1. Chapter 17 Carbonyl Alpha-Substitution and Condensation Reactions

2. a-Substitution and Carbonyl Condensation Reactions
Alpha-substitution reactions occur at the carbon next to the carbonyl carbon – the a position
Involve substitution of a-hydrogen by electrophile
Proceed through enol or enolate ion intermediate
Carbonyl condensation reactions occur between two carbonyl partners
Combination of a-substitution and nucleophilic addition steps
Gives b-hydroxy carbonyl compound

3. 17.1 Keto-Enol Tautomerism
Carbonyl compounds with a-hydrogens rapidly equilibrate with corresponding enol (ene + alcohol)
Interconversion known as keto-enol tautomerism
Greek tauto, meaning “the same,” and meros, meaning “part”
Individual isomers called tautomers

4. Keto-Enol Tautomerism
Tautomers are constitutional isomers
Isomers are different compounds with different structures
Atoms arranged differently
Different from resonance structures that differ only in the position of their electrons
Most carbonyl compounds exist almost exclusively in the keto form at equilibrium

5. Keto-Enol Tautomerism
Mechanism of acid-catalyzed enol formation
Protonated intermediate
can lose H+, either from the
oxygen atom to regenerate
the keto tautomer or from
the a carbon atom to yield
an enol tautomer

6. Keto-Enol Tautomerism
Mechanism of base-catalyzed enol formation
The intermediate enolate
ion, a resonance hybrid
of two forms, can be
protonated either on
carbon to generate
the starting keto tautomer
or on oxygen to give an
enol tautomer

7. Keto-Enol Tautomerism
Only a-hydrogens are acidic
a-Hydrogens are acidic because the enolate ion that results from deprotonation is resonance stabilized with the electronegative oxygen of the carbonyl
b-, g-, d-Hydrogens (and so on) are not acidic because the ion that results from deprotonation is not resonance stabilized

8. 17.2 Reactivity of Enols: a-Substitution Reactions
Enols are nucleophiles that react with electrophiles
There is a substantial build-up of electron density on the a carbon of the enol

9. Reactivity of Enols: a-Substitution Reactions
Mechanism of carbonyl a-substitution reaction on an enol
Enol is formed with
acid catalysis
Electron pair from C=C
bond of enol attacks an
electrophile (E+), forming
new C-E bond and a
resonance stabilized
intermediate
Loss of H+ from oxygen
yields the neutral alpha-
substitution product and
restores the C=O bond

10. Reactivity of Enols: a-Substitution Reactions
Acid-catalyzed a-halogenation (Cl2, Br2, and I2) of aldehydes and ketones is a common laboratory reaction
a-Halogenation occurs in biological systems
a-Halogenation of ketones in marine alga

11. Reactivity of Enols: a-Substitution Reactions
Mechanism of acid-catalyzed bromination of acetone

12. Reactivity of Enols: a-Substitution Reactions
Isotopic labeling experiments support reaction mechanism of acid-catalyzed halogenation
For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation
Enol intermediate involved in both processes

13. Reactivity of Enols: a-Substitution Reactions
a-Bromoketones are dehydrobrominated by base to yield a,b-unsaturated ketones
E2 reaction mechanism
2-Methylcyclohexanone gives 2-methylcyclohex-2-enone on heating in pyridine

14. 17.3 Acidity of a Hydrogen Atoms: Enolate Ion Formation
Presence of neighboring carbonyl
group increases the acidity of the
ketone over the alkane by a factor
of 1040
Proton abstraction from carbonyl occurs when the a C-H bond is oriented parallel to the p orbitals of the carbonyl group
A carbon of the enolate ion has a p orbital that overlaps neighboring p orbitals of the carbonyl group
Negative charge shared with oxygen atom by resonance

15. Acidity of a Hydrogen Atoms: Enolate Ion Formation
Strong base required for enolate formation
If NaOCH2CH3 is used the extent of enolate formation is only about 0.1%
If sodium hydride, NaH, or lithium diisopropylamide (LDA), [LiN(i-C3H7)2], is used the carbonyl is completely converted to its enolate conjugate base
LDA is prepared by reaction of butyllithium with diisopropylamine

