1. Objectives for Chapter 22
Readily convert the enol to the keto tautomers and vice versa under both acidic and basic conditions
Explain which tautomer is the favored one and understand the exceptions
Explain the typical roles adopted by the keto and enol forms in reactivity and apply this information to drawing mechanisms
Predict the products and draw the mechanisms for
Halogenation under acidic conditions
Halogenation under basic conditions
Haloform reaction (basic conditions)
Malonic ester synthesis (basic conditions)
Acetoacetic ester synthesis (basic conditions)
Predict the products, draw the mechanism and give the intermediates for
The Hell-Volhard-Zelinski reaction
Predict the acidity of α-hydrogens, use resonance structures to support your predictions, and relate this to the use of LDA
S. Keyser/A.Rosan Chem 350

2. What is the relationship between the keto and enol forms?
22.1
Keto-enol tautomerism
What is the relationship between the keto and enol forms?
Resonance forms
Constitutional isomers
Conformational isomers
I’m not sure
S. Keyser/A.Rosan Chem 350

3. 22.1 Keto-enol tautomerism
Keto-enol tautomers are constitutional isomers
S. Keyser/A.Rosan Chem 350

4. 22.1
Keto-enol tautomerism
Based on your previous experience, which tautomer is more stable? (Why?)
Enol
Keto
I’m not sure
S. Keyser/A.Rosan Chem 350

5. 22.1 Keto-enol tautomerism
Keto-enol tautomers are constitutional isomers
Typically the keto form is favored
Cyclohexanone is % keto v % enol
S. Keyser/A.Rosan Chem 350

6. 22.1 Keto-enol tautomerism: FYI
Q: Why might the enol be slightly more favorable?
K = 10-6
Energy
K = 3.2
K = 1013
Q: Why might the enol be so favorable?
S. Keyser/A.Rosan Chem 350

7. 22.1 Keto-enol tautomerism
Q: Mechanism under basic conditions?
Q: Acidic conditions? (Where should we protonate to get to the keto form??)
S. Keyser/A.Rosan Chem 350

8. 22.2 Reactivity of enols
A double-check: If water acts as an acid, what is the charge for its conjugate base?
Negative
Positive
I’m not sure
S. Keyser/A.Rosan Chem 350

9. 22.2 Reactivity of enols
Which hydrogens are the most acidic? (Where would a negative charge be best stabilized?)
Hs at alpha position
Hs at beta position
Hs at gamma position
I’m not sure
S. Keyser/A.Rosan Chem 350

10. The keto form is an okay ….
22.2 Reactivity of enols
The keto form is an okay ….
Nucleophile
Electrophile
I’m not sure
S. Keyser/A.Rosan Chem 350

11. The keto form becomes a great electrophile under …. conditions
22.2 Reactivity of enols
The keto form becomes a great electrophile under …. conditions
Acidic
Basic
I’m not sure
S. Keyser/A.Rosan Chem 350

12. 22.2 Reactivity of enols Keto form = electrophile React here Weak
Strong
S. Keyser/A.Rosan Chem 350

13. The enol form is a tolerable ….
22.2 Reactivity of enols
The enol form is a tolerable ….
Nucleophile
Electrophile
I’m not sure
S. Keyser/A.Rosan Chem 350

14. The enol becomes a great nucleophile under …. conditions
22.2 Reactivity of enols
The enol becomes a great nucleophile under …. conditions
Acidic
Basic
I’m not sure
S. Keyser/A.Rosan Chem 350

15. 22.2 Reactivity of enols Keto form = electrophile
Enol form = nucleophile
React here
Weak
Strong
React here? OR
React here?
Weak
Strong
Enol
Enolate
S. Keyser/A.Rosan Chem 350

16. 22.2 Reactivity of enols
Answer the following questions with your group members.
Example. Draw the resonance structure for the enolate.
Q: Suppose we add BrCH3 to our enolate. Which is the nucleophile and which is the electrophile?
Q: Where could our electrophile be added? (Two possibilities!)
Q: Which will be preferred? (Which addition is irreversible?)
S. Keyser/A.Rosan Chem 350

17. 22.2 Reactivity of enols ChemActivity 25
Answer CTQs #5-6 on p451 (CTQ#6).
S. Keyser/A.Rosan Chem 350

18. LDA is a Great nucleophile only Great base only
22.2 Reactivity of enols
LDA is a
Great nucleophile only
Great base only
Great as a nucleophile AND as a base
I’m not sure
CA25: CTQ#6
S. Keyser/A.Rosan Chem 350

19. Which of the following reagents will not quantitatively form an enolate anion upon reaction with 2-propanone (pKA = 19) ? 1. 2. 4. 3.
Choice One
Choice Two
Choice Three
Choice Four

20. Which of the following will occur when the following optically active compound is placed in dilute acid?
It will form an acetal.
It will form a diol.
It will become an alcohol.
It will lose its optical activity.
none of these

21. What is the predominant enol form of the following molecule?1. 2. 3. 4.
none of these is favored over the others 5. 1 2 3 4 5

22. S. Keyser/A.Rosan Chem 350

23. Do Chem Act 25 Model 3 and 4

24. Let’s complete CTQ 9 Perfect, no errors Only small error(s)
At least one major error
Not sure

25. Identify the expected major product of the following reaction.1. 2. 3. 4. 5. 1 2 3 4 5

26. Keto and Enol forms are in Equilibrium

27. Keto and Enol forms are in Equilibrium
Note that these changes do not happen stepwise, but molecule by molecule.

28. 10.

