Mixed aldol

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... 

Indeed formaldehyde is so reactive toward nucleophilic addition that it suppresses the self condensation of the other component by reacting rapidly with any enolate present Aromatic aldehydes cannot form enolates and a large number of mixed aldol con densations have been carried out m which an aromatic aldehyde reacts with an enolate... 

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... 

A mixed aldol condensa tion in which an aromatic aide hyde reacts with an enolizable al dehyde or ketone... 

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

Thus mixed aldol additions can be achieved by the tactic of quantitative enolate for matron using LDA followed by addition of a different aldehyde or ketone... 

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. 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

A conveniently short synthesis of a1prostadi1 begins with a mixed aldol assembly of the requisite cyclopentenone 13. This product is then oxidatively cleaved with periodate-permanganate and the alcohol moiety is protected as the tetra-hydropyranyl ether (14). Aqueous chromous sulfate satisfactorily reduces the olefinic linkage and the trans stereoisomer 15 predominates after work-up. The remainder of the synthesis of involves the usual steps, through 16 to with the exception that thexyl tetrahydrolimonyllithium borohydride is used to reduce the C-15 keto moiety so as to produce preferentially the desired C-15S stereochemistry. 

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

Until now, we ve considered only symmetrical aldol reactions, in which the two carbonyl components have been the same. What would happen, though, if a mixed aldol reaction were carried out between two different carbonyl partners ... 

In general, a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products. For example, base treatment of a mixture of acetaldehyde and propanal gives a complex product mixture containing two "symmetrical" aldol products and two "mixed" aldol products. Clearly, such a reaction is of no practical value. 

On the other hand, mixed aldol reactions can lead cleanly to a single product if either of two conditions is met ... 

I If one of the carbonyl partners contains no or hydrogens, and thus can t form an enolate ion to become a donor, but does contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benz-aldehyde or formaldehyde is used as one of the carbonyl partners. 

The ketone 2-methyfcycloliexanone, for instance, gives the mixed aldol product on reaction with benzaldehyde. 

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 situation can be summarized by saying that a mixed aldol reaction leads to a mixture of products unless one of the partners either has no a hydrogens but is a good electrophilic acceptor (such as benzaldehyde) or is an unusually acidic nucleophilic donor (such as ethyl acetoacetate). 

Problem 23.8 Which of the following compounds can probably be prepared by a mixed aldol reaction Show the reactants you would use in each case. 

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. 

Microwaves, electromagnetic spectrum and. 419 Mincralocorticoid, 1083 Minor groove (DNA), 1104-1105 Mitomycin C, structure of, 970 Mixed aldol reaction, 885-886 requirements for. 885-886 Mixed Claisen condensation reaction, 890-891... 

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