Carbonyl Condensation Reactions
These are combination reactions: carbonyl -substitutions
+ carbonyl nucleophilic additions or substitutions. Usually,
a carbonyl molecule is converted to an enolate anion
(nucleophile) which attacks a second carbonyl molecule in
an addition or substitution reaction. The archetype
reaction is the aldol reaction.
O
+
C
O
C
C
C
H
-substitution
here
nucleophilic
addition
here
1
H
Aldol Condensation —
General for aldehydes and ketones with an -hydrogen.
This is an equilibrium reaction: product is favored for
acetaldehyde and monosubstituted acetaldehyde
(R-CH2-CHO) but reactants are favored for disubstituted
acetaldehyde (RR'CH-CHO) and most ketones.
O
H
H
C
+
C H
H
-substitution
here
NaOH
H2O
O
C
H
C
H H
nucleophilic
addition
here
H
equilibrium favorable
for product: aldol
Mechanism —
O
H
O
H
C
+ NaOH
H2O
C H
H
H
C
H
H
O
H
H
C
C
H
+ H2O
C
+
O
C
H
C
H H
2
H2 O
H
O
C
C
H H
H
+ OH
Other Examples —
O
H
H
C
+
C H
O
NaOH
H2O
H
C
C
H
H 10%
90%
O
O
78%
NaOH
+
H
H 2O
22%
O
H3C
H
C
C H
H
+
O
NaOH
H 2O
H3C
5%
95%
C
H
H H
C
The yield of the product in this case, diacetone alcohol, is quite poor owing
to the unfavorable equilibrium constant (Keq = 0.05). Improving the
situation by distilling off the product (to sidestep around the unfavorable
equilibrium constant problem) is not an option here because the boiling
point of the product is much higher than that of acetone (it is twice the
molecular weight of acetone and, with its -OH group, can hydrogen bond
as donor and acceptor).
3
On the other hand, if somehow the diacetone alcohol, but not the acetone,
could be kept away from the base that catalyzes the reaction, the reverse
reaction would become very slow. This would lead to a satisfactory yield.
So, the idea is to separate some acetone from the diacetone alcohol,
expose it to base for a while, then return the acetone - diacetone alcohol
mixture to the bulk mixture which is not exposed to base. And do this over
and over again until the conversion is complete, or nearly so. But, how?
Enter the Soxhlet extractor. It was
designed to be used for extracting
natural products from their botanical
sources. In this reaction, acetone is
placed in the round-bottom flask. The
filter-paper thimble is charged with
barium hydroxide, a base that is not
soluble in the compounds involved in the
reaction. When the acetone boils its
vapors pass up the large exterior tube of
the extractor to the condenser, where
they are condensed. Warm liquid
acetone drips into the chamber that
contains barium hydroxide in the paper
thimble. A small amount of diacetone
alcohol forms. When the chamber fills to
the top of the small exterior tube the
liquid in the chamber siphons to the
round-bottom flask through this tube.
Boiling continues, the chamber fills with
more acetone (the acetone is more
volatile than the diacetone alcohol),
some of this is converted to diacetone
alcohol, and the chamber empties into
Soxhlet Extractor
the round-bottom flask. Over and over
again — this is an automated process
sans computer or moving parts. Meanwhile, in the round-bottom flask very
little reaction takes place because there is no catalyst there. Eventually,
the acetone is converted to diacetone alcohol in very good yield.
4
If the carbonyl compound does not have an -hydrogen it
cannot form an enolate anion and cannot undergo the
aldol reaction. However, aldehydes, w/o an -hydrogen
can undergo the Cannizzaro reaction in concentrated
aqueous base.
How about competition between a simple substitution
and a condensation? For example, suppose I want to
make 2-methyl-3-phenylpropanal by alkylation of propanal
with benzyl bromide —
base
Ph-CH2Br + CH3CH2CHO > Ph-CH2-CH2(CH3)CHO
Will the propanal undergo an aldol reaction instead?
Well....
This will probably depend on the conditions of the reaction.
If the propanal is reacted with LDA and quickly converted
(almost) completely to enolate anion, it will not be able to
undergo an aldol reaction. The enolate can then be added
to benzyl bromide to form 2-methyl-3-phenylpropanal. On
the other hand, if a small amount of KOH is added to a
mixture of propanal and benzyl bromide, a small
equilibrium concentration of propanal enolate would be
formed, which could react with either propanal or benzyl
bromide, giving both products. [To complicate this
situation even further, the OH- could react with the benzyl
bromide giving benzyl alcohol.]
5
Dehydration of Aldols —
Aldols are alcohols and alcohols can undergo dehydration
under acidic conditions, eg warming t-butyl alcohol,
(CH3)3COH, with acid gives isobutylene, CH2=C(CH3)2.
Aldols are enolized in acid and easily dehydrate to give the
conjugated enone —
H
O
C
C
H H
+
C
H
C
H
C
H O
H3O
H
H O
H
H
C
H
+
H3O
H
H
H
O
+
C
H
C
H
6
H
H
Ordinary alcohols are not dehydrated under basic
conditions (E2) owing to OH- being a poor leaving group.
