Organic Chemistry

1
Organic Chemistry

• William H. Brown Christopher S. Foote

2
Enolate Anions
Chapter 19

• Chapter 18

3
Enolate Anions

• Enolate anions are nucleophiles in SN2 reactions
  and carbonyl addition reactions

4
The Aldol Reaction

• The most important reaction of an enolate anion
  is nucleophilic addition to the carbonyl group of
  another molecule of the same or different
  compound
• Although these reactions may be catalyzed by
  either acid or base, base catalysis is more common

5
The Aldol Reaction

• The product of an aldol reaction is
• a ?-hydroxyaldehyde
• or a ?-hydroxyketone

6
The Aldol Reaction base

• A three-step mechanism
• Step 1 formation of a resonance-stabilized
  enolate anion
• Step 2 the enolate anion adds to the carbonyl
  group of another carbonyl-containing molecule to
  give a TCAI
• Step 3 proton transfer to O- completes the aldol
  reaction

7
The Aldol Reaction acid

• Step 1 acid-catalyzed equilibration of keto and
  enol forms
• Step 2 proton transfer from HA to the carbonyl
  group of a second molecule of aldehyde or ketone

8
The Aldol Reaction acid

• Step 3 attack of the enol of one molecule on the
  protonated carbonyl group of another molecule
• Step 4 proton transfer to A- completes the
  reaction

9
The Aldol Products -H2O

• Aldol products are very easily dehydrated to an
  ?,?-unsaturated aldehyde or ketone
• aldol reactions are reversible and often little
  aldol present at equilibrium
• Keq for dehydration is generally large
• if reaction conditions bring about dehydration,
  good yields of product can be obtained

10
Crossed Aldol Reactions

• In a crossed aldol reaction, one kind of molecule
  provides the enolate anion and another kind
  provides the carbonyl group

11
Crossed Aldol Reactions

• Crossed aldol reactions are most successful if
• one of the reactants has no ?-hydrogen and,
  therefore, cannot form an enolate anion and
• the other reactant has a more reactive carbonyl
  group, namely an aldehyde

12
Aldol Reactions

• Intramolecular aldol reactions are most
  successful for formation of five- and
  six-membered rings

13
Aldol Reactions

• in this example, a six-membered ring forms in
  preference to a four-membered ring

14
Aldol Reactions

• The ?-hydrogens of nitroalkanes are removed by
  strong bases such as KOH and NaOH

15
The Aldol Reaction

• Reduction of a nitro group gives a 1 amine

16
Directed Aldol Reactions

• Kinetic vs thermodynamic control
• when alkali metal hydroxides or alkoxides are
  used as bases, the position of equilibrium for
  formation of enolate anions favors reactants

17
Directed Aldol Reactions

• With stronger bases, however, the formation of
  enolate anion can be driven to the right
• One of the most widely used bases for this
  purpose is lithium diisopropylamide, LDA
• LDA is a very strong base but, because of
  crowding around nitrogen, is a poor nucleophile

18
Directed Aldol Reactions

• With 1 mole of LDA, an aldehyde, ketone, or ester
  is converted completely to its enolate anion

19
Lithium Enolate Anions

• For a ketone with two different sets of
  ?-hydrogens, is formation of the enolate anion
  regioselective?
• The answer depends on experimental conditions
• when a slight excess of LDA, a ketone is
  converted to its lithium enolate anion, which
  consists almost entirely of the less substituted
  enolate anion
• this reaction is said to be under kinetic control
• for a reaction under kinetic control, the
  composition of the product mixture is determined
  by the relative rates of formation of each product

20
Kinetic Control

• with slight excess of LDA
• for formation of lithium enolates, kinetic
  control refers to the rates of removal of
  alternative ?-hydrogens

21
Thermodynamic Control

• In a reaction under thermodynamic control
• reaction conditions permit equilibration of
  alternative products
• under equilibrium conditions, the composition of
  the product mixture is determined by their
  relative stabilities
• with the ketone in slight excess, the lithium
  enolate is richer in the more substituted enolate
  anion

22
Directed Aldol Reactions

• Consider the crossed aldol reaction between
  phenylacetaldehyde and acetone
• each reactant has ?-hydrogens and a mixture of
  four aldol products is possible

23
Directed Aldol Reactions

• the desired reaction can be carried out by
  preforming the lithium enolate anion of acetone
  and treating it with benzaldehyde

24
Claisen Condensation

• Esters also form enolate anions which participate
  in nucleophilic acyl substitution
• the product of a Claisen condensation is a
  ?-ketoester

25
Claisen Condensation

• Claisen condensation of ethyl propanoate gives
  this ?-ketoester

26
Claisen Condensation

• Step 1 formation of an enolate anion

27
Claisen Condensation

• Step 2 attack of the enolate anion on a carbonyl
  carbon gives a TCAI
• Step 3 collapse of the TCAI gives a ?-ketoester
  and an alkoxide ion

