Proton removal condensation reactions

The cyanoacryhc esters are prepared via the Knoevenagel condensation reaction (5), in which the corresponding alkyl cyanoacetate reacts with formaldehyde in the presence of a basic catalyst to form a low molecular weight polymer. The polymer slurry is acidified and the water is removed. Subsequendy, the polymer is cracked and redistilled at a high temperature onto a suitable stabilizer combination to prevent premature repolymerization. Strong protonic or Lewis acids are normally used in combination with small amounts of a free-radical stabilizer. 

Oxidative coupling involves condensation reactions catalyzed by phenol oxidases. In oxidative coupling of phenol, for example, arloxy or phenolate radicals are formed by the removal of an electron and a proton from an hydroxyl group. The herbicide 2,4-D is degraded (Fig. 15.5) to 2,4 dichlorophenol, which can be oxidatively coupled by phenol oxidases (Bollag and Liu 1990). 

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. 

Citrate synthase catalyzes the condensation reaction by bringing the substrates into close proximity, orienting them, and polarizing certain bonds. Two histidine residues and an aspartate residue are important players (Figure 1711). One of the histidine residues (His 274) donates a proton to the carbonyl oxygen of acetyl CoA to promote the removal of a methyl proton by Asp 375. Oxaloacetate is activated by the transfer of a proton from His 320 to its carbonyl carbon atom. The concomitant attack of the enol of acetyl CoA on the carbonyl carbon of oxaloacetate results in the formation of a carbon-carbon bond. The newly formed citryl CoA induces additional structural changes in the enzyme. The active site becomes completely enclosed. His 274 participates again as a proton donor to hydrolyze the thioester. Coenzyme A leaves the enzyme, followed by citrate, and the enzyme returns to the initial open conformation. 

Lithium enolates do not even solve all problems of chemoselectivity most notoriously, they fail when the specific enolates of aldehydes are needed. The problem is that aldehydes self-condense so readily that the rate of the aldol reaction can be comparable with the rate of enolate formation by proton removal. Fortunately there are good alternatives. Earlier in this chapter we showed examples of what can go wrong with enamines. Now we can set the record straight by extolling the virtues of the enamines 96 of aldehydes.17 They are easily made without excessive aldol reaction as they are much less reactive than lithium enolates, they take part well in reactions such as Michael additions, a standard route to 1,5-dicarbonyl compounds, e.g. 97.18... 

Diazine alkyl groups, with the exception of those at the 5-position of pyrimidine, can undergo condensation reactions that utilise a side-chain carbanion produced by removal of a proton. As in pyridine chemistry, formation of these anions is made possible by delocalisation of the charge onto one (or more) of the ring nitrogen atoms. 

The condensation of the acetyl methyl carbon of acetyl-CoA with the carbonyl group of oxaloacetate is common to the surmised transition state of all these enzymes. The acetyl methyl carbon becomes deprotonated during the course of the condensation process and the 2-maleyl group, from oxaloacetate, replaces the proton. Normally one would expect that removal of the proton would be an inefficient process, given the high thermodynamic barrier to formation of such a carbanion and given the pa s of about 20 of carbon acids of this type. However, the only way to avoid the carbanion is to have the proton removal be part of a concerted process with carbon-carbon bond formation. Later in this chapter, I show why we expect the barrier to such a concerted process to be considerably higher than the barriers in reactions that proceed via the carbanion. 

A suitable solid base must have the appropriate base strength for the reaction under investigation. If the initial reaction step is the removal of a proton from a reactant of the form R1-CH2-R2 then the acidity of the proton to be removed depends on the identity of the R) and R2 groups (Table 1). The solid base selected should have sufficient base strength to carry out the reaction but should not have excessive base strength as this may lead to rapid catalyst deactivation or to side-product formation. For aldehyde and ketone condensation reactions therefore with a p.Ka of 19.7 - 20 a strong base is required but not a superbase material. Caustic can be used to carry out reactions with reactants with the removable proton having a pA a of up to around 20. 