However, aldols do undergo dehydration under basic
conditions via an enolate anion —
O
H
C
C
H H
H
OH
O
-
H
C
C
H
H
O
H
C
C
H
+
H
Consequently an aldol may spontaneously dehydrate to a
conjugated enone as it is formed, especially if reaction
conditions are pushed, eg high temperature.
Mixed or "crossed" Aldol Reactions —
If two different carbonyl compounds are allowed to react in
an aldol reaction four products usually result; each
carbonyl compound forms an enolate and each enolate
forms two aldols, one with the carbonyl compound from
which it was formed and one with the other carbonyl
compound.
7
However —
if one component does not have any -hydrogens (eg
formaldehyde, benzaldehyde), and has an
electrophilic carbonyl group, a good yield of one
cross-product may be obtained. The carbonyl
compound having the hydrogen(s) is slowly added
to a basic solution of the one which does not.
O
O
O
H
H3C
H
H
H
When the aldol product can form
an enone in which the C-C double
bond is further conjugated, dehydration
is usually spontaneous.
O
NaOEt
EtOH
H3C
NaOEt
EtOH
+
OH
H3 C
+ NaOH
Chem 221 Experiment, Preparation of Dibenzalacetone—
O
C +
H
OH
C
H
O
NaOH
H2O
+ C
H
OH
C
C
H
H
8
C
H
if one component is especially acidic it will
"completely" convert to enolate and this enolate will
make a nucleophilic attack on the other compontent.
O
EtO C
O
O
CH2 C OEt NaOEt
EtOH
EtO C
O
CH C OEt
Na
O
EtO C
O
CH C OEt
O
O
NaOEt
EtOH
+
EtO C
O
C
C OEt
Na
Unsaturated aldehydes and ketones can be reduced to
give saturated aldehydes and ketones with Pt/H2. They
can also be reduced to saturated alcohols with LAH or
unsaturated alcohols with NaBH4.
9
Reactions Related to the Aldol Condensation
These two examples are mixed or crossed reactions of the
aldol type in which one component does not have αhydrogens.
Perkin Condensation —
RCH2CO Na
Ar
C O + (RCH2C)2O
H
O
Ar CH CH C O C
OH R
O
RCH2CO Na
O
CH2R
Ar CH C C O C
O
Ar CH C C O C
R O
O
R O
CH2R
H2O
CH2R
O
Ar CH C C OH + HO C
R O
O
CH2R
O
Knoevenagel Reaction —
This is a reaction between aldehydes or ketones not
containing an a-hydrogen and a compound of the type
Z-CH2-Z’ or Z-CHR-Z’, where Z and Z’ are electron
withdrawing.
Ar
C
O +
H2C(COOC2H5)2
2o amine
Ar
C
H
H
10
C(COOC2H5)2
R
C
L + R
CH2 Z
:B
R
O
C
CHZ + :L +
HB
O R
C
Z=
CN
NO2
CF3
O
Claisen Condensation: synthesis of -ketoesters —
2 RCH2
C OEt + NaOEt
EtOH
RCH2
C
Na
C C OEt + 2 C2H5OH
O R O
O
11
Mechanism —
RCH2
C OEt + NaOEt
Na
CH C OEt + HOEt
EtOH
O
R
Na
C OEt + CH C OEt EtOH
RCH2
O
EtOH
RCH2
R
C
O
RCH2
O
Na
C
CH C OEt
OEt R
CH C OEt + NaOEt
O R
O
O
EtOH
O
Na
C C OEt + C2H5OH
It is only in this last step --RCH2 C
the formation of the -ketoester
O R O
salt --- that the equilibrium is
favorable. This step pulls the overall reaction. Consequently esters which
do not have 2 protons do not undergo this reaction.
Dieckmann Condensation —
This is just an intramolecular Claisen condensation.
O
EtO C (CH2)4
O
C OEt
NaOEt
H3 O
+
O
C OEt
O
This reaction is good for making compounds of 5, 6, or 7
membered rings and rings of more than 12 carbons.
12
Mixed or Crossed Claisen Condensations —
Generally useful only when one of the reactants has no hydrogens (cf. mixed aldol condensations).
O
O
EtO
EtO
C
CH2 C
+
OEt
O
O
C
CH C
OEt
OEt
NaOEt
This is phenylmalonic ester. It cannot
be made by reacting sodiomalonic
ester with an aryl halide
+ HOEt
13
The Michael Addition Reaction —
nucleophilic addition of (typically stable) enolate anions to
-unsaturated carbonyl compounds.
CH CH C OEt + NaOEt
EtOH
O
CH CH C OEt +
O
CH CH C OEt
CH CH C OEt
O
O
CH CH2 C OEt +
+ EtOH
EtO
O
Another example —
H
H
CH3
C C
H
COOEt
+
NaOEt
EtOH
CH3
H C C H
COOEt
14