Carboxyl group ortho esters

Reactions of the Carboxyl Groups. Carboxyl groups in the ortho position spontaneously form a strainless ftve-membered ring when heated to give anhydrides as shown for (8). Salts and esters (4) are readily formed as shown for (4) and (5), respectively. 

Phtha/k anhydride is the most important type of dibasic acid derivative ki alkyd preparation because of its low cost and the excellent overall properties it imparts to the reski. The anhydride stmcture allows a fast esterification to form half-esters at relatively low reaction temperatures without hberatkig water, thereby avoiding the danger of excessive foaming ki the reactor. However, skice the two carboxyl groups of phthaUc anhydride are ki the ortho position to each other on the benzene ring, cycHc stmctures may and do occur ki the reski molecules. 

There are several variations of the Claisen rearrangement that make it a powerfid tool for the synthesis of y,<5-unsaturated carboxylic acids. The ortho ester modification of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the /-position of allylic alcohols.157 A mixed ortho ester is formed as an intermediate and undergoes sequential elimination and sigmatropic rearrangement. 

Carboxylic acids can also be protected as ortho esters. Ortho esters derived from simple alcohols are very easily hydrolyzed, and a more useful ortho ester protecting group is the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure. These bicyclic orthoesters can be prepared by exchange with other ortho esters, by reaction with iminoethers, or by rearrangement of the ester derived from 3-hydroxymethyl-3-methyloxetane. 

Poly(amic acids) in which the ortho-carboxylic group has been chemically modified to either an ester- or amide moiety have been known for many years. However, their commercial significance was non-existent until very recent applications involving dielectric insulators [48] and photosensitive polyimide precursors [49, 50]. As with many synthetic pathways, there are generally several ways to arrive at the same goal. Similarly, the preparation of derivatized poly(amic acids) can be divided into two general categories ... 

For reviews, see Bergstrom, in Patai, Ref. 336, pp. 881-902 Cockerill Harrison, in Patai The Chemistry of Functional Groups, Supplement A, pt. 1 Wiley New York, 1977, pp. 149-329 Cordes Bull Chem. Rev. 1974, 74, 581-603 Cordes Prog. Phys. Org. Chem. 1967, 4, 1-44 Salomaa. Ref. 446, pp. 184-198 Pindur Muller Flo Witzel Chem. Soc. Rev. 1987, 16, 75-87 (ortho esters) Cordes, in Patai, Ref. 197, pp. 632-656 (ortho esters) DeWolfe Carboxylic Ortho Acid Derivatives, Academic Press New York, 1970, pp. 134-146 (ortho esters) Rckasheva Russ. Chem. Rev, 1968, 37, 1009-1022 (enol ethers). 

Substituent effects on the A,u I reaction have been studied by Bender and Chen55. These authors measured the rates of hydrolysis of a series of 4-substituted 2,6-dimethylbenzoates in 9.70 M sulphuric acid at 25°C, and found that the values for the first-order coefficients with 4-methoxy, 4-methyl, 4-unsubstituted and 4-bromo-compounds (5.0, 0.37, 0.033 and 0.01 x I0 4 sec-1, respectively) are satisfactorily correlated by the Hammett equation, following cr+ with a slope p = —3.22. Since the esters are not fully protonated in 9.70 M H2SOj, part of this factor is due to the effects of the 4-substituent on the protonation equilibrium, p for the protonation of substituted benzoic acids is about — l35, but is likely to be considerably smaller for di-ortho-substituted compounds, since the conjugative interaction of the p-substituents with the protonated carboxyl group requires coplanarity with the ring. 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

Other acyl alkyl esters have been utilized only sporadically. Makita et al. [241] analysed N-isobutyloxycarbonyl methyl esters of protein amino acids. During the first step of the preparation, the amino group reacts with isobutyl chloroformate according to Scheme 5.21. The reaction is accomplished in 10 min in an aqueous medium in the presence of sodium carbonate at room temperature. Excess of the reagent is extracted with diethyl ether and the reaction mixture is saturated with NaCl, acidified with ortho-phosphoric acid to pH 1—2 and extracted with diethyl ether. Methanol is added to the ethereal extract and the carboxyl group is esterified with diazomethane at room temperature for 5 min, The solvent is removed under a stream of nitrogen at 50°C and the residue is dissolved in ethyl acetate. Arg does not provide a volatile derivative when sub-... 

Trimethylbenzoic acid has two methyl groups ortho to the carboxylic acid functional group. These bulky methyl groups block the approach of the alcohol and prevent esterification from occurring under Fischer esterification conditions. A possible route to the methyl ester ... 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

The esterification of carboxylic acids can be provided, also, by synthetic equivalents of alcanols acetals RCH(0R )2 (with acid catalysis), ortho-esters RC(0R )3 (acid catalysis), and dialkylcarbonates C0(0R)2 (base catalysis). The series of bifunctional reagents of this type [dimethylformamide dialkylac-etals (CH3)2N-CH(0R)2] is commercially available. Besides the esterification of carboxyl groups, these compounds react with primary amino groups and, thus, are used for GC analysis of amino acids (see the entry Derivatization of Amines, Amino Acids, and Related Compounds for GC Analysis ) ... 

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