Ketone carbonyl condensation reactions

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction. For example, treatment of acetaldehyde with a base such as sodium ethoxide or sodium hydroxide in a protic solvent leads to rapid and reversible formation of 3-hydroxybutanal, known commonly as aldol (aidehyde + alcohol), hence the general name of the reaction. 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The Knoevenagel reaction is a carbonyl condensation reaction of an ester with an aldehyde or ketone to yield an a,j8-unsaturated product. Show the mechanism of the Knoevenagel reaction of diethyl malonate with benzaldchyde. 

The Darzens reaction involves a two-step, base-catalyzed condensation of ethyl chloroacetate with a ketone to yield an epoxy ester. The first step is a carbonyl condensation reaction, and the second step is an SK2 reaction. Write both steps, and show their mechanisms. 

Aldol reaction (Section 23.1) The carbonyl condensation reaction of an aldehyde or ketone to give a jS-hydroxy carbonyl compound. 

All kinds of carbonyl compounds, including aldehydes, ketones, esters amides, acid anhydrides, and nitriles, enter into condensation reactions, Nature uses these same carbonyl condensation reactions in the biosynthesis of many naturally occurring compounds. 

There are three general mechanisms by which aldehydes and ketones react. These are (i) nucleophilic addition reactions, (ii) a-substitution reactions and (iii) carbonyl-carbonyl condensation reactions. 

Carboxylic acid derivatives, like aldehydes and ketones, can also undergo a-substitution and carbonyl-carbonyl condensation reactions. 

Walsh refers to the enzymes described in this section (which catalyze carbonyl condensation reactions involving one component that is not an aldehyde or ketone) as Claisen enzymes (6). I shall use that terminology here, although these reactions are not formally Claisen condensations, but they are distinguished by their mechanisms from the other adolases mentioned in Section III,A, 1. 

The use of molecular sieves as catalysts for the production of chemicals and fine chemicals has increased over the last two decades (Holderich and van Bekkum 1991, Venuto 1994, 1997, Feast and Lercher 1996, Corma and Garcia 1997). In this way, rare-earth-containing microporous materials appear to be interesting catalysts in fine chemical reactions. This is the case for the synthesis of ketone acetals. Thus, Ce-Y, La-Y and R-Y zeolites are very effective catalysts in the synthesis of cyclohexanone diethyl acetal (Wortel et al. 1977). However, the results obtained in acylation and carbonyl condensation reactions are particularly relevant. 

As the text continues to develop the chemistry of aldehydes and ketones, you will now see how the carbon adjacent to a carbonyl group can become nucleophilic. First, reactions of these new nucleophiles with common electrophiles like luiloalkiines will be covered alkylation reactions. More important arc reactions of the nucleophilic a-carbons of one carbonyl compound with electrophilic carbonyl carbons of another. They are generically termed carbonyl condensation reactions. You see them here for aldehydes and ketones the aldol condensation. (In a later chapter you will be introduced to the analogous reaction of carboxylic esters the Claisen condensation.) The products of aldol condensations are a, j3-un.saturatcd aldehydes and ketones, which contain additional sites of electrophilic and potential nucleophilic character. 

Aldol reaction A carbonyl condensation reaction between two aldehydes or ketones to give a /3-hydroxyaldehyde or a /3-hydroxyketone. 

Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

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