Aspirin, hydrolysis mechanism

We can illustrate the interpretation of pH rate profiles by considering the pH rate profile for the hydrolysis of aspirin. The pH rate profile and that of its methyl ester are shown in Figure 3.30. The methyl ester is a classic case in which there are both acid-and base-catalyzed regions and an uncatalyzed region as described by Equation (3.58). These features are characteristic of the normal ester hydrolysis mechanism outlined on pp. 325-326. Under the reaction conditions, only the more reactive O-aryl ester group is hydrolyzed. Aspirin, however, shows a region between pH 2 and pH 9 that reveals one downward and two upward bends. Thus there must be a fourth variant of the mechanism (since there are a total of three upward bends). 

Edwards [25] investigated the hydrolysis of aspirin in aqueous solution at 17A° and demonstrated that the aspirin is hydrolyzed by general acid-base catalysis and water molecules for ionic and nonionic aspirin, comprising six simultaneous reactions involving H O, O H, and H2O for ionic and nonionic aspirin. The intrinsic hydrolysis rate constant in the heated mixture was comparable with the hydrolysis rate constants of the two-element reactions of nonionic aspirin and H2O or ionic aspirin and H2O in aqueous solution. As aspirin molecules would be adsorbed onto the pore surface of PCC in the molecular state, as a possible mechanism of aspirin hydrolysis in the mixture with PCC it was suggested that the aspirin is dispersed monomolecularly in the heated mixture and reacts with water molecules rather than by acid-base catalysis. 

The case of intramolecular participation in ester hydrolysis has been extensively studied using acetylsalicylic acid (aspirin) and its derivatives. The kinetic data show that the anion is hydrolyzed more rapidly than the neutral species, indicating that the carboxylate group becomes involved in the reaction in some way. Three mechanisms can be considered ... 

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. 

Many examples are present in the scientific Uterature underlining the effort in producing kinetic data [9—11]. The Edwards historical study that started the investigation on the mechanism of the hydrolysis of aspirin required hundreds of kinetic experiments [12,13]. Several examples are reported by Carstensen [1] in his review on the subject where, beside the large space dedicated to the determination of the pH-rate profile, the effect of temperature, ionic strength, buffer concentration, and dielectic constant on the stability of drugs was treated. 

The introduction of an additional carboxy function into the structure of aspirin results in a significant rate enhancement of hydrolysis. The hydrolysis is 6300 times faster than for the monoanion of aspirin. 3-Hydroxyphthalic anhydride is an observable intermediate. The pH-rate profile is shown in Figure 7.P18. Suggest a mechanism to account for the accelerated hydrolysis involving both of the carboxy derivatives. 

W(8) in the crystalline state. The existence of HoO" is supported by the following strong hydrogen bonds of C00 W(23 =2.41, 2.62 A, C00 W(8)=2.77 A. If this crystal structure persists in solution, the classical general base catalysis of the attack by water activated by the carboxyl anion can not be possible. 2) When the crystalline waters are removed but the same type of inclusion as mentioned in 1) is maintained even in solution, the hydrolysis of aspirin will be performed on the proposed mechanism but must proceed much slower than that without 3-CyD, because of the difficulty in movement of the aspirin included by 3-CyD. 

The most thoroughly studied reactions for which this type of behaviour has been proposed are the hydrolysis of aspirin and other O-acylsali-cylic acids [73-78], The pH-rate profiles for these reactions show that the anions react at enhanced rates, and a careful comparison of the rates of hydrolysis of the un-ionized forms with those of the corresponding methyl esters has shown that these are also enhanced, but usually to a smaller extent [79], A possible mechanism for the reactions of the anions involves intramolecular nucleophilic catalysis with the anhydrides 47 as intermediates, and there is good evidence that such... 

It should be noted that similar values are found for the hydrolysis of aspirin and so cannot be used to exclude this mechanism for the latter reaction. 

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. 

If therefore seems that, whereas the experimental evidence for the hydrolysis of the un-ionized form of 3,5-dinitroaspirin can only be explained by a mechanism involving the mixed anhydride as intermediate, that for the un-ionized forms of mono-substituted aspirins and aspirin itself admits both this mechanism and one involving intramolecular general-acid catalysis. 

As a children s medicine, acetaminophen (Tylenol) has a major marketing advantage over aspirin Liquid Tylenol preparations (essentially, acetaminophen dissolved in flavored water) are stable, whereas comparable aspirin solutions are not. Indeed, phenyl alkanoates undergo hydrolysis (and transesteriflcation) considerably more rapidly than alkyl alkanoates, reactivity that underlies the mechanism of action of aspirin (Real Life 22-2). Explain. 

In region 1, aspirin is predominantly in the protonated form (SH) and the mechanism of hydrolysis in this region is... 

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