Chapter 19

Condensation and Conjugate Addition

Reaction of Carbonyl Compounds
- More Chemistry of Enolates -
1
The Claisen Condensation: Formation of !-Ketoesters
from Esters with Enolizable Hydrogens
Esters with enolizable H undergo a reaction similar to the aldol
condensation in the presence of alkoxide bases.
Alkoxide bases are used so that competing nucleophilic addition to
the acyl carbon does not destroy or change the ester function.
-C-C-OR
H
:O: =
pK
a
25
~
~
+ B:
-
-C-C-OR
:O: =
:
-
-C=C-OR
:O:
:
-
enolate anion of ester
-C C OR
O
!"
!"
hybrid
-C-C-OR
O=
H
+ RO
-
Na
+
-C-C-OR
OR
O
-
H
Na
+
competing nucleophilic addition
-C-C-OR
O=
H
+ RO
-
Na
+
no change
2
Condensation Step
The enolate anion of an ester reacts as a nucleophile by way of the
carbanion center in adding to the acyl carbon of a second ester:
-C-C-OR
H
:O: =
-C-C-OR
O=
:
-
+
enolate anion

-C C-OR
:O:
:
-
H C-C-OR
O
=
reversible nucleophilic addition
tetrahedral intermediate
-C C-OR
:O:
:
-
H C-C-OR
O
=
cleavage
-C-C C-C-OR
O
=
O=
H
!-keto ester
+ RO
-
3
Example: The Condensation of Ethyl Acetate.
Ludwig Claisen (1851-1930)
The recommended procedure involves dissolving one equivalent of
sodium metal slowly in absolute (dry) ethanol. An immediate redox
reaction generates one equivalent of sodium ethoxide. Two
equivalents of ethyl acetate are added, and the mixture is heated for
several hours. Acidification of the reaction mixture yields the
condensation product ethyl acetoacetate.
2 CH
3
COC
2
H
5
O=
ethyl acetate
pK
a
= 25
+ Na
+ -
OC
2
H
5
overall reaction
CH
3
CCHCOC
2
H
5
O=O=
:
-
Na
+
+ C
2
H
5
OH
sodium ethyl acetoacetate
CH
3
CCHCOC
2
H
5
O=
:
-
Na
+
workup
H
+
CH
3
CCH
2
COC
2
H
5
O=O=
ethyl acetoacetate
pK
a
= 11
O=
4
Some Observations
One full equivalent of base (NaOEt) is consumed in the reaction.
The product is the sodium salt of ethyl acetoacetate which
accumulates as the condensation reaction proceeds.
The relative acidities of key compounds in this reaction are:
CH
3
CCH
2
COC
2
H
5
O=
O=
ethyl acetoacetate
pK
a
= 11
> CH
3
CH
2
OH
ethyl alcohol
pK
a
= 16
>
CH
3
COC
2
H
5
O=
ethyl acetate
pK
a
= 25
5
A Mechanism for the Claisen Condensation of Esters
formation of the enolate anion in low concentration
CH
3
COC
2
H
5
O=
pK
a
= 25

