Acids, Esters, and Amides

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

Trichloroacetic acid K = 0.2159) is as strong an acid as hydrochloric acid. Esters and amides are readily formed. Trichloroacetic acid undergoes decarboxylation when heated with caustic or amines to yield chloroform. The decomposition of trichloroacetic acid in acetone with a variety of aUphatic and aromatic amines has been studied (37). As with dichloroacetic acid, trichloroacetic acid can be converted to chloroacetic acid by the action of hydrogen and palladium on carbon (17). 

Lubricants. Lubricants are used to improve the melt flow, screw feeding, and mold release of nylons. Long-chain acids, esters, and amides are used together with metal salts, eg, metal stearates. Improved melt flow is mainly a function of molecular weight reduction during mol ding. Mold release is improved by waxes of limited compatibiHty with nylon, which migrate to and lubricate the mold surface. 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

This reaction can be extended to unsaturated nitriles, eg, acrylonitrile, which can give trihalostannyl-functional carboxyHc acids, esters, and amides by the proper choice of solvents and reaction conditions (156). 

The caibonyl group in aldehydes, ketones, acids, esters, and amides is deactivating and wcto-directing. There are distinct limitations on the types of substitution reactions that are satisfiictory for these deactivating substituents. In general, only those electrophiles in category A in Scheme 10.1 react readily. 

Notice in the list of Lewis bases just given that some compounds, such as carboxylic acids, esters, and amides, have more than one atom ivith a lone pair of electrons and can therefore react at more than one site. Acetic acid, for example, can be protonated either on the doubly bonded oxygen atom or on the singly bonded oxygen atom. Reaction normally occurs only once in such instances, and the more stable of the two possible protonation products is formed. For acetic add, protonation by reaction with sulfuric acid occurs on... 

Most carbonyl compounds exist almost exclusively in the keto form at equilibrium, and it s usually difficult to isolate the pure enol. For example, cyclohexanone contains only about 0.0001% of its enol tautomer at room temperature, and acetone contains only about 0.000 000 1% enol. The percentage of enol tautomer is even less for carboxylic acids, esters, and amides. Even though enols are difficult to isolate and are present only to a small extent at equilibrium., they are nevertheless responsible for much of the chemistry of carbonyl compounds because they are so reactive. 

The rx bromination of carbonyl compounds by Br2 in acetic acid is limited tc aldehydes and ketones because acids, esters, and amides don t enolize to a suffi cient extent. Carboxylic acids, however, can be a brominaled by a mixture of Br and PBr3 in the HeJI-Volhard-Zelinskii (HVZ) reaction. 

I2 or with a carbon tetrahalide. " Carboxylic acids, esters, and amides have been... 

Disubstituted 2,4-cyclohexadienones (112) undergo photoinduced electrocyclic ring opening to the transient ketene derivatives 113, which can be trapped by nucleophiles to prepare the corresponding carboxylic acid derivatives (114 equation 44)196 197 j le reaction has been employed successfully for the synthesis of various carboxylic acids, esters and amides. 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

Fig. 3.1. General scheme for chemical hydrolysis of carboxylic acid esters and amides. Pathway a Proton (general acid) catalyzed hydrolysis. Pathway b HO (general base) catalyzed...

Kinetic Enolization of Carboxylic Acid Esters and Amides (Scheme 7)... 

The linker group is immobilized as a urethane to the amino-functionalized carrier (59). It facilitates the attachment of a variety of molecules such as alkyl halides, alcohols or amines bound as carboxylic acid esters and amides. 

Electrophilic additions to 7t-deficient heterocycles are less common than those to 7t-excessive heterocycles. However, intramolecular electrophilic cyclizations have been used to access the heterocycles of interest in this chapter <1996CHEC-II(7)49>. Recent examples include the preparation of a pyrrolo[2,3-f]pyrazole 165 by acid-catalyzed condensation of 163 and 164 (Equation 37) <1999SC311> and the reaction of 3-(4-pyrazolyl)acrylic acids 166 with excess thionyl chloride in the presence of benzyltriethylammonium chloride (BTEAC) to afford 4-chlorothieno[2,3-f]pyrazole-5-carbonyl chlorides 167 (Equation 38) <2003RJ0893, 2003ZOK942>. In the latter case, the reaction products were readily manipulated to prepare corresponding carboxylic acids, esters, and amides using standard procedures. 

Carboxylic acids, esters, and amides are shown in this table to be protonated on the carbonyl oxygen. There has been some controversy on this point, but the weight of evidence is in that direction. See, for example, Katritzky Jones Chem. Ind. (London) 1961, 722 Ottenheym van Raayen Smidt Groenewege Veerkamp Reel. Trav. Chim. Pays-Bas 1961, SO, 1211 Stewart Muenster Con. J. Chem. 1961,39, 401 Smith Yates Can. J. Chem. 1972, 50. 771 Benedetti Di Blasio Baine J. Chem. Soc. Perkin Trans. 2 1980, 500 Ref. 8 Homer Johnson, in Zabicky The Chemistry of Amides Wiley New York, 1970, pp. 188-197. It has been shown that some amides protonatc at nitrogen see Perrin Acc. Chem. Res. 1989, 22, 268-275. For a review of alternative proton sites, see Liler Adv. Phys. Org. Chem. 1975, II, 267-392. 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives.134 The acids or their chlorides or anhydrides can be a chlorinated by treatment with CuCl in polar inert solvents (e.g., sulfolane).135 Acyl halides can be a brominated or chlorinated by use of N-bromo- or N-chlorosuccinimide and HBr or HC1.136 The latter is an ionic, not a free-radical halogenation (see 4-2). Direct iodination of carboxylic acids has been achieved with L-Cu(II) acetate in HO Ac.137 Acyl chlorides can be a iodinated with L and a trace of HI.138 Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium N-isopropylcyclohexylamide in THF and treatment of this solution at - 78° with I2138 or with a carbon tetrahalide.139 Carboxylic acids, esters, and amides have been a fluorinated at -78°C with F2 diluted in Ni.,4°... 

Benzofuran derivatives such as 2-cyanobenzofuran-5-sulfonic acid esters and amides have found wide application as color developers in photographic processes (44USP2350127). The substituted benzofurans (507), (508) and (509) are used as brightening agents in textiles, wool, paper, cellulose and nylon (53MI31201). 

See also page 236, Section 8, for ene reactions leading to unsaturated carboxylic acids, esters and amides. 

In the case of amino acid ester and amide complexes, the intramolecular hydrolysis reaction was not observed directly, but was deduced from the results of lsO tracer studies. However, recently the cis-hydroxo and cis-aqua complexes derived from the bis(ethylenediamine)cobalt(III) system, containing glycinamide, glycylglycine and isopropylglycylglycinate, have been isolated and their subsequent cyclization studied over the pH range 0-14.160,161... 

T FIGURE 23.5 Carbonyl compounds can be classified into two categories. Aldehydes and ketones are less polar, while carboxylic acids, esters, and amides are more polar. 

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