chemistry 2e

10. 5.1 Isomers
Identify the following as either cis, trans, or neither. EXPLAIN
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Klein, Organic Chemistry 2e

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

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

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
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

15. 5.2 Stereoisomers
Identify all of the chirality centers (if any) in the following molecules
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Klein, Organic Chemistry 2e

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

17. 5.2 Enantiomers
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?
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Klein, Organic Chemistry 2e

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

19. 5.3 Designating Configurations
The Cahn, Ingold and Prelog system
Using atomic numbers, prioritize the 4 groups attached to the chirality center
Arrange the molecule in space so the lowest priority group faces away from you
Count the group priorities 1…2…3 to determine whether the order progresses in a clockwise or counterclockwise direction
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

20. 5.3 Designating Configurations
The Cahn, Ingold and Prelog system
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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

21. 5.3 Designating Configurations
The Cahn, Ingold and Prelog system
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

22. 5.3 Designating Configurations
Using atomic numbers, prioritize the 4 groups attached to the chirality center
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

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

24. 5.3 Designating Configurations
Designate each chirality center below as either R or S.
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Klein, Organic Chemistry 2e

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
Is this molecule R or S? 2 3
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

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

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

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

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 4th 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

30. 5.3 Designating Configurations
Practice with SkillBuilder 5.4
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

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

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?
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

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

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

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

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

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
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Klein, Organic Chemistry 2e

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

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
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Klein, Organic Chemistry 2e

42. 5.5 Stereoisomeric Relationships
Categories of isomers
Are cis/trans isomers enantiomers or diastereomers?
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Klein, Organic Chemistry 2e

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

44. 5.5 Stereoisomeric Relationships
Consider a cyclohexane with three substituents
What patterns do you notice?
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Klein, Organic Chemistry 2e

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

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

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

48. 5.6 Symmetry and Chirality
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
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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

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

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

51. 5.6 Symmetry and Chirality
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
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
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Klein, Organic Chemistry 2e

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
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Klein, Organic Chemistry 2e

53. 5.7 Fischer Projections
Fischer projections can be used to quickly draw molecules with multiple chirality centers
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Klein, Organic Chemistry 2e

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

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

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

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

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

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

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

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

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?
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Klein, Organic Chemistry 2e

63. Additional Practice Problems
Draw a pair of constitutional isomers. EXPLAIN
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Klein, Organic Chemistry 2e

64. Additional Practice Problems
Draw a pair of cis-trans isomers. EXPLAIN
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Klein, Organic Chemistry 2e

65. Additional Practice Problems
Draw a pair of diastereomers that are not cis-trans isomers. EXPLAIN
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Klein, Organic Chemistry 2e

66. Additional Practice Problems
Draw a pair of enantiomers. Explain
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Klein, Organic Chemistry 2e

67. Additional Practice Problems
Draw a molecule with 3 chiral centers.
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Klein, Organic Chemistry 2e

68. Additional Practice Problems
For the molecule below, label each chiral center.
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Klein, Organic Chemistry 2e

69. Additional Practice Problems
Designate each chirality center below as either R or S.
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Klein, Organic Chemistry 2e

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

71. Additional Practice Problems
Determine the relationship between the pairs below.
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Klein, Organic Chemistry 2e