Transcript No Slide Title

The Aldol Condensation
In the presence of a strong base, two
molecules of aldehyde or ketone may
combine to form a b-hydroxyaldehyde
or a b-hydroxyketone.
This reaction is called the aldol
condensation.
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The Aldol Condensation
O
R
CH2 C
H
OH
base
+
O
R
CH2 C
H
R
CH2 C
O
CH C
H
R
H
a bhydroxyaldehyde
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Example
O
O
NaOH
CH 3 C
H
+
CH 3 C
H
OH
CH 3 C
O
CH 2 C
H
H
"Aldol"
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Another Example
O
O
NaOH
CH 3 CH 2 C
H
+
CH 3 CH 2 C
H
OH
CH 3 CH 2 C
H
O
CH
C
H
CH 3
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One More:
O
O
NaOH
CH 3 C
CH 3
+
CH 3 C
CH 3
OH
CH 3 C
O
CH 2 C
CH 3
CH 3
"Diacetone alcohol"
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The Aldol Condensation Reaction: Mechanism
1)
: O:
CH 3 C
2)
: O:
CH 3 C
_
..
CH 2
3)
H
..
: O:
_
..
+ : ..O
fast
H
H
slow
H
..
CH 2
+
H
:O :
C
H
CH 2 C
H
an enolate ion
CH 3 C H
:O :
:O :
C
_
..
:O :
acceptor
H
..
O
..
.. _
:O :
donor
: O:
CH 2 C
H
..
:O H
: O:
fast
CH 3 C
H
CH 2 C
+ H2O
H
CH 3 C
H
CH 2 C
H
_ ..
+ :OH
..
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The Aldol Condensation
Reaction: Mechanism
The enolate ion (carbanion) is the
actual nucleophilic reagent.
The reaction breaks down to the
following:
The a-carbon of the donor attaches
itself to the carbonyl carbon of the
acceptor
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The “Heart” of the Mechanism
acceptor
_
O
H
H 3C
+
C
_
..
CH 2
C
H
H
H 3C
C
_
O
CH 2
O
donor
C
O
H
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The Aldol Condensation
The carbonyl group plays two roles in
this reaction:


1. It provides a site for nucleophilic attack
by the enolate ion.
2. It makes the a-hydrogens sufficiently
acidic to enable the formation of
reasonable concentrations of enolate ion.
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The Aldol Condensation
NOTE: The must be a-hydrogens in
order to have an aldol condensation.

