Salicylic acid acetals, hydrolysis

He, B., Huang, W Guo, X., and Yu, Y Catalysis by condensation polymers containing salicylic acid for hydrolysis of p-nitro-phenyl acetate in aqueous solution, Gaofenzi Tongxun, 416,1982 Chem. Abstr., 99,21670,... 

Quantitative Analysis after Chemical Reaction. A large number of fluorometric analyses have been performed after converting a nonfluorescent or weakly fluorescent compound into an intensely fluorescent species. One example, which involves only hydrolysis, is the measurement of acetylsalicylic acid as salicylic acid or the salicylate anion. Because the total concentration of these two acids in blood is very important in the treatment of rheumatic disease, acetylsalicylic acid is converted to salicylic acid by hydrolysis and the total measured as salicylate. First the serum protein is removed, then the acetylsalicylic acid is hydrolyzed under alkaline conditions to salicylic acid and acetic acid (in alkaline solution, an equilibrium mixture of the anions and acids is present). The alkaline solution is then excited at 310 nm and the fluorescence emission is measured at 410 nm. 

Much work has been done since, and it is quite evident that this seemingly simple hydrolysis to acetic and salicylic acids is both complex and controversial. I am fortunate that I can refer the reader to the excellent and detailed review by Clark A. Kelly151 already mentioned in Section 5.61. The most complete and thorough kinetic studies of the factors involved in the hydrolysis of aspirin are undoubtedly those by Edwards17 3, which were further elaborated by Garrett.174... 

Aspirin is an ester, bnt it still contains a carboxylic acid fnnction (p/Ca 3.5). In aqueous solntion, there will thus be significant ionization. However, this ionization now provides an acid catalyst for ester hydrolysis and initiates autolysis (autohydrolysis). The hydrolysis product salicylic acid (pACa 3.0) is also acidic both aspirin and salicylic acid are aromatic acids and are rather stronger acids than aliphatic compounds such as acetic acid (pACa 4.8) (see Section 4.3.5). An aqueous solution of aspirin has a half-life of about 40 days at room temperature. In other words, after about 40 days, half of the material has been hydrolysed, and the biological activity will have deteriorated similarly. 

Numerous methods for the synthesis of salicyl alcohol exist. These involve the reduction of salicylaldehyde or of salicylic acid and its derivatives. The alcohol can be prepared in almost theoretical yield by the reduction of salicylaldehyde with sodium amalgam, sodium borohydride, or lithium aluminum hydride by catalytic hydrogenation over platinum black or Raney nickel or by hydrogenation over platinum and ferrous chloride in alcohol. The electrolytic reduction of salicylaldehyde in sodium bicarbonate solution at a mercury cathode with carbon dioxide passed into the mixture also yields saligenin. It is formed by the electrolytic reduction at lead electrodes of salicylic acids in aqueous alcoholic solution or sodium salicylate in the presence of boric acid and sodium sulfate. Salicylamide in aqueous alcohol solution acidified with acetic acid is reduced to salicyl alcohol by sodium amalgam in 63% yield. Salicyl alcohol forms along with -hydroxybenzyl alcohol by the action of formaldehyde on phenol in the presence of sodium hydroxide or calcium oxide. High yields of salicyl alcohol from phenol and formaldehyde in the presence of a molar equivalent of ether additives have been reported (60). Phenyl metaborate prepared from phenol and boric acid yields salicyl alcohol after treatment with formaldehyde and hydrolysis (61). 

A classic example of ester hydrolysis is demonstrated with aspirin. Aspirin hydrolyzes under acidic and basic conditions to yield acetic and salicylic acid (Fig. 2) (6). Aspirin easily hydrolyzes because it is an activated ester (i.e., the leaving group, carboxylate anion, can readily stabilize the anionic charge). An additional API example that undergoes ester hydrolysis is cyclandelate (7). 

Figure 2 Hydrolysis of aspirin to acetic and salicylic acid.

FIGURE 14-1. Hydrolysis of aspirin to form salicylic acid and acetic 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. 

Acid-Catalyzed Hydrolysis to Salicylic Acid AND Acetic Acid... 

The reaction you have just executed is an organic reaction known as an acid-catalyzed hydrolysis. The suffix -lysis means to cut, and hydrolysis means to cut with water. In this reaction, acetylsalicylic acid is cut with water to form salicylic acid and acetic acid, as shown in figure 2.1.1. 

Figure 8 Hydrolysis of acetylsalicylic acid (aspirin) to acetic acid and salicylic acid (a phenolic acid) by carboxylesterase activity.

