Organic Chemistry

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Chapter 19 Enolates and Enamines
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Formation of an Enolate Anion

• Enolate anions are formed by treating an
  aldehyde, ketone, or ester, which has at least
  one a-hydrogen, with base,
• Most of the negative charge in an enolate anion
  is on oxygen.

oxygen
Reactive carbon
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Enolate Anions

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

SN2
Carbonyl addition
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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.
• Catalysis Base catalysis is most common although
  acid also works. Enolate anions only exist in
  base.

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The Aldol Reaction

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

acid
acid
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Mechanism the Aldol Reaction, Base

• Base-catalyzed aldol reaction (good nucleophile)
• 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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Mechanism the Aldol Reaction Acid catalysis

• Before showing the mechanism think about what is
  needed.
• On one molecule the beta carbon must have
  nucleophilic capabilities to supply an electron
  pair.
• On the second molecule the carbonyl group must
  function as an electrophile.
• One or the other molecules must be sufficiently
  reactive.

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Mechanism the Aldol Reaction Acid catalysis

• Acid-catalyzed aldol reaction (good electrophile)
• 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.

Nucleophilic carbon
Reactive carbonyl
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Mechanism the Aldol Reaction Acid catalysis

• Step 3 Attack of the enol of one molecule on the
  protonated carbonyl group of the other molecule.
• Step 4 Proton transfer to A- completes the
  reaction.

This may look a bit strange but compare to
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The Aldol Products Dehydration to alkene

• Aldol products are very easily dehydrated to
  ?,?-unsaturated aldehydes or ketones.
• Aldol reactions are reversible and often little
  aldol is 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.

acid
Non-acidic, no alpha hydrogens
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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,
• One reactant has a more acidic hydrogen than the
  other (next slide)
• One reactant is an aldehyde which has a more
  reactive carbonyl group.

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Crossed Aldol Reactions, Nitro activation

• 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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Synthesis Retrosyntheic Analysis
Two Patterns to look for
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Synthesis Retrosyntheic Analysis
Recognition pattern
Analysis
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Synthesis Retrosyntheic Analysis
Example
Mixed aldol
Benzaldehyde No alpha hydrogens
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Claisen Condensation, Ester Substitution

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

Recognition Element
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Claisen Condensation

• Claisen condensation of ethyl propanoate

Here the enolate part of one ester molecule has
replaced the alkoxy group of the other ester
molecule.
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Mechanism 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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Mechanism 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. This consumption of base must be
  anticipated.

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Intramolecular Claisen condensation Dieckman
Condensation
Acidic
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Crossed Claisen Condsns

• Crossed Claisen condensations between two
  different esters, each with ?-hydrogens, give
  mixtures of products and are usually not useful.
• But if one ester has no ?-hydrogens crossed
  Claisen is useful.

No ?-hydrogens
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Crossed Claisen Condsns

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

Used in excess
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Synthesis Claisen Condensation

• Claisen condensations are a route to ketones via
  decarboxylation

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Synthesis Claisen Condensation

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

Note that in this Claisen (not crossed) the
ketone is symmetric. Crossed Claisen can yield
non symmetric ketones.
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Synthesis Retrosynthetic Analysis
New bond
Site of acidic hydrogen, nucleophile
Site of substitution, electrophile
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Enamines (and imines, Schiff bases)
Recall primary amines react with carbonyl
compounds to give Schiff bases (imines), RNCR2.
Primary amine
But secondary amines react to give enamines
Secondary Amine
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Formation of Enamines

• Again, 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.

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Formation of Enamines

• Examples

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Enamines Alkylation at a position.

• The value of enamines is that the ?-carbon is
  nucleophilic.
• 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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Compare mechanisms of acid catalyzed aldol and
enamine
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Enamines - Alkylation

• Hydrolysis of the iminium halide gives an
  alkylated aldehyde or ketone.

Overall process is to render the alpha carbonss
of ketone nucleophilic enough so that
substitution reactions can occur.
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Enamines Acylation at a position

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

Could this be made via a crossed Claisen followed
by decarboxylation.
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Overall, Acetoacetic Ester Synthesis

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

RX

• Main points
• Acidic hydrogen providing a nucleophilic center.
• Carboxyl to be removed thermally
• Derived from a halide

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Overall, 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.

