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Organic Chemistry

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Title: 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
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