28
Claisen Condensation

• Step 4 formation of the enolate anion of the
  ?-ketoester drives the Claisen condensation to
  the right

29
Dieckman Condensation

• An intramolecular Claisen condensation

30
Crossed Claisen Condsns

• Crossed Claisen condensations between two
  different esters, each with ?-hydrogens, give
  mixtures of products and are not useful
• Useful crossed Claisen condensations are
  possible, however, if there is an appreciable
  difference in reactivity between the two esters,
  e.g., when one of them has no ?-hydrogens

31
Crossed Claisen Condsns

• the ester with no ?-hydrogens is generally used
  in excess

32
Hydrolysis and -CO2
33
Claisen Condensation

• The result of Claisen condensation,
  saponification, acidification, and
  decarboxylation is a ketone

34
From Acetyl Coenzyme A

• Carbonyl condensations are among the most widely
  used reactions in the biological world for
  formation of new carbon-carbon bonds in such
  biomolecules as
• fatty acids
• cholesterol, bile acids, and steroid hormones
• terpenes
• One source of carbon atoms for the synthesis of
  these biomolecules is acetyl coenzyme A
  (acetyl-CoA)

35
Acetyl-CoA

• Claisen condensation of acetyl-CoA is catalyzed
  by the enzyme thiolase

36
Acetyl-CoA

• this is followed by an aldol reaction with a
  second molecule of acetyl-CoA

37
Acetyl-CoA

• enzyme-catalyzed reduction of the thioester group
• phosphorylation by ATP followed by ?-elimination

38
Acetyl-CoA

• isopentenyl pyrophosphate has the carbon skeleton
  of isoprene and is a key intermediate in the
  synthesis of these classes of biomolecules

39
Enamines

• Enamines are formed by the reaction of a 2 amine
  with the carbonyl group of an aldehyde or ketone
• the 2 amines most commonly used to prepare
  enamines are pyrrolidine and morpholine

40
Enamines

• examples

41
Enamines

• the value of enamines is that the ?-carbon is
  nucleophilic and resembles enols and enolate
  anions in its reactions

42
Enamines - Alkylation

• Enamines undergo SN2 reactions with methyl and
  1 alkyl halides, ?-haloketones, and ?-haloesters
• Step 1 treatment of the enamine with one
  equivalent of an alkylating agent gives an
  iminium halide

43
Enamines - Alkylation

• Step 2 hydrolysis of the iminium halide gives an
  alkylated aldehyde or ketone

44
Enamines - Acylation

• Enamines undergo acylation when treated with acid
  chlorides and acid anhydrides
• the reaction is an example of nucleophilic acyl
  substitution

45
Acetoacetic Ester Synth.

• The acetoacetic ester (AAE) synthesis is useful
  for the preparation of mono- and disubstituted
  acetones of the following types

46
Acetoacetic Ester Synth.

• consider the AAE synthesis of this target
  molecule, which is a monosubstituted acetone

47
Acetoacetic Ester Synth.

• Step 1 formation of the enolate anion of AAE
• Step 2 alkylation with allyl bromide

48
Acetoacetic Ester Synth.

• saponification, acidification, and
  decarboxylation gives the target molecule

49
Acetoacetic Ester Synth.

• to prepare a disubstituted acetone, treat the
  monoalkylated AAE with a second mole of base

50
Malonic Ester Synthesis

• The strategy of a malonic ester (ME) synthesis is
  identical to that of an acetoacetic ester
  synthesis, except that the starting material is a
  ?-diester rather than a ?-ketoester

51
Malonic Ester Synthesis

• Consider the synthesis of this target molecule

52
Malonic Ester Synthesis

• treat malonic ester with an alkali metal alkoxide
• alkylation with benzyl chloride
• saponification, acidification, and
  decarboxylation

53
Michael Reaction

• Michael reaction the nucleophilic addition of an
  enolate anion to an ?,?-unsaturated carbonyl
  compound
• Example

54
Michael Reaction

• Example

55
Michael Reaction

• We can write the following 4 step mechanism for a
  Michael reaction
• Step 1 proton transfer to the base
• Step 2 addition of Nu- to the ? carbon of the
  ?,?-unsaturated carbonyl compound

56
Michael Reaction

• Step 3 proton transfer to HB gives an enol
• Step 4 tautomerism of the less stable enol to
  the more stable keto (not shown) form gives the
  observed product

57
Micheal-Aldol Combination
58
Retro of 2,6-Heptadione
59
Michael Reactions

• Enamines also participate in Michael reactions

60
Gilman Reagents

• Gilman reagents undergo conjugate addition to
  ?,?-unsaturated aldehydes and ketones in a
  reaction closely related to the Michael reaction

61
Gilman Reagents

• Gilman reagents are unique among organometallic
  compounds in that they give almost exclusively
  1,4-addition
• Other organometallic compounds, including
  Grignard reagents, add to the carbonyl carbon by
  1,2-addition
• The mechanism of conjugate addition of Gilman
  reagents is not fully understood

62
Prob 19.18

• Draw the structural formula for the product of
  the aldol reaction of each compound followed by
  dehydration.