29. Which of the above carbonyl compounds is most acidic?

30. Rank the above from least to most acidic.
A < B < C < D
D < B < A < C
D < A < C < B
D < A < B < C
C < B < A < D

32. 22.3 α-halogenation of aldehydes and ketones
Q: Under basic conditions, which form predominates: enol or enolate?
Q: Categorize the three reactants as electrophiles or nucleophiles. Which will react with which?
Q: What should the first step of the mechanism below be?
BASIC CONDITIONS
Example. Draw the mechanism for the following transformation.
Note to self: Don’t erase this mechanism until the next group slide.
S. Keyser/A.Rosan Chem 350

33. 22.3 α-halogenation of aldehydes and ketones
Q: Under acidic conditions, which form predominates: enol or enolate?
ACIDIC CONDITIONS
Example. Draw the mechanism for the following transformation.
Note to self: Don’t erase this mechanism until the next group slide.
S. Keyser/A.Rosan Chem 350

34. Which statement is true?
22.3 α-halogenation of aldehydes and ketones
Which statement is true?
Multiple halogenations occur under acidic conditions only
Multiple halogenations occur under basic conditions only
Multiple halogenations occur under both acidic and basic conditions
I’m not sure
S. Keyser/A.Rosan Chem 350

35. Which alpha hydrogen will be more acidic?
22.3 α-halogenation of aldehydes and ketones
Which alpha hydrogen will be more acidic?
propanal’s
2-bromopropanal’s
I’m not sure
S. Keyser/A.Rosan Chem 350

36. 22.3 α-halogenation of aldehydes and ketones
Example. Halogenation occurs multiple times under basic conditions and only once under acidic conditions.
In your groups, explain why halogenation occurs multiple times under basic conditions.
Then explain why only one halogenation can occur under acidic conditions. (Which mechanistic step will be difficult to do?)
S. Keyser/A.Rosan Chem 350

37. Predict the product. I’m not sure
22.3 α-halogenation of aldehydes and ketones
Predict the product.
I’m not sure
S. Keyser/A.Rosan Chem 350

38. 22.6 Halogenation/reactivity of enolates
Now we’ll be investigating this reaction specifically in lab. Make sure to fill this in after you’ve completed it! For now, we’ll wait!
Example. Predict the product for this reaction.
S. Keyser/A.Rosan Chem 350

39. Let’s talk about halogenation of carboxylic acids… First, we must evaluate the ease of forming the enol/enolate from carboxylic acids…
Worldofstock.com
S. Keyser/A.Rosan Chem 350

40. 22.4 Alpha bromination of carboxylic acids
Which α protons are more acidic or easier to remove: those of carboxylic acids or ketones? (Reasoning?)
Carboxylic acids
Ketones
I don’t know
S. Keyser/A.Rosan Chem 350

41. 22.4 α-bromination of carboxylic acids
Carboxylic acids  α-brominated carboxylic acids
The enols of carboxylic acids are more difficult to access than those of aldehydes/ketones; specific reaction conditions are required =
Hell-Volhard-Zelinskii reaction (HVZ).
1) PBr3, Br2; 2) H2O
Q: What does PBr3 give as a product?
Example. Draw the mechanism for the reaction.
Know reagents and products.
Be able to figure out mechanism if given the intermediates!
HBr is floating around now
S. Keyser/A.Rosan Chem 350

42. Now for acidity trends for carboxylic acids, aldehydes and ketones, and other functional groups!
Worldofstock.com
S. Keyser/A.Rosan Chem 350

43. Which α protons are more acidic? (Why?)
22.5 Acidity of α-hydrogens
Which α protons are more acidic? (Why?)
Ketones
β-diketones
I don’t know
S. Keyser/A.Rosan Chem 350

44. Which α protons are more acidic? (Why?)
22.4 Alpha bromination of carboxylic acids
Which α protons are more acidic? (Why?)
Amides
Ketones
I don’t know
S. Keyser/A.Rosan Chem 350

45. Which is the stronger base?
22.2 Reactivity of enols REVIEW
Which is the stronger base?
Sodium hydroxide (NaOH)
LDA
I’m not sure
S. Keyser/A.Rosan Chem 350

