Aldol Addition Product

This result is not surprising, because we know that the equiUbrium for an aldol addition (the reverse of the reaction above) is not favorable when the enolate adds to a ketone. Bnt, as mentioned earlier, dehydration of an aldol addition product can draw the equilibrium forward. We shall discuss the dehydration of aldols next (Section 19.4C). 

The carbon-carbon bond cleavage step in a retro-aldol reaction involves, under basic conditions, a leaving group that is an enolate, or under acidic conditions, an enol. Write a mechanism for the retro-aldol reaction of 4-hydroxy-4-methyl-2-pentanone under basic conditions (shown above). 

4C Aldol Condensation Reactions Dehydration of the Aldol Addition Product 

Dehydration of an aldol addition product leads to a conjugated a,/8-unsaturated carbonyl system. The overall process is called an aldol condensation, and the product can be called an enal (alkene a/dehyde) or enone (alkene ketone), depending on the carbonyl group in the product. The stability of the conjugated enal or enone system means that the dehydration equilibrium is essentially irreversible. For example, the aldol addition reaction that leads to 3-hydroxybutanal, shown in Section 19.4, dehydrates on heating to form 2-butenal. A mechanism for the dehydration is shown here. 

The double bonds of the alkene and carbonyl groups are conjugated, stabilizing the product. 

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Hydroxy 2 propylheptanal (aldol addition product of pentanal)... 

Conjugation of the newly formed double bond with the carbonyl group stabilizes the a p unsaturated aldehyde provides the driving force for the dehydration and controls Its regioselectivity Dehydration can be effected by heating the aldol with acid or base Normally if the a p unsaturated aldehyde is the desired product all that is done is to carry out the base catalyzed aldol addition reaction at elevated temperature Under these conditions once the aldol addition product is formed it rapidly loses water to form the a p unsaturated aldehyde... 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

To illustrate how aldol condensation may be coupled to functional group modifi cation consider the synthesis of 2 ethyl 1 3 hexanediol a compound used as an insect repellent This 1 3 diol is prepared by reduction of the aldol addition product of butanal... 

Mixed aldol condensations can be effective only if we limit the number of reaction pos sibilities It would not be useful for example to treat a solution of acetaldehyde and propanal with base A mixture of four aldol addition products forms under these condi tions Two of the products are those of self addition... 

Use curved arrows to show the carbon-carbon bond forming processes that lead to the four aldol addition products just shown J... 

Efforts were made by Garcia Gonzalez and his coworkers to elucidate the mechanism of this reaction. In one of the working hypotheses, it was considered that the aldehydo form of the sugar and the 1,3-dicarbonyl compound undergo an aldol reaction to yield a 2-C-(alditol-l-yl)-l,3-dicar-bonyl compound, which is then dehydrated to form the furan. This hypothesis was supported by the isolation of the aldol-addition product of... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

The aldol reaction has been known for over a century. Though largely attributed to Wilrtz, the first aldol reaction was reported several years earlier by Borodin.81 813 Stimulated by the observation that (Z)- and (A)-enolates react stereospecifically to provide syn- and //////-aldol addition products, several catalytic systems for aldol addition... 

The description of a stereoselective reaction primarily requires characterization of enantiomeric and/or diastereomeric products by their configuration (not their stereochemistry , see Introduction). Problems have not arisen with enantiomers but difficulties (see enumerations in refs 1 and 2) are. or perhaps were, apparent for diastereomers, a focal point having been acyclic compounds, in particular aldol addition products. These are pertinent examples to illustrate the problems and their various solutions very well ... 

SAMPLE SOLUTION (a) A good way to correctly identify the aldol addition product of any aldehyde is to work through the process mechanistically. Remember that the first step is enolate formation and that this must involve proton abstraction from the a carbon. 

Figure 17-3 Apparatus for the preparation of monohydroxymethylene aldol-addition products from methanal and carbonyl compounds with more than one a hydrogen...

An important property of aldol addition products is the ease with which they eliminate water in the presence of either acids or bases. For example, when 3-hydroxybutanal is heated in the basic solution in which it is formed (by aldol addition of ethanal), 2-butenal results ... 

The most generally useful preparation of a,/3-unsaturated carbonyl compounds is by dehydration of aldol addition products, as described in Section 17-3D. Conjugation of the carbonyl group and double bond has a marked influence on spectroscopic properties, particularly on ultraviolet spectra, as the result of... 

Dehydration of the aldol addition product involves loss of a proton from the a-carbon atom and hydroxide from the /3-carbon atom. 

This enolate adds to the carbonyl group of benzaldehyde to give the mixed aldol addition product, which then dehydrates under the reaction conditions. 

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