+ Na
+ -
OC
2
H
5
:CH
2
COC
2
H
5
Na
+
-
+ C
2
H
5
OH
pK
a
= 16
O=
addition to acyl carbon
:CH
2
COC
2
H
5
-
CH
3
COC
2
H
5
O=
+
O=
CH
3
C-OC
2
H
5
O
-
CH
2
CO
2
C
2
H
5
Na
+
cleavage and deprotonation
CH
3
C-OC
2
H
5
O
-
CH
2
CO
2
C
2
H
5
Na
+
CH
3
CCH
2
CO
2
C
2
H
5
O=
pK
a
= 11
+ NaOC
2
H
5
fast
CH
3
CCHCO
2
C
2
H
5
O=
:
-
Na
+
+ C
2
H
5
OH
pK
a
= 16
Although the Claisen condensation is a
reversible reaction, it is driven to completion
by essentially irreversible formation of the
anion of ethyl acetoacetate.
6
The Claisen Condensation of Ethyl Propanoate
2 CH
3
CH
2
CO
2
C
2
H
5
NaOC
2
H
5
ethanol, heat
CH
3
CH
2
CCCO
2
C
2
H
5
O
=
CH
3
:-
Na
+
+ C
2
H
5
OH
CH
3
CH
2
CCCO
2
C
2
H
5
O
=
CH
3
:-
Na
+
workup
H
+
CH
3
CH
2
CCHCO
2
C
2
H
5
CH
3
O
=
ethyl 3-oxo-2-methylpentanoate
Note the overall synthetic
strategy of the Claisen
condensation of esters to
yield !"ketoesters:
RCH
2
C CHCO
2
Et
R
O
=
RCH
2
C
CH
2
CO
2
Et
O
=
OEt R
7
Limitations of the Claisen Condensation
Esters with only one enolizable H do not give condensation
products under the usual conditions. Because the condensation
product is not protected by deprotonation to the stable anion, a
"reverse Claisen reaction" can occur that limits the amount of
product formed.
CH
3
CHCO
2
C
2
H
5
CH
3
+
CH
3
CCO
2
C
2
H
5
CH
3
: -
Na
+
CH
3
CHCO
2
C
2
H
5
CH
3
ethyl 2-methylpropanoate
+ NaOEt
CH
3
CCO
2
C
2
H
5
CH
3
:-
Na
+
+ EtOH
enolate anion
CH
3
CHC-C-CO
2
C
2
H
5
O=CH
3
CH
3
+ NaOC
2
H
5
CH
3
reverse Claisen cleaves condensation product
CH
3
CHC-C-CO
2
C
2
H
5
O=CH
3
CH
3
+
-
OC
2
H
5
CH
3
8
Variations of the Claisen Condensation Reaction
The Dieckmann Condensation (1894): An Intramolecular
Claisen Condensation
CH
2
CH
2
CH
CO
2
C
2
H
5
CH
2
C
OC
2
H
5
O
-
Na
+
CH
2
CH
2
CH
2
CO
2
C
2
H
5
CH
2
CO
2
C
2
H
5
diethyl adipate
+ NaOEt
CH
2
CH
2
CHCO
2
C
2
H
5
CH
2
CO
2
C
2
H
5
:-
Na
+
+ EtOH
CH
2
CH
2
CHCO
2
C
2
H
5
CH
2
C-OC
2
H
5
: -
Na
+
intramolecular acyl addition
O
=
9
CH
2
CH
2
CH
CO
2
C
2
H
5
CH
2
C
OC
2
H
5
O
-
Na
+
cleavage
CH
2
CH
2
CH
CO
2
C
2
H
5
CH
2
C=O + NaOEt
fast deprotonation
CH
2
CH
2
C:
-
CO
2
C
2
H
5
CH
2
C=O
Na
+
+ EtOH
workup
CH
2
CH
2
C:
-
CO
2
C
2
H
5
CH
2
C=O
Na
+
H
+
CH
2
CH
2
CH
CO
2
C
2
H
5
CH
2
C=O
ethyl 2-oxocyclopentanecarboxylate
10
The Crossed Claisen Condensation
The condensation reaction of one ester with a second ester, or
with an aldehyde or ketone is called a crossed Claisen. As with
the crossed aldol condensation, it is a synthetically useful reaction
only when it is directed towards one product.
The reaction may be directed by:

using two different esters where only one has enolizable H.

reacting an an ester with aldehydes or ketones with enolizable
H and exploiting the greater acidity of these compounds.
Examples of Crossed Claisen Reactions
COC
2
H
5
O=
+ CH
3
CO
2
C
2
H
5
ethyl benzoate
(no enolizable H)
(i) NaOEt/EtOH
(ii) H
+
C-CH
2
CO
2
C
2
H
5
O=
ethyl 3-oxo-3-phenylpropanoate
11
H-COC
2
H
5
O=
ethyl formate
(no enolizable H)
+ CH
3
CO
2
C
2
H
5
(i) NaOEt/EtOH
(ii) H
+
C-CH
2
CO
2
C
2
H
5
O=
H
ethyl 3-oxopropanoate
CCH
3
O=
acetophenone
(pK
a
22)
~
~
+ CH
3
CO
2
C
2
H
5
(i) NaOEt/benzene
(ii) H
+
(pK
a
=

