Ketones mixed aldol reaction

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. 

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. 

In ToUens reaction, an aldehyde or ketone containing an a hydrogen is treated with formaldehyde in the presence of Ca(OH)2 or a similar base. The first step is a mixed aldol reaction (16-38). 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

For the mixed aldol reaction to be of value in synthetic work, it is necessary to restrict the number of combinations. This can be accomplished as follows. First, if one of the materials has no a-hydrogens, then it cannot produce an enoiate anion, and so cannot function as the nucleophile. Second, in aldehyde plus ketone combinations, the aldehyde is going to be a better electrophile, so reacts preferentially in this role. A simple example of this approach is the reaction of benzaldehyde with acetone under basic conditions. Such reactions are synthetically important as a means of increasing chemical complexity by forming new carbon-carbon bonds. 

The first reaction involves a ketone reaction with an aldehyde under basic conditions, so enolate anion chemistry is likely. This is a mixed aldol reaction the acetone has acidic a-hydrogens to form an enolate anion, and the aldehyde is the more reactive electrophile. The reaction is then driven by the ability of the intermediate alcohol to dehydrate to a conjugated ketone. 

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. 

Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehydes and Ketones... 

Mixed aldol reactions may be broadly classified as the reaction between two different aldehydes or ketones, or the reaction of an aldehyde with a ketone. Apart from the concomitant self-condensation, not less than two possible crossed products can be envisaged. Such reactions are therefore only prepara-tively useful either if appropriate structural conditions are present, or if certain experimental conditions are used to effect a directed aldol condensation. 

At first sight formaldehyde (methanal, CH2=0) seems the ideal electrophilic partner in a mixed aldol reaction. It cannot enolize, (Usually we are concerned with oc hydrogen atoms in an aldehyde. Formaldehyde does not even have a carbon atoms.) And it is a super aldehyde. Aldehydes are more electrophilic than ketones because a hydrogen atom replaces one of the alkyl groups. Formaldehyde has two hydrogen atoms. 

Nature uses the two-carbon acetate fragment of acetyd CoA as the major building block for synthesis. Acetyl CoA can act not only as an electrophilic acceptor, being attacked by nucleophiles at the carbonyl group, but also as a nucleophilic donor by loss of its acidic a hydrogen. Once formed, the enolate ion of acetyl CoA can add to another carbonyl group in a condensation reaction. For example, citric acid is biosynthesized by nucleophilic addition of acetyl CoA to the ketone carbonyl group of oxaloacetic acid (2-oxob i-tanedioic acid) in a kind of mixed aldol reaction. 

The trivial name of the reaction was applied by Wurtz in 1872, and stems from the trivial name of the dimer resulting from the acid-catalyzed self-reaction of acetaldehyde (equation 1). In time, the term came to be applied to the analogous self-condensation reactions of ketones, the first known example of which was the acid-mediated dimerization of acetone, discovered in 1838. The first use of a base as a catalyst for the aldol reaction was in the reaction of furfural with acetaldehyde or acetone (equation 2). This example also illustrates the first example of a mixed aldol reaction, a process that came to be known as the Claisen-Schmidt condensation. ... 

Mixed aldol reactions between ketones and aldehydes are frequently successful because one of the competing side reactions, self-reaction of the ketone, is endothermic. Most commonly, these mixed aldol reactions are carried out under conditions that lead to the a,p-unsaturated ketone pr uct. The principal side reaction is usually aldehyde dimerization. 

McKervey and coworkers have used lithium iodide as a catalyst for mixed aldol reactions several examples are shown in equation (60). In all cases studied, 2-butanone reacts solely at C-1. The process is also applicable to other ketones, but they react much more slowly than do methyl ketones. For... 

The mixed aldol reaction between propionaldehyde and acetone gives an 85% yield of 4-hydroxy-2-hexanone when run in THF at - 78 °C with lithium diisopropylamide (LDA, a powerful base). The reaction is carried out by first adding the ketone to the base, cooling the solution, and then adding the aldehyde. 

Because selective formation of carbon-carbon bonds producing functionalized species, for example, those containing P-hydroxycarbonyl units, subsequently capable of transformation into many useful compounds, is important, a significant effort has been expended to control the mixed aldol reaction between aldehydes and/or ketones. 

Mixed aldol reactions between different aldehydes or ketones are usually plagued by formation of a mixture of products, because each component can function as a CH-acidic and carbonyl-active compound. Whereas the directed aldol reaction [14-16] is a rather general solution to this problem, the traditional aldol addition of non-identical carbonyl compounds is only successful when applied within the framework of a limited substitution pattern. Thus, a fruitful combination in mixed aldol reactions is that of an aldehyde with an enolizable ketone. Obviously, the aldehyde, having higher carbonyl reactivity, reacts as the electrophilic component, whereas the ketone, with comparatively lower carbonyl reactivity, serves as the CH-acidic counterpart. Because the self-aldolization of ketones is endothermic, this type of side reaction does not occur to a significant extent, so the product of the mixed aldol condensation is obtained in fair yield, as illustrated by the formation of ketone 6 from citral 5 and acetone, a key step in the synthesis of j5-ionone (Eq. (7)) [17]. 

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