Tetrahedral mechanism condensation

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. 

A Claisen condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in equilibrium with the ester (cf. Table 13.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 13.57 for the example of the condensation of ethyl butyrate. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 13.57) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of ethyl butyrate and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

Mechanism 20.3 outlines the steps in this reaction. The enolate formed in step 1 adds to the carbonyl group of the ester to give a tetrahedral intermediate in step 2. This tetrahedral intermediate gives the P-keto ester by expelling ethoxide in step 3. Steps 1-3 are reversible and, were the process to end here, the yield of P-keto ester would be low because the overall equilibrium constant is unfavorable. As normally carried out, however, one mole of sodium ethoxide is used for every mole of P-keto ester expected and because the p of the P-keto ester is approximately 11, its deprotonation in step 4 drives the equilibrium to favor condensation. Subsequently (step 5), the reaction product is acidified to convert the enolate of the P-keto ester to its neutral form. 

Claisen reaction is a carbonyl condensation that occurs between two ester components and gives a p-keto ester product. The reaction has a mechanism similar to that of the aldol reaction. The difference from aldol condensation is the expulsion of an alkoxide ion from the tetrahedral intermediate of the initial Claisen adduct. This adduct is not stable and expels the ethoxide ion to give the new carbonyl compound ethyl acetoacetate (p-keto ester). Claisen products can be easily hydrolyzed and decarboxylated (Figure 1.19). There are also many examples of retro-Claisen... 

Such a condensation is mediated by the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS). The mechanism of this catalysis is outlined in Figure 1.21. An initial frani-thioesterase step transfers the acetyl group of the first acetyl-CoA to an enzymatic cysteine. In the Claisen condensation phase of the reaction, the a-carbon of a second acetyl-CoA is deprotonated, forming an enolate. The enolate carbon attacks the electrophilic thioester carbon, forming a tetrahedral intermediate which quickly collapses to expel the cysteine thiol [22]. 

The benzoin condensation is the coupling of two aldehydes to afford ot-hydro>ycarbonyl compounds. In 1958, Breslow proposed the mechanism of the thiazolium-catalysed benzoin condensation reaction. It is believed that tetrahedral intermediate I is formed by nucleophilic attack of the in situ generated carbene A to the aldehyde. After proton transfer, intermediate II, now called the Breslow intermediate, is generated and reacts with an aldehyde to afford a new tetrahedral intermediate III. Elimination of the carbene catalyst affords the benzoin product and completes the catalytic cycle (Scheme 20.1). 

The mechanism of a Dieckmann condensation is identical to the mechanism we described for the Claisen condensation. An anion formed at the a-carbon of one ester in Step 1 adds to the carbonyl of the other ester group in Step 2 to form a tetrahedral carbonyl addition intermediate. This intermediate ejects ethoxide ion in Step 3 to regenerate the carbonyl group. Cyclization is followed by formation of the conjugate base of the j8-ketoester in Step 4, just as in the Claisen condensation. The j8-ketoester is isolated after acidification with aqueous acid. 

In the Claisen condensation catalyzed by the enzyme thiolase, acetyl-CoA is converted to its enolate anion, which then attacks the carbonyl group of a second molecule of acetyl-CoA to form a tetrahedral carbonyl addition intermediate. Collapse of this intermediate by the loss of CoAnSH gives acetoacetyl-CoA. The mechanism for this condensation reaction is exactly the same as that of the Claisen condensation (Section 15.3A) ... 

If Steps 1-3 of this mechanism are read in reverse, it is seen as an example of a Claisen condensation (Section 15.3A)—the attack by the enolate anion of acetyl-CoA on the carbonyl group of a thioester to form a tetrahedral carbonyl addition intermediate, followed by its collapse to give a /3-ketothioester. 

Claisen Condensation (Section 19.3A) The product of a Claisen condensation is a j8-ketoester. Condensation occurs by nucleophilic acyl substitution in which the attacking nucleophile is the enolate anion of an ester. The Claisen condensation mechanism involves reaction of one ester molecule with base to form an enolate anion, which reacts as a nucleophile with another molecule of ester to give a tetrahedral carbonyl addition intermediate, in which the RO" group is lost to give a /3-ketoester, which is deprotonated at the a position by the RO". 

The first two steps of this mechanism are much fike an aldol addition. The ester is first deprotonated to form an enolate, which then fimcdons as a nucleophile and attacks another molecule of the ester. The difference between an aldol reaction and a Claisen condensation is the fate of the tetrahedral intermediate. In a Claisen condensation, the tetrahedral intermediate can expel a leaving group to re-form a C=0 bond. The Claisen condensation is simply a nucleo-phihc acyl substitution reaction in which the nucleophile is an ester enolate and the electrophile is an ester. The product of this reaction is a P-keto ester. 

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