1. Chapter 22: Carbonyl Alpha-Substitution Reactions
Why this Chapter?
Many schemes make use of carbonyl
a-substitution reactions.
These reaction are one the few general methods for making C-C bonds.

2. The  Position
The carbon next to the carbonyl group is designated as being in the  position
Electrophilic substitution occurs at this position through either an enol or enolate ion

3. 22.1 Keto–Enol Tautomerism
A carbonyl compound with a hydrogen atom on its alpha carbon rapidly equilibrates with its corresponding enol
Compounds that differ only by the position of a moveable proton are called tautomers
Tautomers are structural isomers: They are not resonance forms! (Resonance forms are representations of contributors to a single structure)
Tautomers interconvert rapidly while ordinary isomers do not

4. Enols
The enol tautomer is usually present to a very small extent and cannot be isolated
Since the enol is formed rapidly, it can serve as a reaction intermediate

5. Acid Catalysis of Enolization
Brønsted acids catalyze keto- enol tautomerization by protonating the carbonyl and activating the  protons

6. Base Catalysis of Enolization
The hydrogens on the  carbon are weakly acidic and transfer to water is slow
Transfer of the a hydrogen to a base though is rapid

7. Base Catalysis of Enolization
Brønsted bases catalyze keto-enol tautomerization

8. Learning Check:
Name the following and draw structures for their enol tautomers : A. B. C. D. E.

9. Solution:
Name the following and draw structures for their enol tautomers : A.
Cyclopentanone
Ethyl acetate B. C.
Methyl thioacetate
Acetic Acid D.
Phenylacetone E.

10. Learning Check:
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

11. Solution:
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

12. 22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions
Enols behave as nucleophiles and react with electrophiles because the enol double bonds are electron-rich

13. General Mechanism of Addition to Enols
When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

14. 22.3 Alpha Halogenation of Aldehydes and Ketones
Aldehydes and ketones can be halogenated at their  positions by reaction with Cl2, Br2, or I2 in acidic solution

15. Mechanism of Acid-Catalyzed Bromination
The enol tautomer reacts with an electrophile
The keto tautomer loses a proton

16. Evidence for Rate-Limiting Enol Formation
The rate of halogenation is independent of the halogen's identity and concentration
In D3O+ the  H’s are replaced by D’s at the same rate as halogenation (if addition of D were involved in the rate determining step then the rate would have slowed with D20)
This because the barrier to formation of the enol goes through the highest energy transition state in the mechanism
(Formation of the enol is the rate determining step)

17. Elimination Reactions of -Bromoketones
-Bromo ketones can be dehydrobrominated by base treatment to yield ,b-unsaturated ketones

18. Learning Check: Know how to….
Write the complete mechanism of the deuteration of acetone on treatment with D3O+

19. Learning Check:
Show how you might prepare 1-penten-3-one from 3-pentanone.

20. Solution:
Show how you might prepare 1-penten-3-one from 3-pentanone.

21. 22.4 Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii Reaction
Carboxylic acids do not react with Br2 (unlike aldehydes and ketones)
So Carboxylic acids must be converted to acid halides first and then the acid halide hydrolyzed back to the acid.
Bromination of carboxyilic acids by a mixture of Br2 and PBr3 is the Hell–Volhard–Zelinskii reaction

22. Mechanism of Bromination by Hell–Volhard–Zelinskii
PBr3 converts -COOH to –COBr, which can enolize and add Br2

23. Learning Check: Know how to….
If methanol rather than water is added at the end of a Hell- Volhard-Zelinskii reaction a methyl ester is produced. Show the reagents needed and propose a mechanism for each step.

24. 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
Carbonyl compounds can act as weak acids
The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

25. Reagents for Enolate Formation
Ketones are weaker acids than the OH of alcohols so a more powerful base than an alkoxide is needed to form the enolate
Sodium hydride (NaH) or Lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate

26. Lithium Diisopropylamide (LDA)
LDA is from butyllithium (BuLi) & diisopropylamine (pKa  40)
Soluble in organic solvents and effective at low temperature with many compounds
Not nucleophilic

27. -Dicarbonyls Are More Acidic
When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced
Negative charge of enolate delocalizes over both carbonyl groups

30. Learning Check:
Identify the most acidic hydrogens in each of the following:
Rank in order of decreasing acidity.

31. Solution: Identify the most acidic hydrogens in each of the following:
Rank in order of decreasing acidity. (#1 most acidic) 3 2 1

32. 22.6 Reactivity of Enolate Ions
The carbon atom of an enolate ion is electron- rich and highly reactive toward electrophiles (enols are not as reactive)
Reaction on oxygen yields an enol derivative (less common)
Reaction on carbon yields an a-substituted carbonyl compound (more common)
More common

33. Base promoted a-halogenation
Iodoform Reaction: Test for a methyl ketone
Iodoform = CHI3
= yellow solid

34. 22.7 Alkylation of Enolate Ions
Base-promoted reaction occurs through an enolate ion intermediate
SN2 reaction:,the leaving group X can be -Cl, -Br, -I, or tosylate
R should be 1o or methyl and preferably should be allylic (CH=CH-CH2-X ) or benzylic (Ph-CH2-X )
2o halides react poorly, and 3o halides don't react at all because of competing elimination