RX

• Main points
• Acidic hydrogen providing a nucleophilic center
• Carboxyl group removed by decarboxylation
• Introduced from alkyl halide

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Malonic Ester Synthesis

• Consider the synthesis of this target molecule

Recognize as substituted acetic acid. Malonic
Ester Synthesis
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Malonic Ester Synthesis Steps

• Treat malonic ester with an alkali metal
  alkoxide.
• 2. Alkylate with an alkyl halide.

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Malonic Ester Synthesis

• 3. Saponify and acidify.
• 4. Decarboxylation.

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Michael Reaction, addition to ?,?-unsaturated
carbonyl

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

Recognition Pattern Nucleophile C C CO
(nitrile or nitro)
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Michael Reaction
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Michael Reaction in base

• Example
• The double bond of an a,b-unsaturated carbonyl
  compound is activated for attack by nucleophile.

More positive carbon
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Mechanism Michael Reaction

• Mechanism
• 1 Set up of nucleophile Proton transfer to the
  base.
• 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, Cautions 1,4 vs 1,2

• Resonance-stabilized enolate anions and enamines
  are weak bases, react slowly with a,b-unsaturated
  carbonyl compounds, and give 1,4-addition
  products.
• Organolithium and Grignard reagents, on the other
  hand, are strong bases, add rapidly to carbonyl
  groups, and given primarily 1,2-addition.

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Michael Reaction Thermodynamic vs Kinetic

• Addition of the nucleophile is irrevesible for
  strongly basic carbon nucleophiles (kinetic
  product)

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Micheal-Aldol Combination
a, b unsaturated
Carbanion site
Dieckman
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Retrosynthesis of 2,6-Heptadione
Recognize as substituted acetone, aae synthesis
Recognize as Nucleophile C C CO Michael
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Michael Reactions

• Enamines also participate in Michael reactions.

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Gilman Reagents vs other organometallics

• 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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Crossed Enolate Reactions using LDA

• With a strong enough base, enolate anion
  formation can be driven to completion.
• The base most commonly used for this purpose is
  lithium diisopropylamide , LDA.
• LDA is prepared by dissolving diisopropylamine in
  THF and treating the solution with butyl lithium.

LDA
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Crossed Enolate Reactions using LDA

• The crossed aldol reaction between acetone and an
  aldehyde can be carried out successfully by
  adding acetone to one equivalent of LDA to
  completely preform its enolate anion, which is
  then treated with the aldehyde.

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Examples using LDA
Crossed aldol
Michael
Alkylation
Acylation
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Crossed Enolate Reactions using LDA

• Question For ketones with nonequivalent
  a-hydrogens, can we selectively utilize the
  nonequivalent sites?
• Answer A high degree of regioselectivity exists
  and it depends on experimental conditions.

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Crossed Enolate Reactions using LDA

• When 2-methylcyclohexanone is treated with a
  slight excess of LDA, the enolate is almost
  entirely the less substituted enolate anion.
• When 2-methylcyclohexanone is treated with LDA
  where the ketone is in slight excess, the product
  is richer in the more substituted enolate.

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Crossed Enolate Reactions using LDA

• The most important factor determining the
  composition of the enolate anion mixture is
  whether the reaction is under kinetic (rate) or
  thermodynamic (equilibrium) control.
• Thermodynamic Control Experimental conditions
  that permit establishment of equilibrium between
  two or more products of a reaction.The
  composition of the mixture is determined by the
  relative stabilities of the products.

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Crossed Enolate Reactions using LDA

• Equilibrium among enolate anions is established
  when the ketone is in slight excess, a condition
  under which it is possible for proton-transfer
  reactions to occur between an enolate and an
  a-hydrogen of an unreacted ketone. Thus,
  equilibrium is established between alternative
  enolate anions.

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Crossed Enolate Reactions using LDA

• Kinetic control Experimental conditions under
  which the composition of the product mixture is
  determined by the relative rates of formation of
  each product. First formed dominates.
• In the case of enolate anion formation, kinetic
  control refers to the relative rate of removal of
  alternative a-hydrogens.
• With the use of a bulky base, the less hindered
  hydrogen is removed more rapidly, and the major
  product is the less substituted enolate anion.
• No equilibrium among alternative structures is
  set up.

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Example
1. 1.01 mol LDA, kinetic control
1. 0.99 mol LDA, thermodynamic control