Enolate Anions

1
Enolate Anions
Chapter 19

• Chapter 19

2
Reactions of Chapter 19

• Aldol reaction (aldehyde or ketone)
• Crossed Aldol
• Intramolecular Aldol (cyclic)
• Claisen reaction (esters)
• Crossed Claisen
• Dieckmann (cyclic)
• Enamines (2o amine aldehyde or ketone)
• Acetoacetic ester reaction
• Malonic ester reaction
• Michael addition (?, ? -unsaturated carbonyl)
• Robinson Annulation (cyclic from Michael aldol)
• Gilman alkylation (Michael)

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19.1 Formation of an Enolate Anion

• Enolate anions are formed by treating an aldehyde
  or ketone with base.
• most of the negative charge in an enolate anion
  is on oxygen.

4
Reaction Types with Enolate Anions

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

1.
2.
5
The Hell-Volhard-Zelinsky reaction

• This reaction is a synthesis of ?-haloacids.
• The starting acid must have an ?-hydrogen. It is
  treated with Br2 and PBr3 then hydrolyzed.
• Remember we had ?-halogenation of ketones in
  chapter 16.

O
O
O
O
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19.2 The Aldol Reaction

• The most important reaction of enolate anions is
  nucleophilic addition to the carbonyl group of
  another molecule of the same or different
  compound.
• This reaction with aldehydes or with ketones is
  an Aldol reaction.
• although these reactions may be catalyzed by
  either acid or base, base catalysis is more
  common.

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The Aldol Reaction

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

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The Aldol Reaction

• Base-catalyzed aldol reaction
• Step 1 formation of a resonance-stabilized
  enolate anion.
• Step 2 carbonyl addition gives a TCAI.
• Step 3 proton transfer to O- completes the aldol
  reaction.

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The Aldol Reaction acid

• Acid-catalyzed aldol reaction
• 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.

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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.

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The Aldol Products -H2O

• aldol products are very easily dehydrated to
  ?,?-unsaturated aldehydes or ketones.
• 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.

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Crossed Aldol Reactions

• In a Crossed aldol reaction, one kind of molecule
  provides the enolate anion and another kind
  provides the carbonyl group.
• Note Formaldehyde has no ?-carbon.
• To be useful the electrophile must not have a
  hydrogen on the ?-carbon.

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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.

Aldehydes without an ?-H
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Crossed Aldol Reactions

• Nitro groups can be introduced by way of an aldol
  reaction using a nitroalkane.
• nitro groups can be reduced to 1 amines.

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Intramolecular Aldol Reactions

• intramolecular aldol reactions are most
  successful for formation of five- and
  six-membered rings.
• consider 2,7-octadione, which has two a-carbons.

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Cannizzaro Reaction

• An aldehyde which has no a-hydrogens undergoes
  oxidation-reduction when treated with base

O
O

O
O
O


reduced
oxidized
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19.3 A. Claisen Condensation

• Esters also form enolate anions which condense in
  a Claisen condensation.
• the product of a Claisen condensation is a
  ?-ketoester.

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Claisen Condensation

• Claisen condensation of ethyl propanoate gives
  this ?-ketoester. The base generally used is
  the alkoxide corresponding to the alcohol moiety
  of the ester.

19
Claisen Condensation

• Step 1 formation of an enolate anion.
• Step 2 attack of the enolate anion on a carbonyl
  carbon gives a TCAI.

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Claisen Condensation

• Step 3 collapse of the TCAI gives a ?-ketoester
  and an alkoxide ion.
• Step 4 an acid-base reaction drives the reaction
  to completion.

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B. Dieckman Condensation

• A Dieckman condensation is an intramolecular
  Claisen condensation (forms a cyclic product).

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C. 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
  that is, when one of them has no ?-hydrogens.

Esters without an ?-H
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Crossed Claisen Condensations

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

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D. Use of the Claisen Condensation

• Claisen condensations are a route to ketones.