63
Prob 19.19

• Draw the structural formula for the product of
  each crossed aldol reaction followed by its
  dehydration.

64
Prob 19.21

• Show how to prepare each a,b-unsaturated ketone
  by an aldol reaction followed by dehydration.

65
Prob 19.22

• Show how to prepare each a,b-unsaturated ketone
  by an aldol reaction followed by dehydration.

66
Prob 19.23

• Propose a structural formula for the product of
  this aldol/dehydration reaction.

67
Prob 19.24

• Propose a structural formula for the
  intermediate compound C6H10O2 in this conversion.

68
Prob 19.25

• Propose a structural formula for each lettered
  compound.

69
Prob 19.26

• Show how to bring about this conversion.

70
Prob 19.27

• Propose a mechanism for the steam hydrolysis of
  pulegone. Assign an R or S configuration to
  pulegone, and to the 3-methylcyclohexanone formed
  in the reaction.

71
Prob 19.28

• Propose a mechanism for this acid-catalyzed
  aldol reaction and for its acid-catalyzed
  dehydration.

72
Prob 19.35

• Propose structural formulas for A, B, and the
  ketone formed in this reaction sequence.

73
Prob 19.36

• Propose a synthesis for each ketone, using as
  one step in the sequence a Claisen condensation
  followed by hydrolysis and decarboxylation.

74
Prob 19.37

• Propose a mechanism for this conversion.

75
Prob 19.38

• Propose structural formulas for A, B, and the
  diketone, C9H6O2.

76
Prob 19.39

• Show how a Reformatsky reaction can be used to
  prepare each compound from an a-haloester and an
  aldehyde or ketone.

77
Prob 19.40(a)

• Propose a mechanism for the Perkins
  condensation the condensation of an aromatic
  aldehyde with a carboxylic anhydride.

78
Prob 19.40(b)

• Propose a mechanism for the Darzens glycidic
  ester condensation the condensation of an
  a-haloester with a ketone or aldehyde.

79
Prob 19.41

• Why is enamine A with the less substituted
  double bond the thermodynamically favored product?

80
Prob 19.42

• Enamines can undergo C-alkylation and
  N-alkylation. Explain why heating the C- and
  N-alkylated isomers gives only the C-alkylated
  product.

81
Prob 19.43

• Propose a mechanism for this conversion.

82
Prob 19.44

• Propose a synthesis for this target molecule
  from compound A.

83
Prob 19.45

• Propose a mechanism for this reaction.

84
Prob 19.46

• Propose a synthesis for each compound from
  diethyl malonate.

85
Prob 19.49

• Propose a mechanism for the formation of each
  named compound in this sequence.

86
Prob 19.50

• Show how to prepare each lactone using the
  scheme from the previous problem.

87
Prob 19.51

• Draw structural formulas for intermediates A-D
  in this synthesis.

88
Prob 19.52

• Propose a mechanism for the formation of the
  bracketed intermediate and the bicyclic ketone.

89
Prob 19.53

• Show reagents and experimental conditions to
  bring about this synthesis.

90
Prob 19.54

• Show how nifedipine can be synthesized from
  2-nitrobenzaldehyde, methyl acetoacetate, and
  ammonia.

91
Prob 19.55

• Show reagents and experimental conditions to
  bring about this synthesis.

92
Prob 19.56

• Propose a mechanism for the formation of the
  bracketed intermediate and for its conversion to
  compound A.

93
Prob 19.57

• Show how this b-diketone can be synthesized from
  the given starting materials using an enamine
  reaction.

94
Prob 19.58

• Propose a synthesis for the two needed compounds
  starting from diethyl malonate,
  1,5-dibromopentane, and 1,3-dibromopropane.

95
Prob 19.59

• Show reagents and experimental conditions for
  the synthesis of oxanamide from butanal.

96
Prob 19.60

• Show how warfarin can be synthesized from the
  three named starting materials.

97
Prob 19.61

• Propose a synthesis of this vitamin A precursor
  from isoprene and ethyl acetoacetate.

98
Prob 11.62

• Propose reagents for Steps 1-8 and a mechanism
  for cyclization of 8 to give frontalin.

99
Enolate Anions
End Chapter 19