46. Acidity Model 5 It’s not just about carboxylic acids anymore

47. 22.5 Acidity of α-hydrogens
Example. Rank the following compounds in order of acidity of the alpha
hydrogens. (1 = most acidic)
pKa:
Example. Provide an explanation for the order of acidity.
S. Keyser/A.Rosan Chem 350

48. 22.5 Acidity of α-hydrogens
Example. Rank the following compounds in order of acidity of the alpha
hydrogens. (1 = most acidic)
pKa:
Example. Provide an explanation for the order of acidity.
Q: Which enolates can be formed with NaOH?
Which can be formed with LDA? (CQ!)
Note to self: Don’t explain anything yet!
S. Keyser/A.Rosan Chem 350

49. 22.5 Acidity of α-hydrogens
Which α protons can be deprotonated under aqueous basic (NaOH) conditions?
Those of ketones
Those of β-diketones
I don’t know
LDA needed!
S. Keyser/A.Rosan Chem 350

50. Which alpha hydrogens are more acidic?
22.5 Acidity of α-hydrogens
Which alpha hydrogens are more acidic?
alpha H of ester
alpha H of amide
I’m not sure
S. Keyser/A.Rosan Chem 350

51. Which blue hydrogens are more acidic?
22.5 Acidity of α-hydrogens
Which blue hydrogens are more acidic?
alpha H of diketone
H of propanol
I’m not sure
S. Keyser/A.Rosan Chem 350

52. 22.5 Acidity of α-hydrogens
See ChemActivity 25
On page 454, answer CTQs #’s
S. Keyser/A.Rosan Chem 350

53. 22.7 Alkylation of enolate ions
MALONIC ESTER SYNTHESIS
Step 1. Alkylation Step 2. Hydrolysis
Step 3. Decarboxylation
S. Keyser/A.Rosan Chem 350

54. 22.7 Alkylation of enolate ions
MALONIC ESTER SYNTHESIS
Q: What is your reactant?
Q: What is the sequence of reagents?
Q: What is your product?
Q: Can you add on a second alkyl group at the α-position?
S. Keyser/A.Rosan Chem 350

55. 22.7 Alkylation of enolate ions
Q: Could you use the malonic ester synthesis to give the following products? If so, give the synthetic steps! (CQ)
S. Keyser/A.Rosan Chem 350

56. The Malonic Ester Synthesis Creates Substituted Acetic Acids
S. Keyser/A.Rosan Chem 350

57. Could you use the malonic ester synthesis to give the desired product?
22.7 Alkylation of enolate ions
Could you use the malonic ester synthesis to give the desired product?
Yes No
I’m not sure
S. Keyser/A.Rosan Chem 350

58. 22.7 Alkylation of enolate ions
Could you use the malonic ester synthesis to give the other desired product?
Yes No
I’m not sure
S. Keyser/A.Rosan Chem 350

59. Chem Act 25 CTQ 16

60. Chem Act 25 CTQ 17

61. Chem Act 25 CTQ 17

63. Problem 22.25

64. How many protons with a pKa < 22 exist in the following molecule?1 2 3 4

65. Which of the following explains why protons α to a carbonyl group show enhanced acidity?
An inductive effect from the adjacent carbonyl weakens the C-H bond.
The conjugate base is stabilized by resonance.
The charge that results after deprotonation is delocalized.
An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance.
all of these

66. Which of the following reagents will not form an enolate anion upon reaction with a ketone?1. 2. 3. 5. 4.
Choice One
Choice Two
Choice Three
Choice Four
Choice Five

67. 22.7 Alkylation of enolate ions
Example. Predict the product and draw the mechanism for the following reaction. Provide all relevant resonance structures, arrows, and charges.
S. Keyser/A.Rosan Chem 350

68. 22.6 Reactivity of enolate ions
Q: We determined that LDA was needed for the irreversible conversion of ketones to enolates.
However, we used NaOH with the halogenation of ketones.
Why do we expect to obtain significant amounts of product?
S. Keyser/A.Rosan Chem 350

69. S. Keyser/A.Rosan Chem 350

70. 22.7 Alkylation of enolate ions
ACETOACETIC ESTER SYNTHESIS
Q: How does your product change when you change your starting material but leave everything else the same?
Step 1. Alkylation Step 2. Hydrolysis
Step 3. Decarboxylation
S. Keyser/A.Rosan Chem 350

71. 22.7 Alkylation of enolate ions
ACETOACETIC ESTER SYNTHESIS PRODUCES SUBSTITUTED ACETONE
Q: How does your product change when you change your starting material but leave everything else the same?
Step 1. Alkylation Step 2. Hydrolysis
Step 3. Decarboxylation
S. Keyser/A.Rosan Chem 350

72. 22.7 Alkylation of enolate ions
Other direct alkylations
Other α-hydrogens are also acidic and can be removed with strong base
like LDA.
Example. Predict the products for the following reactions.
S. Keyser/A.Rosan Chem 350

73. Problem 22.37
S. Keyser/A.Rosan Chem 350