HYDROLYSIS OF CARBOXYLIC ANHYDRIDES

In summary, therefore, the detailed mechanism of the hydrolysis of carboxylic anhydrides is still in doubt and we must hope for further experimental evidence to clarify the position. As for the hydrolysis of the other carboxylic acid derivatives dealt with in this chapter, none of the mechanistic criteria, that have been used to interpret the kinetic data, gives an unambiguous interpretation, resulting in a situation where details of mechanism are open to argument. This is particularly the case for solvolysis reactions where uncertainty as to the structure and effect of the solvent preclude a firm assignment of transition state structures. This is not to say that the mechanisms are not... 

To prove their hypothesis, Bamford and Block (51) applied the diagnostic test previously designed by Gold and Jefferson (58) in their studies of hydrolysis of carboxylic anhydrides catalysed by tertiary bases. The technique employed involves the use of a series of tertiary bases having different relative abilities to assodate with Lewis acids and to act as Bronsted bases. Pyridine, a-picoline and 2,6-lutidine form... 

The major side reaction to the desired acylation product is hydrolysis of the anhydride. In aqueous solutions anhydrides may break down by the addition of one molecule of water to yield two carboxylate groups. The presence of an excess of the anhydride in the reaction medium usually is enough to minimize the effects of competing hydrolysis. 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

RGURE 8-40 The phosphate ester and phosphoanhydride bonds of ATP. Hydrolysis of an anhydride bond yields more energy than hydrolysis of the ester. A carboxylic acid anhydride and carboxylic acid ester are shown for comparison. 

This chapter deals with the kinetics and mechanisms of the hydrolysis of carboxylic acid derivatives of general formula RCOX. These include carboxylic acid halides, amides, and anhydrides with small sections on carboxylic acid cyanides etc. Many recent developments in this field have been made with acid derivatives in which R is not an aliphatic or aromatic group, for example, carbamic acid derivatives, and these are reported where relevant, as are reactions such as ethanolysis, aminolysis, etc. where they throw light on the mechanisms of hydrolysis. 

In an actual procedure, the carboxylic acid is reacted with an optically active a-methylbenzylamine to crystallize out the less-soluble salt in the quantities of about 50% of the whole diastereomeric salts. The double decompositions of both salts existing in the precipitate and mother liquor give the dicarboxylic acids of (+) and ( ) 60% ee, respectively. When these partially resolved carboxylic acids are recrystallized from water, the precipitated crystals are almost racemic, and the carboxylic acids of 88% ee remain in water. They can be converted into the corresponding acid anhydrides by the action of acetyl chloride. Acid anhydrides of almost 100% ee can be obtained by the recrystallization from acetone, after recovering the active acids from the mother liquor. Optically pure (+)- and (-)- ra .S -l,2-cyclohcxancdicarboxylic acids can be obtained by the hydrolysis of these anhydrides. 

In models for carboxypeptidase A we showed the intracomplex catalyzed hydrolysis of an ester by a metal ion and a carboxylate ion [106], which are the catalytic groups of carboxypeptidase A. Some mechanistic proposals for the action of carboxypeptidase involve an anhydride intermediate that then hydrolyzes to the product and the regenerated enzyme. Although we later found convincing evidence that the enzyme does not use the anhydride mechanism in cleaving peptides [96-99], it may well use such a mechanism with esters. In a mimic of part of this mechanism we showed [107], but see also Ref. 108, that we could achieve very rapid hydrolysis of an anhydride by bound Zn2+, which is the metal ion in the enzyme. In another model, a carboxylate ion and a phenolic hydroxyl group, which are in the enzyme active site, could cooperatively catalyze the cleavage of an amide by the anhydride mechanism [109]. 

All types of alcohols and phenols are acylated by anhydrides. The reaction is catalyzed by a small amount of sulfuric acid, zinc chloride, acetyl chloride, sodium acetate, or pyridine. r-Butyl alcohol gives /-butyl acetate in 60% yield. Acetylation of phenols may be accomplished in an aqueous alkaline solution, the acylation proceeding more rapidly than the hydrolysis of the anhydride. The yields are above SX)%. Phenol, dihydroxybenzenes, naphthols, and phenols carrying nitro, amino, halo, carboxyl, or carbomethoxyl groups are acetylated by this procedure. ... 

The catalysis of hydrolysis of carboxylic acid derivatives by weak bases has not been carefully studied until relatively recently. Koshland reported in 1952 the catalysis of acetyl phosphate hydrolysis by pyridine Bafna and Gold (1953) reported the pyridine-catalyzed hydrolysis of acetic anhydride. A short time later the catalysis of aromatic ester hydrolysis by imidazole was demonstrated (Bender and Turnquest, 1957 a, b Bruice and Schmir, 1957). Since that time a large amount of work has been devoted to the understanding of catalyzed ester reactions. Much of the work in this area has been carried out with the purpose of inquiry into the mode of action of hydrolytic enzymes. These enzymes contain on their backbone weak potential catalytic bases or acids, such as imidazole in the form of histidine, carboxylate in the form of aspartate and glutamate, etc. As a result of the enormous effort put into the study of nucleophilic displacements at the carbonyl carbon, a fair understanding of these reactions has resulted. An excellent review is available for work up to 1960 (Bender, 1960). In addition, this subject has been... 

The reaction of anhydrides with aqueous acid or aqueous base is essentially identical to that of acid chlorides (replace Cl with O2CR in the mechanism for 1-6 or 8-7), and it also gives the parent acid as the product. Anhydrides are converted to the anion of the carboxylic acid precursors by base hydrolysis. Base hydrolysis of dibutanoic anhydride with aqueous sodium hydroxide leads to two molar equivalents of sodium butanoate similar reaction with butanoic ethanoic anhydride gives one molar equivalent of sodium ethanoate and one molar equivalent of sodium butanoate. 

Anhydrides may be prepared by coupling two carboxylic acids under acidic conditions. If ethanoic acid (acetic acid, 21) is heated with HCl, protonation to give an oxocarbenium ion is followed by reaction with a second equivalent of acetic acid to give a tetrahedral intermediate. This reaction is the usual acid-catalyzed acyl addition mechanism. Protonation of the OH unit leads to loss of water and formation of the anhydride. Each step in this process is reversible and steps must be taken to drive the equilibrium (see Chapter 7, Section 7.10, for a discussion of equilibria) toward the anhydride product by removing the water by-product (see Chapter 18, Section 18.6.3). Remember that such techniques are an application of Le Chatelier s principle (discussed in Section 18.3). Even when this is done, isolation of pure anhydrides by this method can be difficult. Unreacted acid may contaminate the product and atternpts to remove the acid with aqueous base may induce hydrolysis of the anhydride. 

The reactivity of anhydrides is similar to that of acid chlorides. A carboxylate anion is the learing group in a variety of syntheses of acyl derivatives, all of which are examples of the addition-elimination process (Fig. 18.29). One reaction of this kind is the basic hydrolysis of phthalic anhydride to phthalic acid. Here the leaving group is an internal carboxylate anion. 

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