Protonation Claisen condensation

Claisen condensations involve two distinct experimental operations The first stage concludes m step 4 of Figure 21 1 where the base removes a proton from C 2 of the p keto ester Because this hydrogen is relatively acidic the position of equilibrium for step 4 lies far to the right... 

At least two protons must be present at the a carbon for the equilibrium to favor prod uct formation Claisen condensation is possible for esters of the type RCH2CO2R but not for R2CHCO2R ... 

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 ... 

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. 

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. 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

If, however, it is necessary to generate a crossed product by the reaction of an enolate derived from one carbonyl compound with a second carbonyl compound as the electrophile, tilings can go bad rapidly. Because both carbonyl groups must be present in solution at the same time and each can form etiolates to some extent, there can be four possible products from the various combinations of etiolates and carbonyl compounds. This problem was illustrated for the crossed-Claisen condensation above. The number of products can be minimized if one carbonyl component lacks a protons and cannot form an enolate and is also a more reactive electrophile than the second carbonyl component. If these conditions are met, then crossed condensations can be carried out successfully using alkoxide bases. Many of the named reactions were developed so that product mixtures could be avoided. 

Ethyl benzoate cannot undergo the Claisen condensation, because it has no protons on its a-carbon atom and so cannot form an enolate. Ethyl pentanoate and ethyl phenylacetate can undergo the Claisen condensation. 

To undergo a Claisen condensation, an ester must have at least two protons on the a carbon ... 

Anions of nitro compounds form quaternary centres with ease in additions to a,(3-unsaturated mono- and diesters. The difference between acidity of the protons next to a nitro group and those next to the esters in the products combined with the very mild basic conditions ensure that no unwanted Claisen condensations oecur. 

The low-energy tandem mass spectra of the deprotonated molecular ions of acylglycerol contain a type of ion whose formal mass-based composition corresponds to a ketone obtained by the combination of two fatty acid chains with a carbonyl group, minus a proton. The ketone contains mainly the chains of the central fatty acid combined with one of the two external fatty acids, even if the ketone containing the two external fatty acids is present with a much weaker intensity. The formation of these ions may be explained by an internal Claisen condensation followed by a fragmentation induced by a nucleophile substitution and then by a decarboxylation, as shown in Figure 8.64. 

The alkylation of p-keto ester enolates followed by decarboxylation affords substituted ketones (acetoacetic ester synthesis). The ester group acts as a temporary activating group. Retro-Claisen condensation can be a serious problem during hydrolysis of the ester, particularly in basic solution if the product has no protons between the carbonyl groups. In these cases, the hydrolysis should be carried out under acidic conditions or using one of the methods of decarbalkoxylation described in the next section. 

In order to avoid the difficulties which could be encountered with Claisen condensations, such as formation of regioisomers, competing O-acylation, proton exchange between the enolate and the product diketone, and generally poor yields, new synthetic approaches to modified and functionalized /3-diketones in R1, R2, and/or R3 positions have been developed. 

The glycolytic pathway includes three such reactions glucose 6-phosphate isomer-ase (1,2-proton transfer), triose phosphate isomerase (1,2-proton transfer), and eno-lase (yS-elimination/dehydration). The tricarboxylic acid cycle includes four citrate synthase (Claisen condensation), aconitase (j5-elimination/dehydration followed by yS-addition/hydration), succinate dehydrogenase (hydride transfer initiated by a-proton abstraction), and fumarase (j5-elimination/dehydration). Many more reactions are found in diverse catabolic and anabolic pathways. Some enzyme-catalyzed proton abstraction reactions are facilitated by organic cofactors, e.g., pyridoxal phosphate-dependent enzymes such as amino acid racemases and transaminases and flavin cofactor-dependent enzymes such as acyl-C-A dehydrogenases others. 

---