1. Alpha Carbon Chemistry: Enols and Enolates
Chapter 22
Alpha Carbon Chemistry: Enols and Enolates
Suggested Problems –

2. Introduction Alpha Carbon Chemistry: Enols and Enolates
For carbonyl compounds, Greek letters are often used to describe the proximity of atoms to the carbonyl center
This chapter will primarily explore reactions that take place at the alpha carbon

3. Introduction Alpha Carbon Chemistry: Enols and Enolates
The reactions we will explore proceed though either an enol or an enolate intermediate

4. Introduction Alpha Carbon Chemistry: Enols and Enolates
Trace amounts of acid or base catalyst provide equilibriums in which both the enol and keto forms are present
How is equilibrium different from resonance?
At equilibrium, >99% of the molecules exist in the keto form.
These are tautomers. Resonance structures do not differ in the arrangement of their atoms.

5. Introduction Alpha Carbon Chemistry: Enols and Enolates
In rare cases such as the example below, the enol form is favored in equilibrium
Give two reasons to explain WHY the enol is favored
The solvent can affect the exact percentages
Intramolecular H bonding and conjugation.

6. Introduction Alpha Carbon Chemistry: Enols and Enolates
Phenol is an example where the enol is vastly favored over the keto at equilibrium. WHY?

7. Introduction Alpha Carbon Chemistry: Enols and Enolates
The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed

8. Introduction Alpha Carbon Chemistry: Enols and Enolates
The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed
The difference between acid and base catalysis is merely the order of events: protonation and deprotonation

9. Introduction Alpha Carbon Chemistry: Enols and Enolates
As the tautomerization is practically unavoidable, some fraction of the molecules will exist in the enol form
Analyzing the enol form, we see there is a minor (but significant) resonance contributor with a nucleophilic carbon atom
Practice with conceptual checkpoints 22.1 through 22.3

10. Introduction Alpha Carbon Chemistry: Enols and Enolates
In the presence of a strong base, an enolate forms
The enolate is much more nucleophilic than the enol. WHY?

11. Introduction Alpha Carbon Chemistry: Enols and Enolates
The enolate can undergo C-attack or O-attack
Enolates generally undergo C-attack. WHY?

12. Introduction Alpha Carbon Chemistry: Enols and Enolates
Alpha protons are the only protons on an aldehyde or ketone that can be removed to form an enolate
Removing the aldehyde proton or the beta or gamma proton will NOT yield a resonance stabilized intermediate
Practice with SkillBuilder 22.1

13. Introduction Alpha Carbon Chemistry: Enols and Enolates
Draw all possible enolates that could form from the following molecule

14. Introduction Alpha Carbon Chemistry: Enols and Enolates
Why would a chemist want to form an enolate?
To form an enolate, a base must be used to remove the alpha protons
The appropriate base depends on how acidic the alpha protons are
What method do we have to quantify how acidic something is?

15. Introduction Alpha Carbon Chemistry: Enols and Enolates
Let’s compare some pKa values for some alpha protons
A base from an acid with a pKa higher than will pull the alpha proton in these molecules.

16. Introduction Alpha Carbon Chemistry: Enols and Enolates
When pKa values are similar, both products and reactants are present in significant amounts
Which side will this equilibrium favor?

17. Introduction Alpha Carbon Chemistry: Enols and Enolates
In this case, it is a disadvantage to have both enolate and aldehyde in solution at the same time as they can react with one another
Show how the electrons might move in the reaction between the enolate and the aldehyde

18. Introduction Alpha Carbon Chemistry: Enols and Enolates
If you want the carbonyl to generate the enolate irreversibly, a stronger base such as H- is necessary
By converting the aldehyde completely to the enolate, it is less likely to react with itself. It can then be employed in a reaction with another nucleophile.

19. Introduction Alpha Carbon Chemistry: Enols and Enolates
LDA is an even stronger base that is frequently used to promote irreversible enolate formation
Why is the reaction effectively irreversible?
LDA features two bulky isopropyl groups. Why would such a bulky base be desirable?

20. Introduction Alpha Carbon Chemistry: Enols and Enolates
When a proton is alpha to two different carbonyl groups, its acidity is increased
Draw the resonance contributors that allow 2,4-pentanedione to be so acidic

21. Introduction Alpha Carbon Chemistry: Enols and Enolates
When a proton is alpha to two different carbonyl groups, its acidity is increased
Draw the resonance contributors that allow 2,4-pentanedione to be so acidic

22. Introduction Alpha Carbon Chemistry: Enols and Enolates
2,4-pentanedione is acidic enough that hydroxide or alkoxides can deprotonate it irreversibly
Figure 22.2 summarizes the relevant factors you should consider when choosing a base
Practice with conceptual checkpoints 22.6
through 22.8