25)
CCH
2
CCH
3
O= O=
1-phenyl-1,3-butanedione
via preferentially formed enolate
anion of acetophenone:
CCH
2
-
O=
+ CH
3
C-OC
2
H
5
O=
12
The Aldol Reaction: Addition of Enolate
Anions to Aldehydes and Ketones
Aldehydes and ketones with enolizable hydrogens (!-H) undergo a
self-reaction to give a "-hydroxyaldehyde or "-hydroxyketone in the
presence of base. This reaction is called the aldol condensation.
Requirements for an aldol reaction:

!-H

Dilute solution of base-usually HO
-
2 CH
3
CH
O
=
acetaldehyde
10% NaOH, H
2
O
5
o
C
CH
3
CHCH
2
CH
O
=
OH
3-hydroxbutanal
an "aldol"
The aldol reaction does not occur with
ArCHO HCHO (CH
3
)
3
CCH
O
=
ArCAr'
O
=
ArCCR
3
O
=
13
Aldol additon is reversible
14
Aldol Dehydration and the Retro-Aldol Reaction
For ketones, the equilibrium does not favor the formation of the
aldol product under based-catalyzed conditions.
If the mixture is heated, a Retro-Aldol Reaction occurs resulting in
primarily the ketone starting material.
With aldehydes the equilibrium favors the aldol product.
Heating the reaction mixture (in the presence of base) results in
dehydration.
15
16
Dehydration of Aldol Products
The !-hydroxyaldehyde and-ketone aldol condensation products,
when isolated, dehydrate very easily to ",!#unsaturated carbonyl
compounds because of the stability inherent in the conjugated
enone structures.
When R = aryl,
dehydration occurs
during the aldol
condensation:
RCCH
3
O=
2
HO
-
or RO
-
CH
3
CCH
2
CR
R
OH
O=
!-hydroxyaldehyde
or -ketone
dil. HCl
heat
fast
(-H
2
O)
CH
3
C=CHCR
O=
R
!,"#unsaturated
aldehyde or ketone
The dehydration yields an
extended ! system with
resonance stabilization:
CH
3
C=CHCR
:O: =
R
CH
3
C-CH=CR
R
:O:
:
+
-
acetophenone
C=C
CH
3
H
C-
O=
CCH
3
O=
1,3-diphenyl-2-buten-1-one
NaOEt
17
18
The Crossed Aldol Condensation
An aldol reaction using two different carbonyl compounds is a
crossed aldol condensation. Because of the possibility of four
different condensation products, this reaction is not synthetically
useful unless it is carefully designed.
Directed Crossed Aldol Condensations
A simple designed synthesis includes one carbonyl compound
with no !-H, which eliminates two of the possible products. An
example is the crossed aldol condensation of benzaldehyde and
acetaldehyde.
To minimize self-condensation of
acetaldehyde, the enolizable carbonyl
is slowly added to a mixture of
benzaldehyde and dilute HO
-
.
CH
O=
benzaldehyde
(no enolizable H)
+ CH
3
CH
O=
dil. HO
-
CHCH
2
CH
O= OH
a directed aldol product
fast
(-H
2
O)
CH=CHCH
O=
cinnamaldehyde
(3-phenyl-2-propen-1-one)
19
Additional examples of directed crossed aldol
reactions using benzaldehyde:
CH
O=
+ HO
-
benzaldehyde
(no enolizable H)
slowly add
CH
3
CCH
3
O=
(-H
2
O)
CH=CHCCH
3
O=
4-phenyl-3-buten-2-one
slowly add
C
6
H
5
CCH
3
O=
(-H
2
O)
CH=CHC
O=
1,3-diphenyl-2-propenone
20
The Acid-Catalyzed Aldol Condensation
The self-aldol reaction of aldehydes and ketones with enolizable-H
