Lecture Notes
Chemistry 342-2008
Lecture 33
Mukund P. Sibi
Intramolecular Aldol Reactions
When two carbonyl groups are present in the same molecule, it is possible to carry out an
intramolecular aldol reaction. All the general rules applicable for an intermolecular (self
or cross) aldol reaction are also applicable to the intramolecular variant. The reaction
allows for the formation of ring structures.
Both aldehydes and ketones participate in the intramolecular aldol reaction. The
mechanism is the same as the intermolecular reaction. An example of intramolecular
aldol reaction is shown below.
O
O
CH3
H3C
NaOH
Ethanol
Cyclic !,"-Unsaturated
Ketone
O
1,4-Diketone
O
O
O
H3C
CH3
NaOH
Ethanol
Cyclic !,"-Unsaturated
Ketone
1,5-Diketone
O
O
CH3
H
O
1,4-Ketoaldehyde
NaOH
Ethanol
Cyclic !,"-Unsaturated
Ketone
You will note that there are multiple enolates one could form with the starting materials.
These could lead to different products. However, the reaction is under equilibrium and
the most stable product is always formed. In the example below, the three-membered ring
is not formed because of strain. The five-membered ring on the other hand is not strained
and is the product of the reaction.
H 2C
O
H 3C
H
H O
O
O
O
-H2O
CH3
H
H O
HO
CH3 NaOH
Ethanol
O
O
CH3
H 3C
H
O
O
CH3
H 3C
H
H3C
CH3
OH
Claisen Condensation
The hydrogens on the alpha carbon of esters are less acidic (pKa = 25) than those on
aldehydes and ketones (pKa = 17-19). Esters undergo self condensation under basic
conditions to give β-keto esters. This reaction is called the Claisen condensation. A
simple example is shown. The reaction requires one equivalent of the base. The reaction
Lecture Notes
Chemistry 342-2008
Lecture 33
Mukund P. Sibi
is under equilibrium except for the last step. Thus the reaction is driven towards the
product.
O
2
H3C
O
O
1. NaOCH3
CH3
O
H3C
CH3OH
2. H3O+
CH3
O
+ CH3OH
Methyl acetoacetate
The mechanism of the reaction is similar to aldol condensation except that in this case the
tetrahedral intermediate formed after nucleophile addition to an ester carbonyl eliminates
an alkoxide molecule to form a carbonyl group. Once the β-keto ester is formed, the
alkoxide will deprotonate the acidic hydrogen to form the enolate. This equilibrium is
towards the product and thus the reaction.
O
H 3C
O
H3C
O
NaOCH3
H 3C
CH3
O
O
C
O
CH3
O
H3C
CH2
O
+ CH3OH
O
H 3C
O
O
O
H3CO -
H3C
CH3
H H
O
OCH3
H H CH3
O
O
CH3
+ H3COH
H
+ H3CO -
Mixed Claisen Condensation:
Two different esters undergo Claisen condensation under basic conditions. Just like in the
case of aldol reactions, mixed Claisen condensation work well when one of the reactants
is an ester that contains no α- hydrogens. In other words, only one of the esters should be
converted to a nucleophile and not both.
O
H3CO
O
CH3
Nucleophile
+
O
C
O
NaOCH3
OCH3
Electrophile
H3CO
O
C
O
H H
!-Keto Ester
no "-CH
Ketone enoaltes can also be condensed with esters to form 1,3-diketones. The reactions
work best if the electrophile (ester) does not contain α- hydrogens. Ethyl formate can be
used in the preparation of β-keto aldehydes.
Lecture Notes
Chemistry 342-2008
Lecture 33
O
H
O
C
O
+
H
O
O
C
NaOCH3
O
OCH3
Electrophile
Nucleophile
Mukund P. Sibi
1,3-Diketones
no !-CH
O
O
H
H
O
+
H
OC2H5
Ethyl Formate
NaOCH2CH3
O
H
"-Keto Aldehyde