Organic Chemistry Text Book (CHEM 3401 and 3402)

A useful carbon-carbon bond-forming reaction known as the Aldol Reaction or the Aldol Condensation is yet another example of electrophilic substitution at the alpha carbon in enols or enolate anions. Three examples of the base-catalyzed aldol reaction are shown in the following diagram, and equivalent acid-catalyzed reactions also occur. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. By clicking the "Structural Analysis" button below the diagram, a display showing the nucleophilic enolic donor molecule and the electrophilic acceptor molecule together with the newly formed carbon-carbon bond will be displayed. Stepwise mechanisms for the base-catalyzed and acid-catalyzed reactions may be seen by clicking the appropriate buttons.

 

 

In the presence of acid or base catalysts the aldol reaction is reversible, and the beta-hydroxy carbonyl products may revert to the initial aldehyde or ketone reactants. In the absence of such catalysts these aldol products are perfectly stable and isolable compounds. Because of this reversibility, the yield of aldol products is related to their relative thermodynamic stability. In the case of aldehyde reactants (as in reactions #1 & 2 above), the aldol reaction is modestly exothermic and the yields are good. However, aldol reactions of ketones are less favorable (e.g. #3 above), and the equilibrium product concentration is small. A clever way of overcoming this disadvantage has been found. A comparatively insoluble base, Ba(OH)₂, is used to catalyze the aldol reaction of acetone, and the product is removed from contact with this base by filtration and recirculation of the acetone.

A. Dehydration of Aldol Products

The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this beta-elimination reaction is an α,β-unsaturated aldehyde or ketone, as shown in the following diagram. Acid-catalyzed conditions are more commonly used to effect this elimination (examples #1, 2 & 5), but base-catalyzed elimination also occurs, especially on heating (examples #3, 4 & 5). The additional stability provided by the conjugated carbonyl system of the product makes some ketone aldol reactions thermodynamically favorable (#4 & 5), and mixtures of stereoisomers (E & Z) are obtained from reaction #4. Reaction #5 is an interesting example of an intramolecular aldol reaction; such reactions create a new ring. 
Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water are termed Condensations. Hence the following examples are properly referred to as aldol condensations. The dehydration step of an aldol condensation is also reversible in the presence of acid and base catalysts. Consequently, on heating with aqueous solutions of strong acids or bases, many α, β-unsaturated carbonyl compounds fragment into smaller aldehyde or ketones, a process known as the retro-aldol reaction.

 

 

The acid-catalyzed elimination of water is not exceptional, since this was noted as a common reaction of alcohols. Nevertheless, the conditions required for the beta-elimination are found to be milder than those used for simple alcohols. The most surprising aspect of beta-elimination, however, is that it can be base-catalyzed. In earlier discussions we have noted that hydroxyl anion is a very poor leaving group. Why then should the base-catalyzed elimination of water occur in aldol products? To understand this puzzle we need to examine plausible mechanisms for beta-elimination, and these will be displayed by clicking the "Beta-Elimination Mechanism" button under the diagram.
As shown by the equations, these eliminations might proceed from either the keto or enol tautomers of the beta-hydroxy aldol product. Although the keto tautomer route is not unreasonable (recall the enhanced acidity of the alpha-hydrogens in carbonyl compounds), the enol tautomer provides a more favorable pathway for both acid and base-catalyzed elimination of the beta oxygen. Indeed, the base-catalyzed loss of hydroxide anion from the enol is a conjugated analog of the base-catalyzed decomposition of a hemiacetal. 

B. Mixed Aldol Condensations

The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective. Some examples are shown below, and in most cases beta-elimination of water occurs under the conditions used. The exception, reaction #3, is conducted under mild conditions with an excess of the reactive aldehyde formaldehyde serving in the role of electrophilic acceptor. The first reaction demonstrates that ketones having two sets of alpha-hydrogens may react at both sites if sufficient acceptor co-reactant is supplied. The interesting difference in regioselectivity shown in the second reaction (the reactants are in the central shaded region) illustrates some subtle differences between acid and base-catalyzed aldol reactions. The base-catalyzed reaction proceeds via an enolate anion donor species, and the kinetically favored proton removal is from the less substituted alpha-carbon. The acid-catalyzed aldol proceeds via the enol tautomer, and the more stable of the two enol tautomers is that with the more substituted double bond. Finally, reaction #4 has two reactive alpha-carbons and a reversible aldol reaction may occur at both. Only one of the two aldol products can undergo a beta-elimination of water, so the eventual isolated product comes from that reaction sequence. The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.

The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.

ACH₂CHO   +   BCH₂CHO   +   NaOH      A–A   +   B–B  +  A–B   +   B–A