Enolates Claisen condensation

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

We already know what happens when simple esters are treated with alkoxide bases— they undergo the Claisen condensation (Section 211) Simple esters have s of approximately 22 and give only a small amount of enolate when treated with alkoxide bases The small amount of enolate that is formed reacts by nucleophilic addition to the carbonyl group of the ester... 

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

Mixed Claisen condensations (Section 21.3) Diethyl carbonate, diethyl oxalate, ethyl formate, and benzoate esters cannot form ester enolates but can act as acylating agents toward other ester enolates. 

The 1,3-dicarbonyl components can be replaced by an enol ether, which can be prepared by Claisen condensation from an ortho ester and a reactive methylene compound. ... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

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 mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

Step 1 of Figure 27.7 Claisen Condensation The first step in mevalonate biosynthesis is a Claisen condensation (Section 23.7) to yield acetoacetyl CoA, a reaction catalyzed by acetoacetyl-CoA acetyltransferase. An acetyl group is first bound to the enzyme by a nucleophilic acyl substitution reaction with a cysteine —SH group. Formation of an enolate ion from a second molecule of acetyl CoA, followed by Claisen condensation, then yields the product. 

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... 

The Claisen condensation of t-butyl acetate with a methyl ester is a general route for the preparation of complex P-ketoesters.4 The reaction requires an excess of the enolate of t-butyl acetate to rapidly deprotonate the product and prevent tertiary alcohol formation. Some workers have also used excess LDA or t-butoxide for this purpose. 

It was unfortunate that we did not detect any product derived from a diketone in the reaction of w-dimethoxybenzene with tetrafluoroben-zyne. We therefore carried out a reaction of tetrafluorobenzyne with 1,3,5-trimethoxybenzene. The di-enol ether (80) could not be isolated, and after the removal of unreacted 1,3,5-trimethoxybenzene we isolated the phenolic acid (81) in good yield. This compound is undoubtedly formed by the hydrolysis of (80) followed by a retro-Claisen condensation, and aromatisation as shown below. 

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

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 Claisen reaction can now proceed smoothly, but nature introduces another little twist. The carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation. Accordingly, we now see that the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base (see Box 10.17). 

Very strong bases can be used in other reactions that are similar to the Claisen condensation. In these reactions, carbanions are formed instead of enolates. Figures 15-7, 15-8, and 15-9 show examples of various reactions employing three different strong bases sodium ethoxide, sodium amide, and sodium triphenylmethanide. Sodium hydride, NaH, is a strong base that would also work. Any of these very strong bases could be used in each of the specific reactions. 

In a Claisen condensation the carbanion-enolate of an ester adds to the C=0 group of its parent ester. The addition is followed by loss of the OR group of the ester to give a -ketoester. In a mixed Claisen condensation the carbanion-enolate adds to the C=0 group of a molecule other than its parent. 

Another important reaction of esters is the Claisen condensation. In this reaction, an enolate anion is formed from the reaction between an ester and a strong base, e.g. sodium ethoxide (NaOEt in EtOH). The enolate anion reacts with another molecule of ester to produce (3-ketoester (see Section 5.5.5). 

When two molecules of ester undergo a condensation reaction, the reaction is called a Claisen condensation. Claisen condensation, like the aldol condensation, requires a strong base. However, aqueous NaOH cannot be used in Claisen condensation, because the ester can be hydrolysed by aqueous base. Therefore, most commonly used bases are nonaqueous bases, e.g. sodium ethoxide (NaOEt) in EtOH and sodium methoxide (NaOMe) in MeOH. The product of a Claisen condensation is a P-ketoester. As in the aldol condensation, one molecule of carbonyl compound is converted to an enolate anion when an a-proton is removed by a strong base, e.g. NaOEt. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

These heterocyclic compounds undergo many reactions which are similar to those of the acetone enolate. Thus, Claisen condensation and o-sulfonylation are exemplified by Scheme 57. 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

Claisen condensations can be carried out between two different esters but, because there are four possible products, mixtures often result. Less difficulty is encountered if one of the esters has no a hydrogen and reacts readily with a carbanion according to Equations 18-11 and 18-12. The reaction then has considerable resemblance to the mixed aldol additions discussed in Section 17-3C. Among the useful esters without a hydrogens, and with the requisite electrophilic reactivity, are those of benzenecarboxyiic, methanoic, ethanedioic, and carbonic acids. Several practical examples of mixed Claisen condensations are shown in Equations 18-14 through 18-16 (all of the products exist to the extent of 10% or so as the enol forms) ... 

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