16. Acidity of a Hydrogen Atoms: Enolate Ion Formation
A C-H bond flanked by two carbonyl groups is even more acidic
Enolate ion is stabilized by delocalization of negative charge over both carbonyl groups
Pentane-2,4-dione has three resonance forms

17. Acidity of a Hydrogen Atoms: Enolate Ion Formation

18. Acidity of a Hydrogen Atoms: Enolate Ion Formation

19. Worked Example 17.1 Identifying Acidic Hydrogens in a Compound
Identify the most acidic hydrogens in each of the following compounds, and rank the compounds in order of increasing acidity:

20. Worked Example 17.1 Identifying Acidic Hydrogens in a Compound
Strategy
Hydrogens on carbon next to a carbonyl group are acidic.
In general, a b-dicarbonyl compound is most acidic, a ketone or aldehyde is next most acidic, and a carboxylic acid derivative is least acidic.
Remember that alcohols, phenols, and carboxylic acids are also acidic because of their –OH hydrogens

21. Worked Example 17.1 Identifying Acidic Hydrogens in a Compound
Solution
The acidity order is (a) > (c) > (b). Acidic hydrogens are shown in red:

22. 17.4 Alkylation of Enolate Ions
Enolate ions are resonance hybrides of two nonequivalent contributors
Enolate ions are vinylic alkoxides (C=C–O-)
Reaction on the oxygen yields an enol derivative
Enolate ions are a-keto carbanions (-C–C=O)
Reaction on the carbon yields an a-substituted carbonyl compound

23. Alkylation of Enolate Ions
Enolate ions undergo alkylation by treatment with an alkyl halide or tosylate
Nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction
Leaving group displaced by backside attack

24. Alkylation of Enolate Ions
Alkylations are subject to all constraints that affect all SN2 reactions
Alkyl group R should be primary or methyl and preferably allylic or benzylic
Secondary alkyl halides react poorly and tertiary are unreactive due to competing E2 reaction

25. Alkylation of Enolate Ions
The Malonic Ester Synthesis
Preparation of carboxylic acids from alkyl halides while lengthening the carbon chain by two atoms

26. Alkylation of Enolate Ions
Diethyl propanedioate, commonly known as diethyl malonate, or malonic ester is more acidic than monocarbonyl compounds (pKa = 13) because its a hydrogens are flanked by two carbonyl groups
Easily converted to enolate ion by sodium ethoxide in ethanol
“Et” is used as an abbreviation for –CH2CH3

27. Alkylation of Enolate Ions
Malonic ester contains two a hydrogens
Product of a-alkylation can itself undergo alkylation

28. Alkylation of Enolate Ions
Alkylated of dialkylated malonic ester undergoes hydrolysis to yield the diacid followed by decarboxylation (loss of CO2) to yield the monoacid

29. Alkylation of Enolate Ions
Decarboxylation is unique to carboxylic acids with a second carbonyl group located at the b position
Decarboxylation occurs via a cyclic mechanism
Involves initial formation of an enol

30. Alkylation of Enolate Ions
Overall result of malonic ester synthesis is the conversion of an alkyl halide into a carboxylic acid while lengthening the carbon chain by two carbons

31. Alkylation of Enolate Ions
Malonic ester synthesis can be used to prepare cycloalkane-carboxylic acids
Three-, four-, five-, and six-membered rings can all be prepared in this way

32. Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a
Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid
How would you prepare heptanoic acid using a malonic ester systhesis?

33. Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a
Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid
Strategy
The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons.
Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane

34. Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a
Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid
Solution

35. Alkylation of Enolate Ions
The Acetoacetic Ester Synthesis
The acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons

36. Alkylation of Enolate Ions
Ethyl-3-oxobutanoate, commonly called ethyl acetoacetate or acetoacetic ester, contains a hydrogens flanked by two carbonyl groups
Enolate ion is readily formed and alkylated under SN2 reaction conditions
A second alkylation product can be derived from monoalkylated product

37. Alkylation of Enolate Ions
Alkylated or dialkylated acetoacetic ester is hydrolyzed in aqueous acid to a b-keto acid
b-Keto acid undergoes decarboxylation to yield ketone product

38. Alkylation of Enolate Ions
Ketone product formed in three-step sequence:
Enolate formation
Alkylation
Hydrolysis/decarboxylation
Sequence applicable to all b-keto esters with acidic a hydrogens

39. Alkylation of Enolate Ions
Cyclic b-keto esters such as ethyl 2-oxocyclohexanecarboxylate can be alkylated and decarboxylated to give 2-substituted cyclohexanones

40. Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone
How would you prepare pentan-2-one by an acetoacetic ester synthesis?

41. Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone
Strategy
The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide:
Thus, the acetoacetic ester synthesis of pentan-2-one must involve reaction of bromoethane

42. Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone
Solution

43. Alkylation of Enolate Ions
Direct Alkylation of Ketones, Esters, and Nitriles
A strong, sterically hindered base such as LDA converts a ketone, ester, or nitrile to its enolate ion
Use of a sterically hindered base avoids nucleophilic addition
A nonprotic solvent such as THF is required
Aldehydes rarely give high yields of alkylation products because their enolate ions undergo carbonyl condensation reactions

44. Alkylation of Enolate Ions
Example alkylations

45. Alkylation of Enolate Ions
Example alkylations

46. Alkylation of Enolate Ions
Example alkylations

47. Worked Example 17. 4 Using an Alkylation Reaction to Prepare a
Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester
How might you use an alkylation reaction to prepare ethyl 1-methylcyclohexanecarboxylate?

48. Worked Example 17. 4 Using an Alkylation Reaction to Prepare a
Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester
Strategy
An alkylation reaction is used to introduce a methyl or primary alkyl group onto the a position of a ketone, ester, or nitrile by SN2 reaction of an enolate ion with an alkyl halide.
Look at the target molecule and identify any methyl or primary alkyl groups attached to an a carbon.
The target has an a methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane

49. Worked Example 17. 4 Using an Alkylation Reaction to Prepare a
Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester
Solution

50. Alkylation of Enolate Ions
Biological Alkylations
Alkylations are not common in biological systems
a-Methylation occurs in the biosynthesis of the antibiotic indolmycin from indolylpyruvate

51. 17.5 Carbonyl Condensations: The Aldol Reaction
Carbonyl condensation reactions occur between an electrophilic carbonyl group of one partner and the nucleophilic enolate ion of the other partner
Combination of a-substitution and nucleophilic addition steps

52. Carbonyl Condensations: The Aldol Reaction
Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction
Treatment of acetaldehyde with sodium ethoxide yields 3-hydroxybutanal (an aldol)

53. Carbonyl Condensations: The Aldol Reaction
Position of the aldol equilibrium depends both on reaction condition and substrate structure
Equilibrium favors condensation product in the case of aldehydes with no a substituent (RCH2CHO)

54. Carbonyl Condensations: The Aldol Reaction
Equilibrium favors reactant for disubstituted aldehydes (R2CHCHO) and most ketones

55. Carbonyl Condensations: The Aldol Reaction
Aldol reactions occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule
Resultant tetrahedral intermediate is protonated to give an alcohol product
The reverse process occurs when base abstracts the –OH hydrogen from the aldol to yield a b-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound

56. Worked Example 17.5 Predicting the Product of an Aldol Reaction
What is the structure of the aldol product from propanal?

57. Worked Example 17.5 Predicting the Product of an Aldol Reaction
Strategy
An aldol reaction combines two molecules of reactant, forming a bond between the a carbon of one partner and the carbonyl carbon of the second partner

58. Worked Example 17.5 Predicting the Product of an Aldol Reaction
Solution

59. Carbonyl Condensations: The Aldol Reaction
Carbonyl Condensations versus a-Substitutions
Carbonyl condensation reactions and a substitutions take place under basic conditions and involve enolate-ion intermediates
Alpha-substitution reactions require a full equivalent of strong base and are carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at low temperature before addition of the electrophile

60. Carbonyl Condensations: The Aldol Reaction
Carbonyl condensation reactions require only a catalytic amount of a relatively weak base
Enolate ion is generated in the presence of unreacted carbonyl compound

61. 17.6 Dehydration of Aldol Products
b-Hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield a,b-unsaturated products, or conjugated enones
Aldol reactions were named condensation reactions due to the loss of water

