Carboxylic adds ester formation

The procedure described is essentially that of Shioiri and Yamada.4 Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis.5 It has been used for racemlzation-free peptide syntheses,4 6 7 thiol ester synthesis, a modified Curtius reaction,6 9 10 an esterification of a-substituted carboxylic add,11 formation of diketopiperazines, an alkyl azide synthesis,13 phosphorylation of alcohols and amines,14 and polymerization of amino acids and peptides.15 Furthermore, diphenyl phosphorazidate acts as a nltrene source3 and as a 1,3-dipole.16 17 An example In the ring contraction of cyclic ketones to form cycloalkanecarboxyllc acids 1s presented 1n the next procedure, this volume. 

In the radiolysis of aliphatic carboxylic acids, carboxylic add esters and amides preferred formation of a-carboxyalkyl type radicals (e.g., R CH COOR) are observed. 

The reaction of olefins and their functional derivatives with carbon monoxide and alcohols to saturated carboxylic add esters generally proceeds at a lower velocity than the formation of the free acids as illustrated in the last chapter [504]. In the presence of nickel halogenide catalysts, reaction temperatures between 180-200 °C and pressures from 100 to 200 atm are required. Yields are in the range of 90 %. With cobalt catalysts reaction temperatures between 140 to 170 °C are recommended [505]. 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the thiol group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and add-catalyzed dehydration would then lead to the thiazolidine and lactam rings. The stereochemistry at the carboxylic add a-... 

In this chapter we want to better understand how monomers react together to form long polymer chains. We have already seen a few reactions of organic compounds. For example, in Chapter 4 we wrote an equation for the esterification reaction of an alcohol with a carboxylic add to produce an ester plus water (Equation 5). We pointed out that monomers are usually difunctional organic compounds, where reaction with other suitable difunctional compounds can lead to polymer formation. In Chapter 4 we illustrated this with a polyesterification reaction (Equation 6). We will see that there are several different types of monomers. After reading this chapter you should be able to identify those organic compounds that are monomers and understand how they can react to form polymers. 

Direct ester formation from alcohols (R1OH) and carboxylic adds (R2C02H) works in acid solution-but does not work at all in basic solution. Why not By contrast, ester formation from alcohols (R1OH) and carboxylic acid anhydrides, (R2C0)2O, or acid chlorides, RCOCl, is commonly carried out in the presence of amines such as pyridine or F.tjN. Why does this work ... 

Figure 5.21. Reaction schemes for the most common types of step-growth polymerization. Shown are (a/c) polyester formation, (b/d) polyamide formation, (e) polyamide formation through reaction of an acid chloride with a diamine, (f) transesterification involving a carboxylic acid ester and an alcohol, (g) polybenzimidazole formation through condensation of a dicarboxyhc add and aromatic tetramines, and (h) polyimide formation from the reaction of dianhydrides and diamines.

The addition of an alcohol to the carbonyl group of a carboxylic acid in the presence of an acid catalyst leads to ester formation (Scheme 2.15a). The acid catalyst increases the electron deficiency of the carbonyl carbon, thus overcoming the electron-donating effect of the hydroxyl group of the acid. This enhancement of the electron deficiency of the carbonyl group of the carboxylic add may be brought about by converting the acid to a derivative such as the anhydride or the acyl chloride. The reaction of these with alcohols leads to esters (Scheme 2.15b). Another method is to carry out the reaction of the alcohol with an acyl chloride or anhydride in the presence of a base such as pyridine, which may facilitate the removal of a proton from the alcohol. 

The general approach for carboxylic adds derivatization is their esterification with formation of alkyl (arylalkyl, halogenated alkyl) or silyl esters ... 

The classical method for making rerf-butyl esters involves mineral acid-catalysed addition of the carboxylic add to isobutene but it is a rather harsh procedure for use in any but the most insensitive of substrates [Scheme 6.33]. °" 2 Moreover, the method is hazardous because a sealed apparatus is needed to prevent evaporation of the volatile isobutene. A simpler procedure (Scheme 6.34] involves use of rm-butyl alcohol in the presence of a heterogeneous acid catalyst — concentrated sulfuric add dispersed on powdered anhydrous magnesium sulfate. No internal pressure is developed during the reaction and the method is successful for various aromatic, aliphatic, olefinic, heteroaromatic, and protected amino adds. Also primary and secondary alcohols can be converted into the corresponding /er/-butyl ethers using essentially the same procedure (with the exception of alcohols particularly prone to carbonium ion formation (e.g. p-... 

The degree of racemization was also monitored through the experiment of a simple carboxylic add used in peptide synthesis, 2-phenylbutyric acid. The penta-fluorophenyl ester of (R)-2-phenylbutyric acid and (S)-l-phenylethylamine reacts with the corresponding amino acid via an EDCI coupling [5]. In a control experiment, (R)-2-phenylbutyric acid and (R)-l-phenylethylamine were reacted as well. For the amino acid formation of (R)-2-phenylbutyric acid and (S)-1 -phenylethylamine, a 4.2% racemization was found [6], Athigher concentration (0.5 M instead ofO.l M), a higher degree of racemization was observed (7.8%). 

Acylating agents that have been employed are carbon dioxide, alkyl chloroformates, alkyl formates, acid chlorides, esters, benzonitrile and dimethylformamide the expected a< lation products from reaction with the above reagents were formed in each case. However, the NJN-dimethyl-amide derivatives of higher carboxylic adds did not yield acylated product as in the case of dimethylformamide . When R = H (equation 63), it was necessary to employ two equivalents of the lithiodithiane due to product enolate formation. 

In Summary Carboxylic acids react with alcohols to form esters, as long as a mineral acid catalyst is present. This reaction is only shghtly exothermic, and its equilibrium may be shifted in either direction by the choice of reaction conditions. The reverse of ester formation is ester hydrolysis. The mechanism of esterification is add-catalyzed addition of alcohol to the carbonyl group followed by acid-catalyzed dehydration. Intramolecular ester formation results in lactones, favored only when five- or six-manbered rings are produced. 

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