35. The Malonic Ester Synthesis
For preparing a carboxylic acid from an alkyl halide
while lengthening the carbon chain by two atoms

36. Formation of Enolate and Alkylation
Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol
The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an a-substituted malonic ester

37. Dialkylation
The product has an acidic -hydrogen, allowing the alkylation process to be repeated

38. Hydrolysis and Decarboxylation
The malonic ester derivative hydrolyzes in acid and loses CO2 (“decarboxylation”) to yield a substituted monoacid

39. Decarboxylation of -Ketoacids
Decarboxylation requires a carbonyl group two atoms away from the CO2H

40. Overall Conversion The malonic ester synthesis converts an
alkyl halide  carboxylic acid while
lengthening the carbon chain by 2 atoms

41. Preparing Cycloalkane Carboxylic Acids
1,4-dibromobutane reacts twice, giving a cyclic product
3-, 4-, 5-, and 6-membered rings can be prepared in this way

42. Learning Check:
Use a malonic ester synthesis to prepare the following:

43. Solution:
Use a malonic ester synthesis to prepare the following:

44. Learning Check:
Use a malonic ester synthesis to prepare the following:

45. Solution:
Use a malonic ester synthesis to prepare the following:

46. Acetoacetic Ester Synthesis
Overall: converts an alkyl halide into a methyl ketone

47. Acetoacetic Ester (Ethyl Acetoacetate)
 carbon flanked by two carbonyl groups readily becomes an enolate ion that can be alkylated by an alkyl halide
Process can be repeated to add a second alkyl halide

48. Generalization: -Keto Esters
The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in general
Cyclic b-keto esters give 2-substituted cyclohexanones

49. Learning Check:
Prepare 2-pentanone using an acetoacetic ester synthesis:
Hint:

50. Solution: Prepare 2-pentanone using an acetoacetic ester synthesis:
Hint:

51. Biological Alkylations

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

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

54. Learning Check: It will form an acetal. It will form a diol.
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

55. Solution: It will form an acetal. It will form a diol.
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

56. Identify the expected major product of the following reaction.
Learning Check:
Identify the expected major product of the following reaction. 3. 1. 2. 5. 4. 1 2 3 4 5

57. Identify the expected major product of the following reaction.
Solution:
Identify the expected major product of the following reaction. 3. 1. 2. 5. 4. 1 2 3 4 5

58. Learning Check: enolate carboxylate acid bromide enol α-bromoketone
Which of the following intermediates is encountered in the Hell-Volhard-Zelinskii reaction?
enolate
carboxylate
acid bromide enol
α-bromoketone
acid bromide enolate

59. Solution: enolate carboxylate acid bromide enol α-bromoketone
Which of the following intermediates is encountered in the Hell-Volhard-Zelinskii reaction?
enolate
carboxylate
acid bromide enol
α-bromoketone
acid bromide enolate

60. How many protons with a pKa < 22 exist in the following molecule?
Learning Check:
How many protons with a pKa < 22 exist in the following molecule? 1 2 3 4

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

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

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

64. Which of these carbonyl compounds is most acidic?
Learning Check:
Which of these carbonyl compounds is most acidic?

65. Which of these carbonyl compounds is most acidic?
Solution:
Which of these carbonyl compounds is most acidic?

66. Rank from least to most acidic.
Learning Check:
Rank 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

67. Rank from least to most acidic.
Solution:
Rank 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

68. The equilibrium will favor the products in the following reaction.
Learning Check:
The equilibrium will favor the products in the following reaction.
True
False

69. The equilibrium will favor the products in the following reaction.
Solution:
The equilibrium will favor the products in the following reaction.
True
False

70. Predict the major product(s) of the following reaction.
Learning Check:
Predict the major product(s) of the following reaction. 2. 1. 3. 5. 4. 1 2 3 4 5

71. Predict the major product(s) of the following reaction.
Solution:
Predict the major product(s) of the following reaction. 2. 1. 3. 5. 4. 1 2 3 4 5

72. Predict the product of the following reaction.
Learning Check:
Predict the product of the following reaction. 1. 2. 3. 4. 5. 1 2 3 4 5

73. Predict the product of the following reaction.
Solution:
Predict the product of the following reaction. 1. 2. 3. 4. 5. 1 2 3 4 5

74. Predict the product of the following sequence of reactions.
Learning Check:
Predict the product of the following sequence of reactions. 2. 3. 1. 4.
None of these 5. 1 2 3 4 5

75. Predict the product of the following sequence of reactions.
Solution:
Predict the product of the following sequence of reactions. 2. 3. 1. 4.
None of these 5. 1 2 3 4 5

76. Learning Check: True False
An acetoacetic ester synthesis can be used to make the following compound.
True
False

77. Solution:
An acetoacetic ester synthesis can be used to make the following compound.
True
False

78. Learning Check:
Which of the following cannot be prepared by the acetoacetic ester synthesis sequence? 1. 2. 3. 5. 4. 1 2 3 4 5

79. Solution:
Which of the following cannot be prepared by the acetoacetic ester synthesis sequence? 1. 2. 3. 5. 4. 1 2 3 4 5