23. Introduction Alpha Carbon Chemistry: Enols and Enolates
Practice with conceptual checkpoints 22.6
through 22.8

24. Alpha Halogenation of Enols and Enolates
H3O+ catalyzes the ketoenol tautomerism. HOW?
The enol tautomer can attack a halogen molecule
The process is autocatalytic –the regenerated acid can catalyze another tautomerization and
halogenation

25. Alpha Halogenation of Enols and Enolates
When an unsymmetrical ketone is used, bromination occurs primarily at the more substituted carbon
The major product results from the more stable (more substituted) enol
A mixture of products is generally unavoidable

26. Alpha Halogenation of Enols and Enolates
This provides a two step synthesis for the synthesis of an α,β-unsaturated ketone
Give a mechanism that shows the role of pyridine
Other bases such as potassium tert-butoxide can also be used in the second step
Practice with conceptual checkpoints 22.9 and 22.10

27. Alpha Halogenation of Enols and Enolates
Give a mechanism that shows the role of pyridine

28. Alpha Halogenation of Enols and Enolates
The Hell-Volhard Zelinski reaction brominates the alpha carbon of a carboxylic acid
PBr3 forms the acyl bromide, which more readily forms the enol and attacks the bromine
Hydrolysis of the acyl bromide is the last step
Draw a complete mechanism
Practice checkpoints and 22.12

29. Alpha Halogenation of Enols and Enolates
Carboxylic acids, esters, and amides do not readily convert to their corresponding enols. However, if the acid is converted to an acid bromide first, the enol can form.

30. Alpha Halogenation of Enols and Enolates
Alpha halogenation can also be achieved under basic conditions
The formation of the enolate is not favored, but the equilibrium is pushed forward by the second step
Will the presence of the α bromine make the remaining α proton more or less acidic?

31. Alpha Halogenation of Enols and Enolates
Monosubstitution is not possible. WHY?
Methyl ketones can be converted to carboxylic acids using excess halogen and hydroxide
Once all three α protons are substituted, the CBr3 group becomes a decent leaving group
The monosubstituted product is more acidic and undergoes enol formation again.

32. Alpha Halogenation of Enols and Enolates
Once all three α protons are substituted, the CBr3 group becomes a decent leaving group
The last step is practically irreversible. WHY?

33. Alpha Halogenation of Enols and Enolates
The carboxylate produced on the last slide can be protonated with H3O+
The reaction works well with Cl2, Br2, and I2, and it is known as the haloform reaction
The iodoform reaction may be used to test for methyl ketones, because iodoform can be observed as a yellow solid when it forms
The haloform reaction is most efficient when the other side of the ketone has no a protons
Practice with conceptual checkpoints and 22.14

34. Alpha Halogenation of Enols and Enolates
Give the major product for the reaction below. Be careful of stereochemistry

35. Aldol Reactions
When an aldehyde is treated with hydroxide (or alkoxide), an equilibrium forms where significant amounts of both enolate and aldehyde are present
If the enolate attacks the aldehyde, an aldol reaction occurs
The product features both aldehyde and alcohol groups
Note the location of the –OH group on the beta C – A b-hydroxy aldehyde is obtained

36. Aldol Reactions
The aldol mechanism

37. Aldol Reactions
The aldol reaction is an equilibrium process that generally favors the products
How might the temperature affect the equilibrium?
Could a dehydration drive the equilibrium to form product?

38. Aldol Reactions
A similar reaction for a ketone generally does NOT favor the β-hydroxy ketone product
Give a reasonable mechanism for the retro-aldol reaction
Practice with SkillBuilder 22.2

39. Aldol Reactions
Give a reasonable mechanism for the retro-aldol reaction

40. Aldol Reactions
Predict the products for the follow reaction, and give a reasonable mechanism. Be careful of stereochemistry

41. Aldol Reactions
Predict the products for the follow reaction, and give a reasonable mechanism. Be careful of stereochemistry
Because of the basic conditions, each stereocenter at an alpha carbon will be racemized

42. Aldol Reactions
When an aldol product is heated under acidic or basic conditions, an α,β-unsaturated carbonyl forms
Such a process is called an aldol condensation, because water is given off
The elimination reaction above is an equilibrium, which generally favors the products
WHY? Consider enthalpy and entropy

43. Aldol Reactions
The elimination of water can be promoted under acidic or under basic conditions
Give a reasonable mechanism for each

44. Aldol Reactions Give a reasonable mechanism for each Base promoted
Acid promoted

45. Aldol Reactions When a water is eliminated, two products are possible
Which will likely be the major product? Use the mechanism to explain

46. Aldol Reactions
Because the aldol condensation is favored, often it is impossible to isolate the aldol product without elimination
Condensation is especially favored when extended conjugation results

47. Aldol Reactions
At low temperatures, condensation is less favored, but the aldol product is still often difficult to isolate in good yield
Practice with SkillBuilder 22.3

48. Aldol Reactions
Predict the major product of the following reaction. Be careful of stereochemistry
Because of the basic conditions, each stereocenter at an alpha carbon will be racemized

49. Aldol Reactions
Substrates can react in a crossed aldol or mixed aldol reaction. Predict the 4 possible products in the reaction below
Such a complicated mixture of products is not very synthetically practical.

