The addition of an enolate to an aldehyde or ketone is called the aldol reaction. In the classical aldol reaction, compounds 1 and 2 are aldehydes or ketones. However, there are closely related reactions where compound 1 is an aldehyde, ketone, ester, anhydride, or nitrile. The aldol and related reactions are base-catalyzed, but in some cases it is possible to use acid catalysis. b-hydroxyaldehyde 3, which is called an aldol, may be dehydrated under the reaction conditions to give a,b-unsaturated carbonyl compound 4 if R2 or R3 is an hydrogen atom. The aldol reaction is an equilibrium, which may lie to the right or to the left depending on circumstances (see below).
The aldol reaction may occur between two molecules of the same aldehyde or the same ketone, or between different molecules (crossed aldol reaction). There are five possibilities:
Two molecules of the same aldehyde. This is the classical case: there is only one product (or two, considering the dehydrated product) and the equilibrium lies far to the right.
Two molecules of the same ketone. In this case the equilibrium lies to the left, but it can be shifted by using appropiate reaction conditions, such as continuous extraction. If the ketone is unsymmetrical the condensation might occurr on either side, giving a mixture of products. In practice, the condensation occurs usually on the side that has more hydrogens (that is, the kinetic enolate is formed).
Two different aldehydes. In general a mixture of four products is obtained (eight counting the dehydration products). However, if one of the aldehydes does not have a hydrogens (e.g., benzaldehyde), only two products are obtained, and in many cases the crossed product is the main one. The crossed aldol reaction is often called the Claisen-Schmidt reaction.
Two different ketones. This is the most problematic case, but it can be done if one of the ketones is transformed first into a preformed enolate.
An aldehyde and a ketone. This is usually feasible because aldehydes are stronger enolates than ketones, so usually it is the a carbon of the ketone the one which adds to the aldehyde. This reaction is also called the Claisen-Schmidt reaction. To insure regioselectivity when using unsymmetrical ketones it is necessary to use preformed enolates.
Other problems that may occur with the aldol reaction include polycondensation and undesirable Michael Additions if the product is dehydrated. The aldol reaction may be used intramolecularly to close five- and six-membered rings, like in the Robinson annulation reaction.
Stereoselectivity: this reaction may be carried out stereoselectively by using a chiral auxiliary group such as oxazolidinone derivatives and/or asymmetric aldehydes or ketones. This requires the use of preformed enolates with a certain geometry (E/Z) which can be obtained by varying the reaction conditions (termodynamic vs kinetic).
March, J. Advanced Organic Chemistry, 4th ed., reactions 6-39, 6-40, 6-41
More information about the aldol condensation
An introduction to the aldol reaction
A quick quiz about aldol condensations
Organic Reactions at Penn State - Includes 49 reactions, including aldol condensation (reaction number 29).
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OSET Project Organic Reactions Index
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