62. Dehydration of Aldol Products
Aldol products dehydrate easily because of carbonyl group
Under basic conditions, an acidic a hydrogen is removed, yielding an enolate ion that expels the –OH leaving group in an E1cB reaction
Under acidic conditions an enol is formed, the –OH group is protonated, and water is expelled in an E1 or E2 reaction

63. Dehydration of Aldol Products
Reaction condition needed for aldol dehydration are often only slightly more vigorous than conditions for aldol formation
Conjugated enones are often obtained directly from aldol reactions without isolating the intermediate b-hydroxy carbonyl compounds
Conjugated enones are more stable than nonconjugated enones
Interaction between p electrons of C=C bond and the p electrons of the C=O bond

64. Dehydration of Aldol Products
Removal of water from reaction mixture drives the aldol equilibrium toward product

65. Worked Example 17.6 Predicting the Product of an Aldol Reaction
What is the structure of the enone obtained from aldol condensation of acetaldehyde?

66. Worked Example 17.6 Predicting the Product of an Aldol Reaction
Strategy
In the aldol reaction, H2O is eliminated and a double bond is formed by removing two hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner.

67. Worked Example 17.6 Predicting the Product of an Aldol Reaction
Solution

68. 17.7 Intramolecular Aldol Reactions
Some dicarbonyl compounds react when treated with base in an intramolecular aldol reaction
Leads to formation of cyclic product

69. Intramolecular Aldol Reactions
Intramolecular aldol reactions may lead to product mixtures
Most thermodynamically stable product formed selectively
All reaction steps are reversible
Most thermodynamically stable product predominates at equilibrium

70. 17.8 The Claisen Condensation Reaction
Reversible condensation reaction between two esters is called the Claisen condensation reaction
Esters have weakly acidic a hydrogens
When an ester with an a hydrogen is treated with 1 equivalent of a base a b-keto ester is formed

71. The Claisen Condensation Reaction
Claisen condensation mechanism proceeds through a tetrahedral intermediate
The tetrahedral intermediate expels an alkoxide leaving group to yield an acyl substitution product
If the product b-keto ester has another acidic a proton, 1 full equivalent of base is used for deprotonation
Deprotonation of b-keto ester drives reaction to the product side giving high yields of Claisen product

72. Worked Example 17. 7 Predicting the Product of a Claisen
Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction
What product would you obtain from Claisen condensation of ethyl propanoate?

73. Worked Example 17. 7 Predicting the Product of a Claisen
Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction
Strategy
The Claisen condensation of an ester results in loss of one molecule of alcohol and formation of a product in which an acyl group of one reactant bonds to the a carbon of the second reactant.

74. Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction
Solution

75. 17.9 Intramolecular Claisen Condensations
Intramolecular Claisen condensations are called Deickman cyclizations
Reaction works best for 1,6 and 1,7 diesters
1,6 Diester gives a five-membered cyclic b-keto ester
1,7 Diester gives a six-membered cyclic b-keto ester

76. Intramolecular Claisen Condensations
Mechanism of Dieckmann cyclization
Same as Claisen reaction mechanism

77. Intramolecular Claisen Condensations
The cyclic b-keto ester produced in an intramolecular Claisen cyclization can be further alkylated and decarboxylated
2-cyclohexanones and 2-cyclopentanones are prepared by the following sequence:
Intramolecular Claisen cyclization
b-Keto ester alkylation
Decarboxylation

78. 17.10 Conjugate Carbonyl Additions: The Michael Reaction
The conjugate addition of a nucleophilic enolate ion to an a,b-unsaturated carbonyl compound is known as the Michael reaction
Best reactions are derived from addition of a b-keto ester or other 1,3-dicarbonyl compound to an unhindered a,b-unsaturated ketone
Ethyl acetoacetate reacts with but-3-en-2-one in the presence of sodium ethoxide to yield the Michael addition product

79. Conjugate Carbonyl Additions: The Michael Reaction
Conjugate addition of a nucleophilic enolate ion to b carbon of an a,b-unsaturated carbonyl compound
Best Michael reactions between stable enolate ions and unhindered a,b-unsaturated ketones

80. Conjugate Carbonyl Additions: The Michael Reaction
Michael reaction occurs with a variety of a,b-unsaturated carbonyl compounds