50. Aldol Reactions
Practical crossed aldol reactions can be achieved through one of two methods
One of the substrates is relatively unhindered and without alpha protons

51. Aldol Reactions
One of the substrates is relatively unhindered and without alpha protons

52. Aldol Reactions
Practical crossed aldol reactions can be achieved through one of two methods
One substrate is added dropwise to LDA forming the enolate first. Subsequent addition of the second substrate produces the desired product
Practice with SkillBuilder 22.4

53. Aldol Reactions
Describe a synthesis necessary to yield the following compound

54. Aldol Reactions
Describe a synthesis necessary to yield the following compound

55. Aldol Reactions
Cyclic compounds can be formed through intramolecular aldol reactions
One group forms an enolate that attacks the other group
Recall that 5 and 6-membered rings are most likely to form. WHY?
Practice conceptual checkpoints through 22.27

56. Claisen Condensations
Esters also undergo reversible condensations reactions
Unlike a ketone or aldehyde, an ester has a leaving group

57. Claisen Condensations
Esters also undergo reversible condensations reactions
The resulting doubly-stabilized enolate must be treated with an acid in a last step. WHY?
A beta-keto ester is produced

58. Claisen Condensations
There are some limitations to the Claisen condensation
The starting ester must have 2 alpha protons, because removal of the second proton by the alkoxide ion is what drives the equilibrium forward
Hydroxide cannot be used as the base to promote Claisen condensations, because a hydrolysis reaction occurs between hydroxide and the ester
An alkoxide equivalent to the –OR group of the ester is a good base, because transesterification is avoided
Practice conceptual checkpoints and 22.29

59. Claisen Condensations
Crossed Claisen reactions can also be achieved using the same strategies employed in crossed aldol reactions
Practice with conceptual checkpoint 22.30
In the first example, there are no alpha protons on the one ester so an enolate will not be generated from it to interfere.
In the second example, LDA converts all of the aldehyde into the enolate before the second ester is added.

60. Claisen Condensations
Intramolecular Claisen condensations can also be achieved
This Diekmann cyclization proceeds through the expected 5-membered ring transition state. DRAW it
Practice with conceptual checkpoints and 22.32

61. Claisen Condensations
Give reagents necessary to synthesize the following molecules

62. Claisen Condensations
Give reagents necessary to synthesize the following molecules

63. Alkylation of the Alpha Proton
The alpha position can be alkylated when an enolate is treated with an alkyl halide
The enolate attacks the alkyl halide via an SN2 reaction

64. Alkylation of the Alpha Proton
When 2° or 3° alkyl halides are used, the enolate can act as a base in an E2 reaction.
The aldol reaction can compete with the desired alkylation, so a strong base such as LDA must be used
Regioselectivity is often an issue when forming enolates
If the compound below is treated with a strong base, two enolates can form – see next few slides

65. Alkylation of the Alpha Proton
What is meant by kinetic and thermodynamic enolate? See next few slides for details

66. Alkylation of the Alpha Proton
For clarity, the kinetic and thermodynamic pathways are exaggerated below
Explain the energy differences below using steric and stability arguments

67. Alkylation of the Alpha Proton
LDA is a strong base, and at low temperatures, it will react effectively in an irreversible manner
NaH is not quite as strong, and if heat is available, the system will be reversible
Practice with conceptual checkpoints and 22.24

68. Alkylation of the Alpha Proton
Give necessary reagents to synthesize the compound below starting with carbon fragments with 5 carbons or less

69. Alkylation of the Alpha Proton
The malonic ester synthesis allows a halide to be converted into a carboxylic acid with two additional carbons
Diethyl malonate is first treated with a base to form a doubly-stabilized enolate

70. Alkylation of the Alpha Proton
The enolate is treated with the alkyl halide
The resulting diester can be hydrolyzed with acid or base using heat

71. Alkylation of the Alpha Proton
One of the resulting carboxylic acid groups can be decarboxylated with heat through a pericyclic reaction
Why isn’t the second carboxylic acid group removed?

72. Alkylation of the Alpha Proton
Here is an example of the overall synthesis

73. Alkylation of the Alpha Proton
Double alkylation can also be achieved
The acetoacetic ester synthesis is a very similar process
Practice with SkillBuilder 22.5

74. Alkylation of the Alpha Proton
Give a complete mechanism for the process below
Practice with SkillBuilder 22.6

75. Alkylation of the Alpha Proton
Give a complete mechanism for the process below

76. Conjugate Addition Reactions
Recall that α,β-unsaturated carbonyls can be made easily through aldol condensations
α,β-unsaturated carbonyls have three resonance contributors
Which contributors are electrophilic?