When a ketone reacts with a suitable base (secs. 9.1, 9.2) an enolate anion is formed by removal of the a-proton. In the case of an unsymmetrical ketone such as 30, a mixture of (Z)-enolate (31) and ( )-enolate (32) usually results (secs. 9.2.E, 9.5.A). This mixture influences the diastereoselectivity and enantioselectivity of enolate condensation reactions (sec. 9.5). Such a mixture of geometrical isomers generates both syn- and antiproducts upon reaction with aldehydes so it is important to control or at least identify the geometry of the enolate. Several solutions to this problem have been developed, including formation of stable and separable enolate isomers and controlling reaction conditions to maximize production of one isomer. 

B.vii. Acid Dianions. All of the named reactions discussed in Section 9.4 constitute relatively minor variations of the fundamental condensation reaction of aldehydes, ketones, or acid derivatives with another aldehyde, ketone, or acid derivative. The ability to produce kinetic enolates from acid derivatives has made possible another useful modification of the enolate reaction. Carboxylic acids have an acidic proton that is removed by 1 equivalent of base to first give a carboxylate (see 226). Addition of a second equivalent of a powerful base such as a dialkylamide leads to the dianion (227). Subsequent reaction with an electrophilic species, in this case 1-bromobutane, occurred first at the more nucleophilic a-carbon to give hexanoic acid. 2 The carboxylate is usually generated with n-butyllithium and the enolate with LDA, although 2 equivalents of LDA can be used. As discussed in Chapter 8, treatment of a carboxylic acid with an excess of an organo-... 

Condensation reactions with the carbonyl compounds essentially involve nucleophilic addition. It is, however, pertinent to mention here that since the active hydrogen component is not itself sufficiently nucleophilic to add to the carbonyl group, base removal of a proton from the a-position with respect to the active hydrogen component (i.c., the most acidic position) is required. 

For the removal of the proton at the a-carbon atom, besides alkaline hydroxides or alcoholates in lower alcohols (methanol or ethanol), sodium or potassium amide in liquid ammonia, diethyl ether, toluene or benzene, sodium hydride in a toluene-THF mixture, or aluminium tri-r-butoxide in benzene have been used as bases. Aldol condensations have been performed over a temperature range between -33°C and around 100°C. The reaction times can vary from some minutes to several days. The yields of the aldol condensation reactions are enhanced by applying a large excess of the ketone. This can even lead to complete replacement of any other solvent by the keto compound. 

The Claisen condensation is reversible and favors the reactant since it is more stable than the S-keto ester. The condensation reaction can be driven to completion, however, if a proton is removed from the S-keto ester (Le ChStelier s principle Section 5.7). A proton is easily removed because the central a-carbon of the 8-keto ester is flanked by two carbonyl groups, making its a-hydrogen much more acidic than the a-hydrogen of the ester. 

The first step is a Claisen condensation. The nucleophile needed for a Claisen condensation is obtained by removing CO2— rather than a proton— from the a-carbon of malonyl thioester. (Recall that 3-oxocarboxylic acids are easily decarboxylated Section 18.17.) Loss of CO2 also drives the condensation reaction to completion. 

Electrolytes I-III were prepared from TMSPIm precursor by adding (I) trifluoroacetic acid (TFA) or (II, III) acetic acid (AcOH) in a molar ratio of 1 5.5. Equivalents of 4.5 were used for solvolysis, and 1 equivalent served for protonation for formation of ionic liquid. In electrolyte III, a mixture of acetic anhydride as dehydrating agent, and lithium acetate dihydrate as a source of lithium ions were added. Solvolysis and condensation reactions of trimethoxysilanes were stimulated by heat treatment of the mixtures at 120 °C. Lastly, the product was heated under reduced pressure to remove the remaining volatile components from the electrolytes. 

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 ... 

Ammonium salts of the zeolites differ from most of the compounds containing this cation discussed above, in that the anion is a stable network of A104 and Si04 tetrahedra with acid groups situated within the regular channels and pore structure. The removal of ammonia (and water) from such structures has been of interest owing to the catalytic activity of the decomposition product. It is believed [1006] that the first step in deammination is proton transfer (as in the decomposition of many other ammonium salts) from NH4 to the (Al, Si)04 network with —OH production. This reaction is 90% complete by 673 K [1007] and water is lost by condensation of the —OH groups (773—1173 K). The rate of ammonia evolution and the nature of the residual product depend to some extent on reactant disposition [1006,1008]. 

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