Lecture 5
'Crossed' aldol condensations - reaction between two different
aldehydes
'Crossed' aldol condensations normally produce four different addition
products - and hence four different dehydration products.
Consider the possibilities for the reaction:
O
O
C
H3C
C
+
H
OH
CH3CH2
H
Aldol condensation
O
Self-condensation of
C
H3C
H
OH
CH3
O
CH CH2 C
H
O
Self-condensation of
C
CH3CH2
H
OH
CH3CH2
C
H3C
CH CH C
C
+
H
Electrophile
H
CH3
O
O
O
CH3CH2
H
Nucleophile
(enolate)
OH
CH3
O
CH CH C
H
CH3
O
C +
CH3CH2
H
Electrophile
O
C
H3C
H
Nucleophile
(enolate)
OH
CH3CH2
Complex mixtures - often difficult to separate.
O
CH CH2 C
H
Revision: The aldol condensation:
O
O
H2C
H
CH3
-
H2 C
Partial deprotonation only pKa ca. 20
OH
Low equilibrium
concentration of
the enolate anion
O
_
H2 C
Nucleophilic site
H3C
O Š
+
C
H
CH3
Š
O
_
H2C
+ H2 O
CH3
C
CH3
H
O
O
C
CH2 C
H
H
Electrophilic site
New C-C bond
formed
OH
CH3CHO + CH3CHO
Base
H2O
CH3
C
O
C C
H2
H
H
Aldol
Base - H2O
-Unsaturated aldehyde
O
H
CH3
C
H
Electrophile
O
H
C
H
C
O
Š H2O
H
Nucleophile
CH3
C
H

C
H

C
H
Consider the possibilities for the 'crossed' or 'mixed' aldol
condensation of acetaldehyde and propionaldehyde under basic
conditions:
O
C
H3C
O
OHŠ
C
+
H
H CH3 CH2
O
OH
C
Self-condensation of
Aldol condensation
CH3
H3 C
Self-condensation of
H3 C
OH
C
CH3CH2
CH3 CH2
H
CH3CH2
Electrophile
CH3
CH3
H
O
CH CH C
H
CH3
OH
O
+
C
H
Electrophile
H
Nucleophile
(enolate)
O
CH3 CH2
O
OH
C
+
H
CH CH C
H
O
C
CH CH2 C
H
O
O
O
CH3 CH2
C
H3C
O
CH CH2 C
H
Nucleophile
(enolate)
Mixture of four products - difficult to separate.
H
How can we control the selectivity of 'crossed' aldol condensations?
(A) Use one carbonyl compound which has no enolisable hydrogens e.g. benzaldehyde, C6H5CHO or trimethylacetaldehyde, (CH3)3CCHO.
This component can only act as the electrophile in the reaction:
O
C
+ CH 3CHO
OH
-
H
O
C6H5
O
H
+
CH3
'crossed' condensation
H
self-condensation
The probability that acetaldehyde (via the derived enolate) will react
with the un-enolisable component (i.e. benzaldehyde in the example)
rather than with itself can be enhanced by using an excess of
benzaldehyde.
Quite good yields of the 'crossed' product can be
obtained in this manner.
(B) Condense an aldehyde with a ketone.
Since the Keq for self-
condensation of ketones is quite unfavourable this will favour the
'crossed' product. If, in addition, the aldehyde is not enolisable very
good yields of a single product can be obtained.
O
O
O
OH
C
Ph
H
Ph
+
H
Major product
(C) Use a pre-formed enolate anion:
O Li+
O
LDA
Quantitative - no ketone
remains for self-condensation
O Li+
O
O Li+
O
C
C
H
H
Ph
Ph
H2O
O
H
O
C
Ph
OH
- H2O
OH
C
Ph
H
Aldol condensations with unsymmetrical ketones - regioisomeric
enolate anions:
O
O
C
H 3C
CH3
CH2
-
O
C
H 2C
CH2
Kinetically
favoured
Inequivalent protons - hence
two isomeric
enolates.
CH3
-
C
H 3C
CH
CH3
Thermodynamically
favoured
PhCHO
OH
O
O
Ph
Ph
- H 2O
O
- H2O
O
Ph
Ph
OH
Intramolecular Aldol Condensations - a useful synthesis of cyclic
organic molecules
- O
+
C
O
C
CH3
Electrophile
CH3
Base
C
CH3
O
OH CH
3
C
H
C
H
C
O
- H 2O
CH3
C
CH
C
O
C
_
CH2
O
Nucleophile
O
H 2O
OH
CH3
C
CH2
C
O
Notice that the overall reaction here - and in any aldol condensation - is
a dehydration - the two aldehyde/ketone structures become united with
the splitting out of a small molecule - water - i.e. a condensation:
O
C
CH3
CH3
C
Base
CH
H
C
C
New bonds
+ H2O
C
O
H
H
O
Intramolecular aldol condensation between ketones are more
favourable than intermolecular condensation provided that unstrained e.g. 5-membered or 6-membered - rings are formed:
O
O
OH
- H2 O
O
OH
-
- H+
O
_
O
Regioisomeric enolate anions - potential for mixtures of isomers with
differently-sized rings. Entropic factors favour 5- and 6-carbon rings
over those with 7 or more carbons:
O
O
B:
_
O
O
O
O
O
B:
_
O
O
O
Ring-strain factors favour 5- and 6-carbon rings over those with 3 or 4
carbons
O
O
O
B:
O
_
O
O
O
O
B:
O
_
O
Dialdehydes also undergo intramolecular aldol condensations:
O
O
OH
H
_ H
H
pKa ca. 20
H
O
O
O
O
OH
_ H
H
-
H
H
O
O
H 2O
H
OH
H
OH
- H 2O
H
O
H
H
OH
O
Identifying the original reactants from aldol condensation products:
From electrophile
- carbonyl group
O
O
H
C
C
H3C
CH3
C
H
CH2
H2O
H
C
C
H3C
CH2 O
H
CH2
From nucleophile
- enol or enolate
O
O
HC
H
H2C
H2O
O
CH3