77. Conjugate Addition Reactions
Grignard reagents generally attack the carbonyl position of α,β-unsaturated carbonyls yielding a 1,2 addition
In contrast, Gilman reagents generally attacks the beta position giving 1,4 addition or conjugate addition

78. Conjugate Addition Reactions
Conjugate addition of α,β-unsaturated carbonyls starts with attack at the beta position
WHY is the nucleophile generally favored to attack the beta position?

79. Conjugate Addition Reactions
More reactive nucleophiles (e.g., Grignard) are more likely to attack the carbonyl directly. WHY?
Enolates are generally less reactive than Grignards but more reactive than Gilman reagents, so enolates often give a mixture of 1,2- and 1,4- addition products
Doubly-stabilized enolates are stable enough to react primarily at the beta position

80. Conjugate Addition Reactions
When an enolate attacks a beta carbon, the process is called a Michael addition

81. Conjugate Addition Reactions
Give a mechanism showing the reaction between the two compounds shown below
Practice with conceptual checkpoints through 22.46

82. Conjugate Addition Reactions
Because singly-stabilized enolates do not give high yielding Michael additions, Gilbert Stork developed a synthesis using an enamine intermediate
Recall the enamine synthesis from chapter 20

83. Conjugate Addition Reactions
Enolates and enamines have reactivity in common
The enamine is less nucleophilic and more likely to act as a Michael donor

84. Conjugate Addition Reactions
Water hydrolyzes the imine and tautomerizes and protonates the enol

85. Conjugate Addition Reactions
Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis
Practice with SkillBuilder 22.7

86. Conjugate Addition Reactions
Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis

87. Conjugate Addition Reactions
The Robinson Annulation utilizes the a Michael addition followed by an aldol condensation
Practice checkpoints and 22.50

88. Synthetic Strategies
Most of the reactions in this chapter are C-C bond forming
Three of the reactions yield a product with two functional groups
The positions of the functional groups in the product can be used to design necessary reagents in the synthesis – see next few slides
Practice with SkillBuilder 22.8

89. Synthetic Strategies
Stork enamine synthesis  1,5-dicarbonyl compounds
Aldol and Claisen  1,3-difunctional compounds

90. Synthetic Strategies We have learned two methods of alkylation
The alpha position of an enolate attacks an alkyl halide
A Michael donor attacks the beta position of a Michael acceptor
These two reactions can also be combined
Give a reasonable mechanism
Practice with SkillBuilder 22.9

91. Synthetic Strategies
Give a reasonable mechanism

92. Synthetic Strategies
Give reagents necessary for the following synthesis

93. Synthetic Strategies
Give reagents necessary for the following synthesis

94. Additional Practice Problems
Explain why an enolate is more likely to produce products resulting from attack by the alpha carbon than direct attack by the oxygen. Is the argument kinetic or thermodynamic or both? Kinetically, an enolate might be expected to attack from the oxygen, because the oxygen can stabilize the partial negative charge that is present during the transition state. On the other hand, a double bond is also present during the transition state, and the C=O double bond is more stable than the C=C double bond. The more stable C=O during that transition state stabilizes attack from the alpha carbon position. However, it is thermodynamics that generally determines the products, because these reactions are often readily reversible, the C=O stability in one product favors its formation once equilibrium is reached.

95. Additional Practice Problems
Give the major products for the reaction below

96. Additional Practice Problems
Using both kinetic and thermodynamic arguments, explain why aldol reactions involving a ketone are less product favored than those involving aldehydes. Kinetic: When acting as an electrophile colliding with enolates, ketones are BOTH more sterically hindered, so they form higher energy transition states AND have less of a partial positive charge (due to hyperconjugation and induction), so they are lower in energy and have higher Eact. Also, the enolate that forms from a ketone has a C=C in its major resonance contributor that is more stabile bc it is more substituted with carbons making it lower in energy and giving it a higher Eact. Thermodynamic: Sterics is the main reason why the product of an aldol reaction with a ketone is less stable shifting the reaction to the reactants in the equilibrium.

97. Additional Practice Problems
Give reagents necessary to produce the product below using aldol chemistry.
NaOH is chosen because it promotes the thermodynamic enolate formation
Elimination cannot occur after the reaction, because there is no alpha proton to remove

98. Additional Practice Problems
Give reagents necessary for the synthesis below
In step 5, a mixture of products may form due to competition between the kinetic and thermodynamic enolates

99. Additional Practice Problems
Give reagents necessary for the synthesis below