Salicylic hydrolysis

Salicin is a colourless crystalline substance, soluble in water. It does not reduce Fehling s solution nor does it give a coloration with ferric chloride. On hydrolysis with emulsin, glucose and salicyl alcohol are produced the former reduces Fehling s solution and the latter gives a violet coloration with ferric chloride. 

Many pharmaceutical compounds contain chromophores that make them suitable for analysis by UV/Vis absorption. Products that have been analyzed in this fashion include antibiotics, hormones, vitamins, and analgesics. One example of the use of UV absorption is in determining the purity of aspirin tablets, for which the active ingredient is acetylsalicylic acid. Salicylic acid, which is produced by the hydrolysis of acetylsalicylic acid, is an undesirable impurity in aspirin tablets, and should not be present at more than 0.01% w/w. Samples can be screened for unacceptable levels of salicylic acid by monitoring the absorbance at a wavelength of... 

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. 

Salicylic acid was used for phosphite protection in the synthesis of glycosyl phosphites and phosphates. This derivative is very reactive and readily forms a phosphite upon treatment with an alcohol or a phosphonic acid upon aqueous hydrolysis. ... 

The Dakin reaction proceeds by a mechanism analogous to that of the Baeyer-Villiger reaction. An aromatic aldehyde or ketone that is activated by a hydroxy group in the ortho or para position, e.g. salicylic aldehyde 12 (2-hydroxybenzaldehyde), reacts with hydroperoxides or alkaline hydrogen peroxide. Upon hydrolysis of the rearrangement product 13 a dihydroxybenzene, e.g. catechol 14, is obtained ... 

Since reproducibility of the flow system is critical to obtaining reproducibility, one approach has been to substitute lower-performance columns (50-to 100-p packings) operated at higher temperatures.1 Often, improvements in detection and data reduction can substitute for resolution. Chemometric principles are a way to sacrifice chromatographic efficiency but still obtain the desired chemical information. An example of how meaningful information can be derived indirectly from chromatographic separation is the use of system or vacancy peaks to monitor chemical reactions such as the titration of aniline and the hydrolysis of aspirin to salicylic acid.18... 

Fig. 25. Protonation and ligand dissociation mechanism for 0-TRENSOX (26) (176). (A) Four-step hydrolysis mechanism of O-TRENSOX where Q represents 8-hydroxyquinolyl and S the corresponding salicylate coordinating moiety. Charge on the complex has been omitted for clarity. (B) Schematic representation of the salicylate shift of the 8-hydroxyquinolyl donor groups of O-TRENSOX.

This compound can be considered as a derivative of the hydrolysis product, [(H20)3Be(0H)Be(H20)3]3+, in which the bidentate 3-methyl-salicylate ligands each replace two water molecules, the other two water molecules being replaced by a carbonate ion bridging between two beryllium atoms. Similar carbonate bridges have been proposed previously (132). 

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... 

Once absorbed, aspirin is rapidly converted to salicylic acid. After i.v. administration, the half life of aspirin in the human organism was found to be only 15 minutes191 by Rowland and Riegelman who also estimated that only 20% of the in vivo hydrolysis takes place in blood.192... 

Determination in Biological Fluids and Tissues All the advances in pharmacokinetics and drug metabolism described in Sections 7 and 8 would not have been possible without the availability of the proper analytical methods. The following is a tabulation of publications in this field, most of which have already been discussed in Section 5. It should be mentioned that a few publications talk about aspirin blood levels, but really mean salicylate levels. The following tabulation covers only those papers where aspirin was differentiated from other salicylates by chromatography or other means. It seems that the "workhorse" for serum salicylate levels is still the colorimetric (ferric-nitrate) method of Brodie, Udenfriend and Coburn153 published in 1944, or modifications thereof. Simplified versions (cf. 206) may lead to erroneous results under certain conditions.207 The method is also applicable for urinary metabolites after proper hydrolysis (cf. 208). For other methods restricted to salicylic acid, see Section 5.61. 

It is clear that the high efficiency is a property of the salicylate system and is not limited to acetal hydrolysis. Similar highly efficient catalysis is observed also in the hydrolysis of salicyl phosphate [12], and a similar mechanism appears to be involved (Bromilow and Kirby, 1972). The essential structural... 

The thermodynamic EM for the hydrolysis of the salicylate derivative is therefore favoured by a factor presumably similar to that which favours the hydrogen-bonded form of the salicylate anion. In terms of the dissociation constant of the phenol group, which is some 3 pAT units less acidic than expected for a phenol with an ortAo-carboxylate group (Eberson, 1969), a factor of 103, which is of the right order of magnitude to explain the observed effect, could be involved. 