81. Worked Example 17.8 Using the Michael Reaction
How might you obtain the following compound using a Michael reaction?

82. Worked Example 17.8 Using the Michael Reaction
Strategy
A Michael reaction involves the conjugate addition of a stable enolate ion donor to an a,b-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product
Usually the stable enolate ion is derived from a b-diketone, b-keto ester, malonic ester or similar compound
The C-C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the b carbon of the unsaturated acceptor

83. Worked Example 17.8 Using the Michael Reaction
Solution

84. 17.11 Carbonyl Condensations with Enamines: The Stork Reaction
Enamine nucleophiles add to a,b-unsaturated acceptors in Michael-like reactions
Reactions are particularly important in biological chemistry
Enamines are prepared by reaction between a ketone and a secondary amine

85. Carbonyl Condensations with Enamines: The Stork Reaction
Enamines are electronically similar to enolate ions
Overlap of the nitrogen lone-pair orbital with the double-bond p orbitals leads to an increase in electron density on the a carbon atom

86. Carbonyl Condensations with Enamines: The Stork Reaction
Enamine adds to an a,b-unsaturated carbonyl acceptor in a Michael-like reaction
Initial product is hydrolyzed by aqueous acid to yield a 1,5-dicarbonyl compound
Overall reaction is a three-step sequence:
Enamine formation from a ketone
Michael addition to an a,b-unsaturated carbonyl compound
Enamine hydrolysis back to ketone

87. Carbonyl Condensations with Enamines: The Stork Reaction
The net effect of the Stork reaction is a Michael addition of a ketone to an a,b-unsaturated carbonyl compound

88. Carbonyl Condensations with Enamines: The Stork Reaction
Two advantages to the enamine-Michael reaction that make the pathway useful in biological systems
Enamine is neutral and easily prepared and handled
Enolate is charged and difficult to prepare and handle
Enamine from a monoketone can be used in the Michael addition
Only enolate ions from b-dicarbonyl compounds can be used

89. Worked Example 17.9 Using the Stork Enamine Reaction
How might you use an enamine reaction to prepare the following compound?

90. Worked Example 17.9 Using the Stork Enamine Reaction
Strategy
The overall result of an enamine reaction is the Michael addition of a ketone as donor to an a,b-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product
The C-C bond made in the Michael addition step is the one between the a carbon of the ketone donor and the b carbon of the unsaturated acceptor

91. Worked Example 17.9 Using the Stork Enamine Reaction
Solution

92. 17.12 Some Biological Carbonyl Condensation Reactions
Biological Aldol Reactions
Aldol reactions are particularly important in carbohydrate metabolism
Enzymes called aldolases catalyze addition of a ketone enolate ion to an aldehyde
Type I aldolases occur primarily in animals and higher plants
Operate through an enolate ion
Type II aldolases occur primarily in fungi and bacteria

93. Some Biological Carbonyl Condensation Reactions
Mechanism of Type I aldolase in glucose biosynthesis
Dihydroxyacetone phosphate is first converted into an enamine by reaction with the –NH2 group on a lysine amino acid in the enzyme
Enamine adds to glyceraldehyde 3-phosphate
Resultant iminium ion is hydrolyzed

94. Some Biological Carbonyl Condensation Reactions
Mechanism of Type II aldolase in glucose biosynthesis
Aldol reaction occurs directly
Ketone carbonyl group of glyceraldegyde 3-phosphate complexed to a Zn2+ ion to make it a better acceptor

95. Some Biological Carbonyl Condensation Reactions
Biological Claisen Condensations
Claisen condensations occur in a large number of biological pathways
In fatty acid biosynthesis an enolate ion generated by decarboxylation of malonyl ACP adds to the carbonyl group of another acyl group bonded through a thioester linkage to a synthase enzyme
The tetrahedral intermediate expels the synthase, giving acetoacetyl ACP

96. Some Biological Carbonyl Condensation Reactions
Mixed Claisen consensations occur frequently in living organisms
Butyryl synthase, in the fatty-acid biosynthesis pathway, reacts with malonyl ACP in a mixed Claisen condensation to give 3-ketohexanoyl ACP