Functional derivatives acid anhydrides

The chemistry of carboxylic acids is the central theme of this chapter The impor tance of carboxylic acids is magnified when we realize that they are the parent com pounds of a large group of derivatives that includes acyl chlorides acid anhydrides esters and amides Those classes of compounds will be discussed m Chapter 20 Together this chapter and the next tell the story of some of the most fundamental struc tural types and functional group transformations m organic and biological chemistry... 

After acyl halides acid anhydrides are the most reactive carboxylic acid derivatives Three of them acetic anhydride phthahc anhydride and maleic anhydride are mdus trial chemicals and are encountered far more often than others Phthahc anhydride and maleic anhydride have their anhydride function incorporated into a nng and are referred to as cyclic anhydrides... 

Substitution at the Alcohol Group. Acylation of the OH group by acylating agents such as acid chlorides or anhydrides is one of the important high yielding substitution reactions at the OH group of lactic acid and its functional derivatives. AUphatic, aromatic, and other substituted derivatives can be produced. 

The most important group of derivatives for the amino function (Fig. 7-4) is the carbamate group, which can be formed by reactions with acids, acid chlorides or acid anhydrides. A series of chlorides as 2-chloroisovalerylchloride [1], chrysanthe-moylchloride [2] and especially chloride compounds of terpene derivatives (cam-phanic acid chloride [3], camphor-10-sulfonyl chloride [4]) are used. The a-methoxy-a-trifluoromethylphenylacetic acid or the corresponding acid chloride introduced by Mosher in the 1970s are very useful reagents for the derivatization of amines and alcohols [5]. 

Ill spectroscopy is a valuable tool for the structural analysis of acid derivatives. Acid chlorides, anhydrides, esters, and amides all show characteristic IR absorptions that can be used to identify these functional groups. 

There are some problems associated with the use of functional derivatives of carboxylic acids. Long-chain acid anhydrides are not commercially available, and one half of the acylation reagent is not utilized. Acyl chlorides require the use of tertiary base catalysts, whose double role has been explained before. Some of the intermediate acyl ammonium compounds formed are, however, insoluble in the solvent system. Examples include RCO - N+EtsCL in LiCl/DMAc, where RCO refers to the propionyl, hexanoyl, and stearoyl moiety, respectively. Hexanoyl- and stearoyl-pyridinium chlorides are also insoluble in the same solvent system [185]. 

Polycondensation of diols with dicarboxylic acids is often performed in the melt. However, it does not always lead to high-molecular-weight polyesters. Sometimes, the starting materials or the resulting polyester are thermally unstable at the high condensation temperatures. If the reactants and the polyester are well soluble, one can carry out the polycondensation in solution (see Example 4-2). The elimination of water from diols and dicarboxylic acids frequently occurs rather slowly. In such cases suitable functional derivatives of the diols and dicarboxylic acids (esters or anhydrides) can be used instead of the direct condensation, as described in Sect. 4.1.1.3. 

Limiting essential amino acids covalently attached to proteins by using activated amino acid derivatives can improve the nutritional quality and change the functional properties of proteins. The best chemical methods for incorporating amino acids into water-soluble proteins involve using car-bodiimides, N-hydroxysuccinimide esters of acylated amino acids, or N-carboxy-a-amino acid anhydrides. The last two methods can give up to 75% incorporation of the amount of amino acid derivative used. With the anhydride method, as many as 50 residues of methionine have been linked to the 12 lysine residues of casein. The newly formed peptide and isopeptide bonds are hydrolyzed readily by intestinal aminopeptidase, making the added amino acids and the lysine from the protein available nutritionally. 

WeVe talked at length about the interconversions of acid derivatives, explaining the mechanism of attack of nucleophiles such as ROH, H20, and NH3 on acyl chlorides, acid anhydrides, esters, acids, and amines, with or without acid or base present. We shall now go on to talk about substitution reactions of acid derivatives that take us out of this closed company of compounds and allow us to make compounds containing functional groups at other oxidation levels such as ketones and alcohols. 

The results of these studies and others reported previously demonstrate that the 1-oxypyridinyl group is an effective catalyst for the transacylation reactions of derivatives of carboxylic and phosphoric acids when incorporated in small molecules and polymers. Furthermore, this catalytic site exhibits high selectivity for acid chlorides in the presence of acid anhydrides, amides, and esters. Therefore, catalysts bearing this group as the catalytic site can be used successfully in synthetic applications that require such specificity. The results of this work suggest that functionalized polysiloxanes should be excellent candidates as catalysts for a wide variety of chemical reactions, because they combine the unique collection of chemical, physical, and dynamic-mechanical properties of siloxanes with the chemical properties of the functional group. Finally, functionalized siloxanes appear to mimic effectively enzyme-lipophilic substrate associations that contribute to the widely acknowledged selectivity and efficiency observed in enzymic catalysis. 

Appropriate quenching of a reductively formed lithium enolate with a carboxylic acid anhydride, chloride, methyl chloroformate or diethyl phosphorochloridate yields the corresponding enol esters, enol carbonates or enol phosphates. These derivatives may be transformed into specific alkenes via reductive cleavage of the vinyl oxygen function, as illustrated by the example in Scheme 8. 

Closely related to the carboxylic acids and to each other are a number of chemical families known as functional derivatives of carboxylic acids acid chlorideSy anhydrides, amides, and esters. These derivatives are compounds in which the —OH of a carboxyl group has been replaced by —Cl, —OOCR, —NH2, or —OR. ... 

Another consequence of the reactivity differences among carboxylic acid derivatives is that only esters and amides are commonly found in nature. Acid halides and acid anhydrides undergo nucleophilic attack by water so rapidly that they can t exist in living organisms. Esters and amides, however, are stable enough to occur widely. All protein molecules, for example, contain amide functional groups. 

The preparation of the acid derivatives is organized according to their precursors. The synthetic method of choice in a particular case will depend on a number of factors of which the presence of other functional groups in the molecule under study is not the least important. The methods will be evaluated with respect to their scope of application. The chemistry of acid halides has been reviewed. Methods of preparation are treated in Houben-WeyP as well as in other reference books. This applies also to acid anhydrides and a-ketonitriles. ... 

Activation of carboxylic acids by phosphoms acid halides in the form of different derivatives (3-7) has been used extensively in more recent years. These methods have been tested not only for saturated aliphatic or aromatic carboxylic acids but also for functionalized derivatives. In Table 6 some examples are collected where (3) and (4) were applied successfully. The reactions are carried out at room temperature in acetone or dichloromethane by treatment of the carboxylic acid with 1 equiv. of triethylamine or A -ethylpiperidine and 0.5 equiv. of the reagent (equation 25). The anhydrides are either collected by filtration or recovered by evaporation of the solvent after washing with water. 

A conceptual alternative way to the activation of the carboxylic acid function is the reaction of carboxylic acids with amino groups activated as isocyanates - and isothiocyanates (equation 16). Preparation of these derivatives is racemization free. The reaction proceeds via mixed acid anhydrides in aromatic hydrocarbon solvents at elevated temperatures, and decarboxylation leads to the V-substituted amide. Pyridine as solvent enhances the conversion rate but increases also the amount of the urea side product via disproportionation. Application to peptide chemistry is limited, because peptide ester fragments tend to form hydantoins. ... 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

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