Without a-hydrogens, the only possible
reaction is the Cannizarro reaction
(Chapter 17, Section 17.3 -- we skipped
this)
NOTE ALSO: The aldol condensation is
not an end-to-end condensation!
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Synthesis Problem
OH
CH 3 CH 2 CH
O
CH
C
H
CH 3
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Synthesis Problem
OH
CH 2 CH 2 CH
O
CH
C
H
CH 2
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Dehydration of Aldol Products
Aldol products are often very easily
dehydrated, yielding a,b-unsaturated
aldehydes or ketones.
After dehydration, the a,b-unsaturated
aldehydes and ketones are stabilized by
resonance, thereby providing a driving
force for the dehydration.
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Dehydration of Aldol Products
O
OH
H
O
H
C
H
dilute HCl
CH 3 C
C
C
H
C
C
warm
H
H
CH 3
H
Crotonaldehyde
+
H 2O
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Dehydration of Aldol Products
O
OH
CH 3 C
H
C
O
C
CH 3
CH 3
I2
C
C
CH 3
C
warm
CH 3 H
CH 3
H
Mesityl oxide
+
Note here that iodine is a sufficiently strong
Lewis acid to bring about dehydration.
H 2O
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Chalcone Formation
OH
O
"spontaneous"
C
CH 2 C
H
(formed from an aldol
condensation)
O
CH
CH
C
a chalcone
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Dehydration of Aldol Products
The mechanism for the dehydration
is E1.
The dehydration happens because
the product is conjugated (i.e.,
resonance-stabilized)
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Dehydration Products
O
CH 3
C
CH 3
C
C
O
CH 3
CH 3
C
H
CH 3
C
CH 3
C
H
O
CH 3
C
CH 3
C
CH 3
C
H
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Dehydration of Aldol Products
CH 3
C
CH 3
CH
C
O
CH 3
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Preparation via Aldol
Condensation
CH3 CH
CH
CH2 OH
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Preparation via Aldol
Condensation
CH 3 CH 2 CH 2 CH 2 CH
CH 2 OH
CH 2
CH 3
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Also:
O
O
CH 2
a
CH 3
CH 2
CH 3
C
C
O
NaOH
a
C2H5OH
25°
CH 3
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Synthesis of:
O
C
H
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The Crossed Aldol
Condensation
What if we tried mixing two different
aldehydes (or ketones) together?
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O
CH 3 C
H
OH
O
CH 3 CH
CH 2 C
+
NaOH
+
OH
O
CH 3 CH 2 C
H
H
CH 3 CH 2 CH
O
CH
C
H
CH 3
+
OH
CH 3 CH
O
CH
C
H
CH 3
+
OH
O
CH 3 CH 2 CH
CH 2 C
H
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Crossed Aldol Condensation
If both carbonyl compounds have a-hydrogens,
then we can’t control which is the donor and
which is the acceptor.
But if we choose one carbonyl compound that
does not have a-hydrogens, it can only act as
an acceptor.
Then, but adding the donor to a dilute solution
of acceptor, we can control the reaction to give
only one product.
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Crossed Aldol Condensations
O
C
H
acceptor
OH
NaOH
+
C
O
H
CH 3 C
O
CH 2 C
H
H
donor
- H2O
(spontaneously)
O
CH
CH
C
H
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From Experiment 35
O
C
CH 3
NaOH
+
OH
O
CH
CH 2 C
O
C
H
NO 2
- H 2O
(spontaneous)
NO 2
O
CH
CH
C
NO 2
3-Nitrochalcone
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Do the synthesis of:
O
CH
C
C
H
CH 3
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Uses of the Aldol
Condensation
The aldol condensation is very useful in the
preparation of large molecules from simple
starting materials.
In biosynthesis, where large molecules are
products, condensation reactions provide the
only reasonable route, since all of the starting
materials are small molecules containing only
two or three carbons.
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Synthesis of an Insect Repellent
O
CH 3 CH 2 CH 2 C
OH
H
NaOH
CH 3 CH 2 CH 2 C
O
CH 3 CH 2 CH 2 C
a
CH 3 CH 2 CH
H
ALDOL
CONDENSATION
OH
CH 3 CH 2 CH 2 C
CH 3 CH 2 CH
H
C
H
O
2-Ethyl-3-hydroxyhexanal
OH
H2
H
C
O
H
CH 3 CH 2 CH 2 C H
Ni
CH 3 CH 2 CH
HYDROGENATION
H
C
H
O H
2-Ethyl-1,3-hexanediol
--used in "6-12"
repellent
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-- Chemistry
Synthesis of a Compound used in Perfumery
O
C
CH 2
O
cis
a
CH 2 CH 2 CH CH
C
CH 2 CH 3
KOH
CH 2
O
CH
CH 2
CH 2 CH
cis
CH
CH 2 CH 3
CH 2
C
ALDOL
CONDENSATION
CH 3
C
OH
CH 3
- H2O
O
CH 2 CH 3
CH 2
C
H
DEHYDRATION
C
H
CH 3
cis-Jasmone
--- used for the scent of jasmine
in perfumes
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Biological Synthesis of Fructose
O
O
CH 2 CH
O
O
OH
P
O
C
+
H
a
CH 2 C
CH 2 O
P
OH
OH
O
Dihydroxyacetone phosphate
OH
Glyceraldehyde-3-phosphate
O
CH 2 CH
C
CH
O
OH
H
OH
P
O
OH
ALDOL
CONDENSATION
enzyme
OH
O
O
C
O
CH 2 O
P
OH
O
Fructose-1,6-diphosphate
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Condensation Reactions
The aldol condensation serves as the
prototype for a large number of
condensation reactions.
In virtually every case, a carbanion is
generated, usually by the action of a
base to remove an a-hydrogen that has
been activated by a near-by group
(C=O, C,2)
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Condensation Reactions
The carbanion then acts as a
nucleophile to attack the carbonyl
carbon of the other reagent used in the
reaction.
This is an important process in
biosynthesis, where large and complex
molecules can be built from simple
precursors.
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Condensation Reactions
We will not examine all of the other
possible reactions that follow this
general pathway, with one exception:
We will examine the Claisen ester
condensation.
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