also occurs under acid-catalyzed conditions. The nucleophile in the
addition reaction is the enol (not the enolate anion), and the rate of
the addition step is increased by acid catalysis, as shown below.
A Mechanism
acid-catalyzed enol formation
RCCH
3
:O: =
+ H-B
+
fast
RCCH
3
:O-H =
+ B:
+
While only a low
concentration of enol is
present under equilibrium
conditions, it is a reactive
nucleophile.
Overall Reaction
2 RCCH
3
O=
H
+
heat
RCCH
2
CCH
3
O=
R
OH
(-H
2
O)
RCCH=CCH
3
O=
R
RCCH
3
:O-H =
+ B:
+
slow
RC=CH
2
:O-H
:
+ H-B
+
enol
low conc.
21
In general the dehydration
product is formed in the acid
catalyzed mechanism
22
A Directed Intramolecular Aldol Reaction
O
CH
2
CH
2
CCH
3
O=
H
+
O
To understand the selectivity of this reaction, the four possible
reaction pathways need to be evaluated. Also, favorable
intramolecular reactions proceed much faster than comparable
intermolecular reactions.
The acid-catalyzed intramolecular aldol reaction of the diketone
below yields a single product even though four different reaction
pathways are possible.
23
Four Intramolecular Aldol Pathways
OH
CH
2
CH
2
CCH
3
O=
O
CH
3
OH
strained bicyclic
ring system
OH
CH
2
CH
2
CCH
3
O=
O
CH
2
CH
2
C
CH
3
OH
highly strained
spiran system
O
CH
2
CH=CCH
3
OH
CH
2
CH
HO
C=O
CH
3
highly strained
cyclobutane
O
CH
2
CHC=CH
2
OH
OH
O
stable product
24
Claisen-Schmidt Reactions: !,"-Unsaturated Ketones
Crossed aldol reactions where ketones are one component are called
Claisen-Schmidt reactions. These reactions were discovered and
developed by two Germans chemists in the 1880s: J.G. Schmidt and
Ludwig Claisen.
The crossed aldol product is favored over the self-reaction of the
ketones because of the irreversibility of the cross product (a
conjugated enone), while the self-reaction of the ketones is
reversible.
C
6
H
5
CH
O=
benzaldehyde
+ CH
3
CCH
3
O=
HO
-
100
o
C
C
6
H
5
CH=CHCCH
3
O=
4-phenyl-3-buten-2-one
(benzalacetone) 70%
acetone
25
A Mechanism for the Claisen-Schmidt Reaction of
Benzaldehyde and Acetone
enolate anion formation
CH
3
CCH
3
O=
+ HO
-
:CH
2
CCH
3
:O: =
-
CH
2
=CCH
3
:O:
:
-
+ H
2
O
C
6
H
5
CH
=
+
:CH
2
CCH
3
:O: =
-
:O:
nucleophilic addition
C
6
H
5
CH-CH
2
CCH
3
:O: = :O:
:
-
H
2
O
C
6
H
5
CH-CH
2
CCH
3
= O
OH
+ HO
-
aldol
dehydration
C
6
H
5
CH-CHCCH
3
= O
OH
+ HO
-
H
C
6
H
5
CH=CHCCH
3
O=
+ H
2
O+ HO
-
The dehydration step occurs readily.
26
27
28
Additions to !,"-Unsaturated Aldehydes and Ketones
C=C-C-
:O:
=
C=C-C-
:O:
:
+
-
C-C=C-
:O:
:
+
-
C C C
O
!"
!+ !+
Nu:
-
modes of nucleophilic attack
!,"-Unsaturated aldehydes and ketones react with nucleophiles by
simple (1,2) addition, and/or conjugate (1,4) addition. These two
modes of reaction are understandable from an examination of the
resonance structures for a conjugated enone system that shows two
electropositive carbon centers.
29
Reaction Schemes for Simple and Conjugate Additions
C=C-C-
O=
+ Nu:
-
+H
+
simple addition
(1,2-addition)
+H
+
conjugate addition