Capon and Ghosh, 1966. No appropriate reference intermolecular reaction rate has been measured for an aryl benzoate. The reference used is the intramolecular general base-catalysed hydrolysis of salicyl salicylate (Kemp and Thibault, 1969) which has fchyd = 2.89 x 10-6 s-1 in water at 30°. If the EM is assumed to be the same as for aspirin (13 M) this corresponds to an intermolecular reaction of an aryl benzoate catalysed by benzoate with k2 = 2.22 x 10-7 dm3 mol-1 s 1. The correction from the pA"-value of salicyl salicylate (3.6) to the pA", of the substrate uses / = 0.5 (cf. 0.52 for the aspirin reaction). The temperature sensitivity is also taken to be equal to that of the aspirin reaction... 

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. 

The salicylimides (4.169) were found to be markedly more resistant to chemical hydrolysis than 4.166. These compounds were hydrolyzed exclusively at the distal amide bond, meaning that hydrolysis produced only sali-cylamide (4.170) and not salicylic acid. This behavior has been ascribed to steric hindrance by the 2-OH group. An intramolecular general base catalysis does not seem to be involved since, as stated, the salicylamides were less reactive than the corresponding benzamides. The rate of plasma-catalyzed hydrolysis of the A-acylsalicylamides was also dependent on the nature of... 

A simple compound to begin our presentation is acetylsalicylic acid (aspirin, 7.44), the well-known analgesic and anti-inflammatory drug whose primary metabolite, salicylic acid (7.45), is also an anti-inflammatory agent but not an analgesic. Extensive kinetic data have been published on the chemical hydrolysis of acetylsalicylic acid as a function of temperature and... 

A variety of hydrolases catalyze the hydrolysis of acetylsalicylic acid. In humans, high activities have been seen with membrane-bound and cytosolic carboxylesterases (EC 3.1.1.1), plasma cholinesterase (EC 3.1.1.8), and red blood cell arylesterases (EC 3.1.1.2), whereas nonenzymatic hydrolysis appears to contribute to a small percentage of the total salicylic acid formed [76a] [82], A solution of serum albumin also displayed weak hydrolytic activity toward the drug, but, under the conditions of the study, binding to serum albumin decreased chemical hydrolysis at 37° and pH 7.4 from tm 12 1 h when unbound to 27 3 h for the fully bound drug [83], In contrast, binding to serum albumin increased by >50% the rate of carboxylesterase-catalyzed hydrolysis, as seen in buffers containing the hydrolase with or without albumin. It has been postulated that either bound acetylsalicylic acid is more susceptible to enzyme hydrolysis, or the protein directly activates the enzyme. 

NSAIDs) has been reported [36]. As shown in Table 8.3, the hydrolysis of the methyl esters in human plasma proceeds far too slowly to be of therapeutic interest, with tm values ranging from ca. 5 to 150 h. In contrast, the carbamoylmethyl benzoates are hydrolyzed very rapidly (perhaps too rapidly ) with tm values in the order of minutes. But Table 8.3 also illustrates another important point, namely the marked influence of the acyl moiety on the rate of hydrolysis, with a more than 500-fold difference between the smallest and the largest acid (salicylic acid and sulindac, respectively). 

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... 

Most published examples of prodrugs of relevance in the present context contain an a-amino acyl moiety. A number of reasons may explain this fact, such as the lack of toxicity of these natural compounds, the large differences in lipophilicity and other properties between amino acids, and the variability afforded by A-substituents. Interesting examples are provided by salicylic acid and metronidazole. Thus, the hydrolysis of tyrosine and methionine prodrugs of salicylic acid (8.104 and 8.105, respectively) was examined in rabbits after intraduodenal and intracecal administration [134], The former ester, but not the latter, was hydrolyzed in the mucosa of the small intestine. In addition, both prodrugs underwent marked hydrolysis by intestinal microflora. 

J. Nakamura, M. Kido, K. Nishida, H. Sasaki, Effect of Oral Pretreatment with Antibiotics on the Hydrolysis of Salicylic Acid-Tyrosine and Salicylic Acid-Methionine Prodrugs in Rabbit Intestinal Microorganisms , Chem. Pharm. Bull. 1992, 40, 2572-2575. 

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... 

In another estimate (Kirby and Percy, 1989), the carboxyl group in l-methoxymethoxy-8-naphthoic acid and the dimethylammonium group in the l-methoxymethoxy-8-A, A -dimethylnaphthylammonium ion are estimated to lead to rate increases by intramolecular catalysis of < ca. 900 and 1.9 X 10 compared to the value of ca. 1 x 10 calculated for the intramolecular catalytic effect of the carboxyl group in 2-methoxymethoxybenzoic acid. The salicylate ion remains the most efficient leaving group thus far discovered that can take part in hydrogen-bond catalysis of the hydrolysis of acetals. 

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