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. 

Intramolecular general acid catalysis is normally detected in the first instance by a horizontal portion on the plot of logiokobs versus pH, governed by the add dissociation constant of the substrate. Thus, the hydrolyses of various salicyl acetals (including the P-D-glucopyranoside below pH 10, " where a base-catalysed process occurs) obey the rate law of eqn (3.7), where ko is the first-order rate constant for hydrolysis of the neutral molecule and ka is the second-order rate constant for the acid-catalysed hydrolysis of the neutral molecule ... 

An obvious starting point was to look for general acid catalysis of the attack of nucleophiles on a methyoxymethyl acetal known to be subject to efficient carboxyl-catalyzed hydrolysis. Participation by nucleophiles other than water in the hydrolysis of the salicylic acid derivative 3.17 could not be convincingly distinguished from specific salt effects (the range of nucleophiles is limited by the requirement that the COOH group (pKa 3.77) be protonated) [49]. On the other hand there is clear involvement of nucleophiles, including carboxylate anions, in the reaction of the dimethylammonium system 3.18 [44] (Scheme 2.24). The difference is presumably simply quantitative. 

Pharmaceutical Incompat, (from Remington s Pharmaceutical Sciences) Aspirin forms a damp to pasty mass when triturated with acetanilide, phenacetin, antipyrine, amidopyrine, methenamine, phenol or phenyl salicylate. Powders containing aspirin with an alkali salt such as sodium bicarbonate become gummy on contact with atmospheric moisture. Hydrolysis oecnrs in admixture with salts contg water of crystallization. Solns of the alkaline acetates and citrates, as well as alkalies themselves, dissolve aspirin but the result -ing solns hydrolyze rapidly to form salts of acetic and salicylic acids. Sugar and glycerol have been shown to hinder this decompn. Aspirin very slowly liberates hydriodic acid from potassium or sodium iodide. Subsequent oxidation by air produces free iodine. 

Acetylsalicylic acid, or aspirin, is a white powder that is stable in a dry environment but that is hydrolyzed to salicylic acid and acetic acid under humid or moist conditions. Hydrolysis also can occur when aspirin is combined with alkaline salts or with salts containing water of hydration. Stable aqueous solutions of aspirin are thus unobtainable despite the addition of modifying drugs that tend to decrease hydrolysis. Aspirin is rapidly absorbed largely intact from the stomach and upper small intestine on oral administration but is rapidly hydrolyzed by plasma esterases. 

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. 

Carbasalate calcium is a relatively unstable solid active substance, as it degrades through hydrolysis in the presence of moisture. Upon degradation, salicylic acid and acetic acid are formed. The latter can be smelt in very low quantities. To prevent patients becoming needlessly worried, carbasalate calcium powders should be packaged in lightly ventilating material such as paper. 

It was pointed out in the mechanistic discussion concerning acetal and ketal hydrolysis that general acid catalysis occurs only for acetals and ketals having special structural features (see p. 453). Usually, specific acid catalysis operates. The question of whether general acid catalysis could be observed in intramolecular reactions has been of interest because intramolecular general acid catalysis is postulated to play a part in the mechanism of action of the enzyme lysozyme, which hydrolyzes the acetal linkage present in certain polysaccharides. One group of molecules that has been examined as a model system is acetals derived from o-hydroxybenzoic acid (salicylic acid) ... 

Methoxymethoxy-l-naphthoic acid is the only acetal, not a salicylic-acid derivative, for which there is any evidence for intramolecular general-acid catalysis in its hydrolysis at present, and the rate enhancement is not very large. Thus at pH 4.10 the rate is only fifteen times greater than that estimated for the hydrolysis of 1-methoxymethoxy-naphthalene at this pH [6]. 

One factor which may be important in the hydrolysis of acetals derived from salicylic acid is that on ionization they give an intramolecularly hydrogen-bonded anion and that this hydrogen bonding... 

Suitably substituted acetals have been shown to hydrolyse rapidly by a mechanism that involves intramolecular general acid catalysis similar to that proposed for Glu-35 in (34), The largest effects have been found for acetals with the salicylate ion as the leaving group. For example, the spontaneous hydrolysis (35) of 2-methoxymethoxybenzoic acid [73] occurs 300-fold more rapidly than the same reaction of 4-methoxymethoxybenzoic acid [74] and ca. 600-fold more rapidly than the reaction of 2-methoxymethoxybenzoic acid methyl ester [75] (Capon et al, 1969 Dunn and Bruice, 1970). The... 

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