(1,4-addition)
C=C-C-
O-H
Nu
C-C=C-
O-H
Nu
enol
(initial product)
C-C-C-
Nu
O=
H
ketone
30
Examples
Often both modes of addition compete giving a mixture of 1,2-
and 1,4-addition products.
CH
3
CH=CHCCH
3
O=
(i) CH
3
MgBr
(ii) H
3
O
+
3-penten-2-one
CH
3
CH=CHCCH
3
CH
3
OH
+
CH
3
CHCH
2
CCH
3
O=
CH
3
1,2-addition product
72%
1,4-addition product
20%
While Grignard reagents give mixtures from both addition modes,
organocopper reagents tend to give conjugate addition products.
O=
CH
3
4-methyl-2-cyclohexen-1-one
(i) (CH
3
)
2
CuLi
(ii) H
3
O
+
O=
CH
3
CH
3
O=
CH
3
CH
3
+
98% 2%
(two diastereomers of 1,4-addition)
Only products from conjugate addition are found as a mixture of
diastereomers. The dominant product results from addition from
the less hindered side away from the methyl group in the
4-position.
31
Michael Additions: Conjugate Additions of Enolate Anions
The conjugate additions of enolate anions to !,"-unsaturated
carbonyl compounds are called Michael additions in honor of Arthur
Michael (1853-1942), a Harvard professor who studied these reactions.
The reactions are often carried out in alcohol solvents (ROH) with a
catalytic amount of NaOR to drive the reaction to completion.
C
O=
C
O=
CH
2
pKa ~ 12-14
+ B:
-
C
O=
C
O=
C
:
H
-
+ B-H
enolate anion
resonance stabilized
The enolate anions (nucleophiles) typically used in Michael
additions are derived from 1,3-dicarbonyl compounds, and other
systems with pK
a
values close to 12-14.
32
The Michael Addition of Diethyl Malonate to 3-Buten-2-one
H
2
C
CO
2
Et
CO
2
Et
diethyl malonate
pKa = 12.9
+ CH
2
=CHCCH
3
O=
3-buten-2-one
(methyl vinyl ketone)
cat. NaOEt
EtOH
CH
2
-CH
2
CCH
3
O=
CH
EtOOC
EtOOC
65%
A Mechanism
A catalytic amount of NaOEt produces a low
concentration of the anion of diethyl malonate.
CH
2
(CO
2
Et)
2
+ NaOEt
pKa = 12.9
Na
+ -
CH(CO
2
Et)
2
+ HOEt
pKa = 15.9
generation of nucleophile
CH
2
-CH-CCH
3
O
CH
EtOOC
EtOOC
-
simple enolate anion
conjugate addition
Na
+ -
CH(CO
2
Et)
2
+ CH
2
=CH-CCH
3
O=
33
The overall energetics for the Michael addition are
favorable, and the reaction goes to completion,
because the carbon-carbon !-bond formed is
stronger than the carbon-carbon "-bond that is lost.
protonation and regeneration of nucleophile
CH
2
-CH-CCH
3
O
CH
EtOOC
EtOOC
-
+ CH
2
(CO
2
Et)
2
pKa = 12.9
CH
2
-CH=CCH
3
CH
EtOOC
EtOOC
OH
enol
+
Na
+ -
CH(CO
2
Et)
2
nucleophile regenerated
CH
2
-CH=CCH
3
CH
EtOOC
EtOOC
OH
enol
ketone-enol equilibration
CH
2
-CH
2
CCH
3
O=
CH
EtOOC
EtOOC
ketone
(stable product)

34
The Robinson Annulation
CH
3
H
O
=
2-methyl-1,3-cyclohexadione
+ CH
2
=CHCCH
3
O
=
HO
-
CH
3
OH
CH
3
O
=
CH
2
CH
2
CCH
3
O
=
Michael addition
O
O
The addition product reacts further by way of an
intramolecular aldol condensation:
CH
3
O
=
CH
2
CH
2
C=O
CH
3
+ HO
-
O
CH
3
O
=
CH
2
-CH
2
C=O
CH
2
:
-
enolate anion
O
CH
3
O
=
O
CH
2
-CH
2
C=O
CH
2
-
CH
3
O
=
O
CH
2
-CH
2
C=O
CH
2
H
CH
3
OH
(-H
2
O)
O
=
CH
3
65%
dehydration
O
35