Acetyl salicylate hydrolysis

The level of phenol detected in blood or urine may not accurately reflect actual phenol exposure because phenol may also appear as a metabolite of benzene or other drugs. It has been shown that under certain acidic conditions used for the hydrolysis of conjugated phenols, acetyl salicylic acid (aspirin) may produce phenol (Baldwin et al. 1981) and yield spuriously higher values for phenol in blood and urine. 

Intramolecular general base catalysis of hycholysis (21a) was unexpected since the ester has a phenolic leaving group. Felton and Bruice (1968, 1969) reasoned that, if nucleophilic attack occurred, the leaving phenolate ion group would be properly positioned to attack the intermediate acylimidazole and thereby reverse the reaction. The normally less efficient general base reaction then becomes the favoured pathway, as in hydrolysis of acetyl salicylate (see Section 4). Likewise, Fife and McMahon (1970) explained bimolecular general base catalysis by imidazole (21b) in hydrolysis of o-(4-nitrophenylene) carbonate 3 49) by reversibility... 

Esters (and certain other compounds) may be susceptible to hydrolysis by low or especially high pH, or in the presence of alkaline metal or alkaline earth salts. In the presence of acid, i.e., anion and hydrogen ion, the reaction is at equilibrium. However, in the presence of base and the associated cations, the reaction is driven to completion (e.g., acetyl salicylic acid and the effect of sodium and magnesium salts on the rate and extent of reaction). 

Many decomposition reactions in the solid phase (section 4.3) or in suspensions apparently follow zero-order kinetics. Figure 4.1 shows the hydrolysis of a suspension of acetyl-salicylic acid. 

In the case of certain other esters, however (e.g., ethyl benzoate and acetyl salicylate [Nogami, 1962 Mitchell, 1964]), both anionic and cationic micelles retard the rate of hydrolysis. These effects are attributed either to small binding constants between substrate and micelle or to solubilization into micelles in such fashion as to remove the reaction site from the attacking reagent. 

FIGURE 6.16 Degradation reaction of acetyl salicylic acid due to hydrolysis. 

Rate of alkaline hydrolysis of acetyl salicylate ion (AS ) is proportional to both [HO] and [AS ] at a constant ionic strength. Pseudo-first-order rate constants (k, ) at a constant [NaOH] and different concentrations of inert salt (= NaCl, Na2C03, KCl, and BaCl2) fit to Equation 7.48. These observations have been explained in terms of ion-pair formation mechanism as shown in Schane 7.3... 

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

The term hydrolysis comes from the word hydro meaning water and lysis meaning breakdown. A hydrolysis reaction is one in which a a bond is cleaved by the addition of the elements of water to the fragments formed in the cleavage. A hydrolysis reaction is catalysed by acid, base or hydrolysing enzyme. For example, the analgesic drug aspirin (acetyl salicyhc acid) is easily hydrolysed in the presence of acid, moisture and heat to form salicylic acid. 

By-product acetic acid is obtained chiefly from partial hydrolysis of cellulose acetate [9004-35-7 /. Lesser amounts are obtained through tke reaction of acetic anhydride and cellulose. Acetylation of salicylic acid [69-72-7] produces one mole of acetic acid per mole of product and the oxidation of ally alcohol using peracetic acid to yield glycerol furnishes by-product acid, but the net yield is low. 

Aspirin, the widely used analgesic, is the acetyl ester of salicylic acid and is very susceptible to hydrolysis moisture in the air is sufficient to bring about significant decomposition. A bottle of aspirin tablets smells of vinegar when opened this is due to the reaction shown in Figure 8.20 taking place to liberate salicylic and acetic acids. The rate of decomposition is increased because members of the public often store medicines in a cabinet in the bathroom, the one room in the house that is almost guaranteed to have a hot, steamy atmosphere ideal for hydrolysis reactions. 

For many years, acetylsalicylic acid (ASA) was thought not to fluoresce and was commonly determined by hydrolysis to salicylic acid, followed by fluorometric determination of the salicylic acid. A tedious separation of the salicylic acid from the acetyl derivative was therefore necessary for the determination of both in aspirin tablets. Recently, it was found that ASA does indeed fluoresce in a solvent of 1 % acetic acid in chloroform [14]. ASA is excited at 280 nm and emits at 335 nm. 

It should be noted that the proposed attack of acylate ion at the sahcoyl carbon, unlike attack of water, would not lead to hydrolysis and that attack at the salicyl carbonyl group would be more adversely affected by an electrostatic effect than attack at the acetyl group. 

It is therefore clear that any intramolecular catalysis of the hydrolysis of the ionized form of the mixed acetic salicylic anhydride can produce only a small rate enhancement. This is reasonable since the ratio in the rates of hydrolysis of the ionized to un-ionized forms of p-nitrophenyl 5-nitrosalicylate is about 30 [28], and a reduced catalytic effect would be expected with a less basic dinitrophenolate ion. It has recently been claimed, on the basis of the variation of fc(ionized) with atom fraction of deuterium for hydrolysis in HjO—D2O mixtures, that the acetic salicylic anhydride reacts with 39 per cent attack at salicyl carbon and 61 per cent attack at acetyl carbon [86]. This conclusion does, however, depend on several unproven assumptions. 

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. 

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