Mixed Aldol Condensations

Know the meaning of keto form, enol form, tautomers, tautomerism, enolate anion, a-hydrogen and a-carbon, aldol condensation, mixed aldol condensation. 

As was the case with the aldol condensation, mixed ester condensations can be useful if one of the components can only act as the electrophile—that is, if it cannot form an enolate anion (no hydrogens on the o-carbon). The following esters are most commonly employed in this role ... 

Analogous to mixed aldol condensations, mixed Claisen condensations involve carbon-carbon bond formation between the a-carbon atom of one ester and the carbonyl carbon of another. 

The carbon-carbon bond forming potential of the aldol condensation has been extended beyond the self condensations described in this section to cases in which two different carbonyl compounds react m what are called mixed aldol condensations... 

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... 

The mixed aldol condensations that are the most synthetically useful are those m which... 

Give the structure of the mixed aldol condensation product of... 

As actually carried out the mixed aldol condensation product 1 3 diphenyl 2 propen 1 one has been isolated in 85% yield on treating benzaldehyde with ace tophenone in an aqueous ethanol solution of sodium hydroxide at 15-30°C... 

Mixed aldol condensations in which a ketone reacts with an aromatic aldehyde are known as Claisen-Schmidt condensations... 

Kelkar and McCarthy (1995) proposed another method to use the feedforward experiments to develop a kinetic model in a CSTR. An initial experimental design is augmented in a stepwise manner with additional experiments until a satisfactory model is developed. For augmenting data, experiments are selected in a way to increase the determinant of the correlation matrix. The method is demonstrated on kinetic model development for the aldol condensation of acetone over a mixed oxide catalyst. 

Aromatic aldehydes cannot fonn enolates, and a large number of mixed aldol condensations have been cariied out in which an aromatic aldehyde reacts with an enolate. 

Mixed Claisen condensations aie analogous to mixed aldol condensations and involve carbon-caibon bond fonnation between the a-caibon atom of one ester and the carbonyl car bon of another. 

G If one of the carbonyl partners is much more acidic than the other and so is transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful. Ethyl acetoacetate, for instance, is completely converted into its enolate ion in preference to enolate ion formation from monocarbonyl partners. Thus, aldol condensations of monoketones with ethyl acetoacetate occur preferentially to give the mixed product. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

Cinnamaldehyde, the aromatic constituent of cinnamon oil, can be synthesized by a mixed aldol condensation. Show the starling materials you would use, and write the reaction. 

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

The synthesis in Scheme 13.5 also makes use of an aromatic starting material and follows a retrosynthetic plan similar to that in Scheme 13.3. The starting material was 4-methoxybenzaldehyde. This synthesis was somewhat more convergent in that the entire side chain except for C(14) was introduced as a single unit by a mixed aldol condensation in step A. The C(14) methyl was introduced by a copper-catalyzed conjugate addition in Step B. 

Mixed Aldol Condensations with Aromatic Aldehydes... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Scheme 2.2 presents some representative examples. 

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. 

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol condensations (Section 2.1.2) One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations which work most effectively involve one ester that cannot form an enolate but that is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples are shown in Section C of Scheme 2.13. 

The addition of the nucleophilic carbanion-enolate, usually of an aldehyde, to the C=0 group of its parent compound is called an aldol condensation. The product is a /3-hydroxycarbonyl compound. In a mixed aldol condensation the carbanion-enolate of an aldehyde or ketone adds to the 0=0 group of a molecule other than its parent. The more general condensation diagramed above is termed an aldol-type condensation. Since the C, not the O, is the more reactive site in the hybrid, the enolate contributing structure is usually omitted when writing equations for these reactions. This is done even though the enolate is the more stable and makes the major contribution. 

Problem 17.27 Mixed aldol condensations are useful if (a) one of the two aldehydes has no a H, (b) a symmetrical ketone reacts with RCHO. Explain and illustrate. 4... 

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