Mechanism of Carbonyl Condensation Reactions

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. 

When acetaldehyde is treated with a base, such as sodium ethoxide or sodium hydroxide, a rapid and reversible condensation reaction occurs. The product is a /3-hydroxy aldehyde, or aldol (oidehyde -l- alcohoZ). 

Called the aldol reaction, base-catalyzed dimerization is a general reaction for all aldehydes and ketones with an a hydrogen atom. If the aldehyde or ketone does not have an a hydrogen atom, however, aldol cotiden- 

The general mechanism of a carbonyl condensation reaction. One partner (the donor) acts as a nucleophile, while the other (the acceptor) acts as an electrophile. 

One carbony) partner with an alpha hydrogen atom is converted by base into its enolate ion. 

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Many types of carbonyl condensation reactions have acquired specialized names, after the nineteenth-century organic chemists who first studied them. Propose mechanisms for the following named condensations. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

Mechanism of the aldol reaction, a typical carbonyl condensation. 

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. 

Step 5 of Figure 29.5 Condensation The key carbon-carbon bond-forming reaction that builds the fatty-acid chain occurs in step 5. This step is simply a Claisen condensation between acetyl synthase as the electrophilic acceptor and malonyl ACP as the nucleophilic donor. The mechanism of the condensation is thought to involve decarboxylation of malonyl ACP to give an enolate ion, followed by immediate addition of the enolate ion to the carbonyl group of acetyl... 

As a starting point for an examination of the mechanisms of gas phase reactions, the Claisen condensation is a multistep reaction that appears to proceed by essentially the same mechanism in the gas phase as in solution, as illustrated in Figure 5. In the gas phase, in cases where this reaction occurs, all that is observed is a disappearance of the enolate reactant and the appearance of P-carbonyl enolate product. The intermediate ions in the mechanism react too rapidly to exist long enough for detection. In the ICR spectrometer, unless an ion exists for at least a millisecond or longer, there are not enough cyclotron cycles to create a detectable signal. Intermediates such as the ones postulated for this reaction, with 10-50... 

The dicarboxyic acid 66 (alkylidenesuccinic acid), obtained by hydrolysis and decarboxylation of the triester 65, resembles the product (half-ester) 73 of the Stobbe condensation (Scheme 11-21) [21]. In order to prepare the half-ester, carbonylation in benzyl alcohol to prepare the monomethyl ester and dibenzyl ester 75, followed by hydrogenolysis of the dibenzyl ester, was attempted, expecting the formation of the halfester. However, /S-keto ester 76 was obtained, an entirely different product (Scheme 11-22) [22]. The mechanism of this unexpected reaction is unknown. 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

Carbonyl condensation reactions take place between two carbonyl partners and involve a combination of nucleophilic addition and a-substitution steps. One partner (the nucleophilic donor) is converted into its enoiate ion and undergoes an a-substitution reaction when it adds as a nucleophile to tl second partner (the electrophilic acceptor). The general mechanism of a carl bonyl condensation reaction is shown in Figure 23.1. 

Scheme 2 Proposed reaction mechanisms of Knoevenagel condensation on the pair site consisting of the Si-NHz and the neighboring Si-OH. The neighboring Si-OH functions as an acid site to activate the carbonyl group.

The mechanism of the condensation between allenyl organometallics and carbonyl groups is thought to be a cyclic Se< (or 5e2 ) process. In the reaction of aldehydes with 1,2-butadienylmagnesium halides, the anti syn product ratio depends on the size of substitutent group of the aldehyde and may be rationalized as shown in (1). ... 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

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