Mechanisms anhydride hydrolysis

Anhydrides are somewhat more difficult to hydrolyze than acyl halides, but here too water is usually a strong enough nucleophile. The mechanism is usually tetrahedral. Only under acid catalysis does the SnI mechanism occur and seldom even then.s06 Anhydride hydrolysis can also be catalyzed by bases. Of course, OH- attacks more readily than water, but other bases can also catalyze the reaction. This phenomenon, called nucleophilic catalysis (p. 334). is actually the result of two successive tetrahedral mechanisms. For example, pyridine catalyzes the hydrolysis of acetic anhydride in this manner.507... 

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. 

Acetic-mesitoic anhydride hydrolysis was found to be dependent upon /i0, to have AS = — 3.8 eu and bond fission was found to be predominantly mesitoyl-oxygen. This evidence strongly suggests the A-l mechanism in-... 

Although, so far in this section, we have discussed the kinetic evidence in terms of the A-l and A-2 mechanisms favoured by Bunton et al. (p. 224), the same points which give rise to differences in detailed interpretation of mechanism for hydrolysis of acyl halides apply with equal weight to the hydrolysis of anhydrides. Butler and Gold67,68,298,299 have studied the spontaneous hydrolysis of acetic anhydride and presented the following scheme. 

Some evidence234 for Zn—OH attack in anhydride hydrolysis has been obtained using the complex (65) (Section 61.4.11) but the evidence is not definitive, and other mechanisms could apply. Large rate enhancements occur in the Zn11- and Cu -promoted hydrolysis of the lactam (66) (Section 61.4.10). Rates increase commensurate with the ionization of a metal-bound water molecular and sigmoidal pH-rate profiles are observed. Rate enhancements of 9 x 105 and 1 x 103 occur with (66)—Cu—OH and (66)—Zn—OH compared with the free ligand. A number of other reactions which are believed to proceed via M—OH species, in kinetically labile systems, are considered in Section 61.4.3. 

One possible mechanism for the hydrolysis of peptides or esters by carboxypeptidase A involves two steps with an anhydride (acyl-enzyme) intermediate.418 In the first step, the zinc(II) activates the substrate carbonyl group towards nucleophilic attack by a glutamate residue, resulting in the production of a mixed anhydride (127). Breakdown of the anhydride intermediate is rate determining with some substrates.419 An understanding of the chemistry of metal ion effects in anhydride hydrolysis is therefore of fundamental importance in regard to the mechanism of action of the enzyme. Until recently there have been few studies of metal ion-catalysed anhydride solvolysis. 

Long-range substituent effects of unknown mechanism influence the esterification of 5-en-3)3-ols by racemic a-phenylbutyric anhydride. Hydrolysis of the resulting esters gave a-phenylbutyric acid with modest optical activity, the sign depending upon the nature of C-17 substitution in the steroid employed. "... 

Acyl triazoles and carboxylic anhydrides have similar mechanisms of hydrolysis, and consistently ionic micelles inhibit hydrolysis of triazoles with k+/k > 1 (52). 

Acylation of amines by anhydrides has not been subjected to extensive mechanistic investigation but it seems highly probable that the mechanism is similar to that of anhydride hydrolysis, which brings the reaction in line with the mechanism of amine acylation by other reagents. Since acyl halides hydrolyse by an Sff2 mechanism, acyl acetate (acetic anhydride) should be more inclined to react in this way. Thus acetic anhydride would be expected to react with amines, stronger nucleophiles than water, via an Sjf2 reaction also. More direct evidence in support ofan S 2 mechanism comes from the work... 

To decide the mechanism of hydrolysis of the ionized and unionized forms of aspirin and monosubstituted aspirins is more difficult because these lead to no incorporation of label into the product salicylic acid when reaction is carried out in 0-enriched water, and there is no formation of the methyl salicylate when reaction is carried out in aqueous methanol [77]. Therefore either the reaction does not proceed via a mixed anhydride or this anhydride reacts exclusively by attack at the acetyl group. 

Blackburn, R.A.M., Capon, B., McRitchie, A.C. The mechanism of hydrolysis of phthalamic acid and N-phenylphthalamic acid the spectrophotometric detection of phthaUc anhydride as an intermediate. Bioorg. Chem. Wll, 6, 71-78. 

Bender and Feng s report of a slight reduction in rate (kn/ko = 1.05 0.04) of the hydrolysis in water of acetie-d anhydride is, mechanistically speaking, doubly ambiguous. Not only is the mechanism of anhydride hydrolysis uncertain, but— whatever the mechanism—heterolysis leads to two non-equivalent labeled moieties the stability of each of which is subject to different isotope effects. 

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

FIGURE 20.3 An acid catalyzes the hydrolysis of a carboxylic acid anhydride by increasing the rate of the first stage of the mechanism. The faster the tetrahedral intermediate is formed, the faster the rate of hydrolysis. 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

For the mechanism of azolide hydrolysis under specific conditions like, for example, in micelles,[24] in the presence of cycloamyloses,[25] or transition metals,[26] see the references noted and the literature cited therein. Thorough investigation of the hydrolysis of azolides is certainly important for studying the reactivity of those compounds in chemical and biochemical systems.[27] On the other hand, from the point of view of synthetic chemistry, interest is centred instead on die potential for chemical transformations e.g., alcoholysis to esters, aminolysis to amides or peptides, acylation of carboxylic acids to anhydrides and of peroxides to peroxycarboxylic acids, as well as certain C-acylations and a variety of other preparative applications. 

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