Enolate ions 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 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... 

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... 

In one of the few examples not involving enolate ions, the substitution of Br in o-bromo-benzaldehyde or -acetophenone by "SCHaCChEt ion followed by Claisen condensation of the resulting sulfides, (46) and (47), under the reaction conditions ultimately gave substituted benzo[ft]thiophenes (48) and (49) in... 

The Claisen reaction involves the condensation or linking of two ester molecules to form a 3-ketoester (Fig.T). This reaction can be considered as the ester equivalent of the Aldol reaction The reaction involves the formation of an enolate ion from one ester molecule which then undergoes nucleophilic substitution with a second ester molecule (Fig.U, Step 1). 

In both these last two examples, a very strong base is used in the form of LDA such that the enolate ion is formed quantitatively (from ethyl acetate and acetone respectively). This avoids the possibility of self-Claisen condensation and limits the reaction to the crossed Claisen condensation. 

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations ... 

The Claisen condensation is a nucleophilic acyl substitution on an ester, in which the attacking nucleophile is an enolate ion. 

The jS-keto ester products of Claisen condensations are more acidic than simple ketones, aldehydes, and esters because deprotonation gives an enolate whose negative charge is delocalized over both carbonyl groups. jS-Keto esters have pA values around 11, showing they are stronger acids than water. In strong base such as ethoxide ion or hydroxide ion, the /3-keto ester is rapidly and completely deprotonated. 

The ethoxide ion released in this first reaction will, as usual, form a stable enolate from the 1,3-diketone but this now cyclizes in a second Claisen condensation on to the second ester group,... 

Claisen condensation reaction (Section 23.7) a nucleophilic acyl substitution reaction that occurs when an ester enolate ion attacks the carbonyl group of a second ester molecule. The product is a p-keto ester. 

The next stage is an intramolecular Claisen ester condensation. We can easily discover which enolate reacts with which ester by drawing the starting material in the shape of the product. The alternatives are three- or sbt-membered rings five-membered rings are more stable than three- and more rapidly formed than six-membered. Under the reaction conditions there is no stereochemistry as the product exists as a stable conjugated enolate ion (p. 724). 

The mechanism of the Claisen condensation is similar to that of the aldol condensation. As shown in Figure 23.5, the Claisen condensation involves the nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule. 

It will be observed that throughout this discussion of carbanions no mention has been made of the intermediate formation of an enol or of enolization. It now seems extremely probable that in reactions such as aldol formation (p. 176), the Claisen condensation (p. 185), acetoacetic or malonic ester reactions (pp. 182, 201), and the halogenation of ketones (pp. 206, 207) the carbanion is the actual reaction intermediate and that the formation of an enol simply represents an alternative non-essential course of reaction for the carbanion. In the alkylation of malonic ester, for example, a carbanion (XXV and XXVI) may be formed by reaction of the neutral ester with ethoxide ion. 

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