Enols and Enolates:

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Enols and Enolates Alpha Substitution Reactions
of Carbonyl Compounds
Review Aldehydes/Ketones undergo Nucleophilic
Addition.
?
?
Acid Deriviatives under Nucleophilic Acyl
Substitution
?
?
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Carbonyl compounds like aldehydes, ketones and
esters can also be Converted into nucleophiles,
which may then attack another carbonyl
..
?

Acid-base





?
..
?
H




?




..
Nucleophilic Addition








?
..
?
Nucleophilic Substitution
X
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Keto-Enol Tautomerism
Ketones and aldehydes are in equilibrium with the
enol forms
Keto Form Enol Form
These forms are isomers of each other. The
process of converting from one form to the other
is called tautomerism. The two forms called
tautomers
Mechanism 1. Base-catalyzed process
?
H2O
..
?
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In most cases the keto form is favored at
equilibrium
99.98 0.02
2. Acid-Catalyzed Process
?
H2O
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Acidities of Common Functional Groups
Functional Group Structure
pKa Carboxylic Acid 3-5 Phenol 10 ?
-dicarbonyl 9-11 Alcohols 15-19
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Aldehydes, Ketones 17-20 Esters
20-25 Nitriles 25 Alkynes 25 Alkanes
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Q How do we know when a base is strong enough to
completely deprotonate an acid?
A As a general guideline, the pKa of the
conjugate acid of the base must be at least 5
pKa units larger than the pKa of the acid.
Example Will hydroxide completely deprotonate
acetone?
..
?
gt99.9 lt 0.1
pKa H2O (conj. acid) 15.7 pKa acetone
20
No, it wont completely deprotonate it.
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Example Will lithium diisopropylamide (LDA)
completely deprotonate acetone?
..
?
100
pKa LDA-H (conj. acid) 35 pKa acetone
20
Yes, it will completely deprotonate it.

• LDA commonly used base due to
• Very strong base
• Poor nucleophile (why?)

?
?
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Reactions involving Enols/Enolates
1. Alpha-Halogenation of Ketones with base.
?
?
Reaction is base-promoted (not catalyzed) since
hydroxide is consumed and a full equivalent is
required.
Mechanism
?
?
..
?
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If more than one alpha-H is present, multiple
halgenations will occur, assuming excess halogen
and base are present.
?
?
?
?
?
If X2 is I2, then iodoform forms as a yellow
precipitate. This reaction is known as The
iodoform test for methyl ketones, because it
forms only for methyl ketones.
?
?
Methyl ketone
iodoform
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2. Alpha-halogenation of ketones in acid.

• Multiple halgenation does not occur here.
• It does not work with aldehydes.

Mechanism On blackboard
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3. Alpha-Halogenation of Carboxylic Acids
Hell-Volhard-Zelinsky Reaction
Mechanism Blackboard
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4. Alkylation of Enolates
?
..
C-alkylation
O-alkylation
These reactions compete with each other, with
usually C-alkylation the major product.
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5. Wittig reaction formation of a CC double
bond. This reactions uses a phosphorus ylid,
a source of nucleophilic carbon
?
..
?
Phosphorus Ylid
Ketone or Aldehyde
Alkene
Enolate type structure
Mechanism see Chapter 19 notes.
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Vitamin A Synthesis used the Wittig
P(Ph)3, HCl
What carbonyl compound is necessary here?
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6. Aldol Condensation self-condensation of a
ketone or aldehyde in the presence of base.
?
?
?
?
?
Usually, the initially-formed ?-hydroxyketone
dehydrates to the ?,?-unsaturated ketone since
the double bonds are conjugated in the product.
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The aldol condensation can be conducted with
mixed aldehydes or ketones, but this results in
a mixture of products. For example, the
condensation of acetone and acetaldehyde results
in four possible products. Can you predict these
products?
?
4 products
On the other hand, some mixed aldol reactions
yield only one product.
?
OH
OH
?
No alpha hydrogens
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7. Claisen Condensation
- self-condensation of an ester in base.
?
?
?-ketoester product
Mechanism
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?
?
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Dieckman Reaction Intramolecular Claisen
condensation
Write a mechanism for this reaction as practice.
Show how a Claisen condensation can used to
synthesise these molecules.
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For 1,3-dicarbonyl compounds like this, make a
disconnection on one of the bonds between the
carbonyl groups.
?
?
The molecule is the ketoester.
enolate
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EtONa
?
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There is another product that may form from this
reaction. What is it?
EtONa
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?
-H2O
EtOH
We dont know which product will predominate in
this reaction but it is clear that two viable
products may form. Is there an alternative
synthesis? Yes.
?
?
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?
Is this the preferred synthesis? Yes, because it
wont give a mixture of products AND the
starting materials are readily available
cyclopentanone and ethyl benzoate.
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Professor Elias J. Corey, Harvard University,
Nobel Prize, 1990, for his important
contributions to synthetic organic chemistry. He
has developed theories and methods that have made
it possible to produce a large variety of
biologically highly active, complicated natural
products, thereby making, among other things,
certain pharmaceuticals commercially available.
Corey's work has also led to new general methods
of producing, synthesising, compounds in simpler
ways.
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Why is the diester of malonic acid so much more
acidic than the monoester?
The anion is highly stabilized by resonance.
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The goal of the malonic ester synthesis is to
make an alkylated acetic acid molecule, for
example
acetic acid
butyl group

• Three-step synthesis starting with malonic ester
• Deprotonation of malonic ester in base.
• Alkylation with unhindered alkyl halide.
• Decarboxylation (loss of CO2).

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Ester hydrolysis and decarboxylation occur in one
step.
H H2O
Mechanism of decarboxylation
Intramolecular H-bond
rewrite as
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Enol of Carboxylic Acid
Carboxylic Acid - more stable
Give a synthesis of the following molecule using
the malonic ester reaction.
Two alkyl groups must be added. Add them
consecutively, then hydrolyze and decarboxylate.
How about this one?
Hint Use 1,5-dibromopentane
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Acetoacetic acid synthesis - synthesis of
substituted acetone.
The mechanism of this reaction is parallels that
of the malonic ester synthesis.
Acetoacetic ester
Alkylated acetone