Carbonyl condensations

You may wonder why aldehyde A doesn t react, with itself but reacts instead with formaldehyde. This is just one aspect of control in carbonyl condensations, treated thoroughly in frames 217-315 of the Carbonyl Programme. In this case, only aldehyde A can enolise but formaldehyde is more electrophilic. Now try this problem How would you... 

Monooximes of a-diketones have found applicability in the synthesis of 2-aminopyrazine 1-oxides by condensation with a-aminonitriles, and this reaction was used by White and coworkers in an approach to the synthesis of Cypridina etioluciferamine (Scheme 66 R = 3-indoloyl) (73T3761). In this instance, the use of TiCU as a catalyst was essential, since the carbonyl group in 3-acylindoles is normally deactivated and the required amine/carbonyl condensation is impractically slow. Under normal circumstances the carbonyl group in simple alkyl-substituted monoximes of a-diketones is the more reactive site and the reaction is rapid, requiring no catalysis (69LA(726)loo). 

Mechanistically, the reaction of diketosulfides and glyoxal likely proceeds via an initial aldol reaction to provide 22. A second intramolecular aldol reaction and the elimination of two equivalents of water produce the thiophene 23. The timing of the elimination reactions and the ring-closing, carbonyl condensation reaction is not completely understood. However, 2,5-disubstituted thiophenes 23 are available in good yields via this process. 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

The fourth and last fundamental reaction of carbonyl groups, carbonyl condensation, lakes place when two carbonyl compounds react with each other. When acetaldehyde is treated with base, for instance, two molecules combine to yield the hydroxy aldehyde product known as aldol aidehyde + alcoho/) ... 

Although the carbonyl condensation reaction appears different from the three processes already discussed, it s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 5. 

A carbonyl condensation reaction between two molecules of acetaldehyde yields a hydroxy aldehyde product. 

Identify each of the following reactions as a nucleophilic addition, nucleophilic acyl substitution, an a substitution, or a carbonyl condensation ... 

We said in A Preview ofCnrbonyl Compounds that much of the chemistry of carbonyl compounds can be explained by just four fundamental reaction types nucleophilic additions, nucleophilic acyl substitutions, o substitutions, and carbonyl condensations. Having studied the first two of these reactions in the past three chapters, let s now look in more detail at the third major carbonyl-group process—the a-substitution reaction. 

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. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

We ll see later in this chapter and again in Chapter 29 that carbonyl condensation reactions occur frequently in metabolic pathways. In fact, almost all classes of biomolecules—carbohydrates, lipids, proteins, nucleic acids, and many others—are biosynthesized through pathways that involve carbonyl condensation reactions. As with the or-substitution reaction discussed in the previous chapter, the great value of carbonyl condensations is that they are one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. We ll see how and why these reactions occur in this chapter. 

Carbonyl condensation reactions take place between two carbonyl partners and involve a combination of nucleophilic addition and -substitution steps. One partner is converted into an enolate-ion nucleophile and adds to the... 

Active Figure 23.1 MECHANISM The general mechanism of a carbonyl condensation reaction. One partner becomes a nucleophilic donor and adds to the second partner as an electrophilic acceptor. 

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. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Mechanism of the aldol reaction, a typical carbonyl condensation. 

Two of the four general carbonyl-group reactions—carbonyl condensations and basic conditions and involve enolate-ion intermediates. Because the experimental conditions for the two reactions... 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

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 Condensations with Enamines The Stork Reaction... 

Interactive to use a web-based palette to design syntheses utilizing carbonyl condensation and addition reactions. 

Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for tire synthesis of polycyclic molecules. The word annulation comes from the Latin annulus, meaning "ring," so an annulation reaction builds a new ring onto a molecule. 

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

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