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Claisen Condensation

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

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19.4 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).

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Acetyl-CoA

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

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Acetyl-CoA

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

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Acetyl-CoA

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

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Acetyl-CoA

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

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19.5 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.

O
N
N
H
H
Pyrrolidine
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Enamines

• Examples

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A. Enamines The Stork Reaction

• The value of enamines is that the ?-carbon is
  nucleophilic and gives an SN2 alkylation.
• enamines undergo SN2 reactions with methyl and
  1 haloalkanes, ?-haloketones, and ?-haloesters.
• treatment of the enamine with one equivalent of
  an alkylating agent gives an iminium halide.

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Enamines - Alkylation

• hydrolysis of the iminium halide (Schiff base)
  gives an alkylated aldehyde or ketone.

O
O
O

N


N
H
H
Remember, a CN is a Schiff base. These will
hydrolyze in acid to give the amine and carbonyl.
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B. Enamines - Acylation

• enamines undergo acylation when treated with acid
  chlorides and acid anhydrides.

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19.6 Acetoacetic Ester Synthesis

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

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Acetoacetic Ester Synthesis

• this occurs by alkyation of the carbon between
  the carbonyl groups followed by hydrolysis of the
  ester then decarboxylation of the ?-ketoacid
• consider the AAE synthesis of this target
  molecule, which is a monosubstituted acetone.

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Acetoacetic Ester Synthesis

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

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Acetoacetic Ester Synthesis

• Steps 3 4 saponification followed by
  acidification.
• Step 5 thermal decarboxylation.

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Acetoacetic Ester Synthesis

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

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19.7 Malonic Ester Synthesis

• The strategy of a Malonic ester (ME) synthesis is
  similar to that of an acetoacetic ester
  synthesis. The starting material is a ?-diester
  rather than a ?-ketoester.

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Malonic Ester Synthesis

• is useful for the preparation of mono- and
  disubstituted acetic acids.
• Consider the synthesis of this target molecule.

This is the R group from alkylation of malonic
ester
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Malonic Ester Synthesis

• treat malonic ester with an alkali metal
  alkoxide.
• alkylate with 1-bromo-3-methoxypropane.

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Malonic Ester Synthesis

• saponify and acidify.
• decarboxylation.

Disubstitution can be obtained in the same manner
as used with acetoacetic ester
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19.8 A. Michael Reaction

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

Electron donor
Electron recipient
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Michael Reaction, Table 19.1
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Michael Reaction

• Example
• the double bond of an a,b-unsaturated carbonyl
  compound is activated for nucleophilic attack.

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Michael Reaction

• Mechanism
• Step 1 proton transfer to the base.
• Step 2 addition of Nu- to the ? carbon of the
  ?,?-unsaturated carbonyl compound.

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Michael Reaction

• Step 3 proton transfer to HB gives an enol.
• Step 4 tautomerism of the less stable enol form
  to the more stable keto form.

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Michael Reaction

• A final word about nucleophilic addition to
  a,b-unsaturated carbonyl compounds.
• resonance-stabilized enolate anions and enamines
  are weak bases, react slowly with a,b-unsaturated
  carbonyl groups, and instead give 1,4-addition
  products.
• organolithium and Grignard reagents, on the other
  hand, are strong bases, add rapidly to carbonyl
  groups, and give primarily 1,2-addition.

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Michael Reaction

• Thermodynamic versus kinetic control.

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Michael Reactions

• enamines also participate in Michael reactions.

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B. Robinson Annulation
A Michael reaction followed by a cyclic aldol.
O
O

(Michael reaction)
O
O
O
(Aldol reaction)
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Another example

• Michael addition followed by an aldol
  condensation.

O
O
O
O
- OH

Michael
O
O
- OH
O
Aldol
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C. Gilman Reagents

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

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Retrosynthesis of 2,6-Heptadione
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Enolate Anions
End Chapter 19