Salicylic acid: esterification

Methyl salicylate is produced synthetically for commercial purposes by the esterification of salicylic acid with methanol or by extraction by steam distillation of wintergreen leaves or sweet birch bark. The source, natural or synthetic, is declared on the label. The methyl salicylate NF must assay not less than 98.0% and not more than 100.5% and be processed by Good Manufacturing Practice described in USP (20). 

However, this method is appHed only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, cellulose esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsahcyhc acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is greatiy increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphoms pentoxide, 2inc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4-dimethylaminopyridine. 

The esterification of the phenolic hydroxyl group in salicylic acid with acetic acid results not only in an... 

Only four years after Kekule proposed the ring structure for benzene, and before the configuration of salicylic acid was established, Kraut concluded on the basis of sound chemical evidence that the products obtained on heating acetylsalicylic acid possess chain structures formed through intermolecular esterification. He assigned the dimeric and tetrameric formulas... 

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... 

Note that in nature, these are all enzyme-catalysed reactions. This makes the reactions totally specific. It means possible competing Sn2 reactions involving attack at either of the two methylene carbons in SAM are not encountered. It also means that where the substrate contains two or more potential nucleophiles, reaction occurs at only one site, dictated by the enzyme. The enzymes are usually termed methyltransferases. Thus, in animals an A-methyltransferase is responsible for SAM-dependent A-methylation of noradrenaline (norepinephrine) to adrenaline (epinephrine), whereas an O-methyltransferase in plants catalyses esterification of salicylic acid to methyl salicylate. 

The esters of salicylic acid account for an increasing fraction of the salicylic acid produced, about 15% in the 1990s. Typically, the esters are commercially produced by esterification of salicylic acid with the appropriate alcohol using a strong mineral acid such as sulfuric as a catalyst. To complete the esterification, the excess alcohol and water are distilled away and recovered. The cmde product is further purified, generally by distillation. For the manufacture of higher esters of salicylic acid, transesterification of methyl salicylate with the appropriate alcohol is the usual route of choice. However, another reaction method uses sodium salicylate and the corresponding alkyl halide to form the desired ester. 

Sahcylsalicylic acid [532-94-3] (salsalate) is prepared by the action of phosphoms trichloride, phosphoms oxychloride, or thionyl chloride on salicylic acid at low temperatures in an appropriate solvent. The cmde product is recrystallized rapidly from ethyl alcohol to avoid hydrolysis and esterification. It is used as an analgesic and an antipyretic, as well as in the treatment of acute and chronic rheumatism and arthritis. It does not induce gastric disturbances because it is only slowly hydrolyzed in the intestine. Owing to the slowness of its hydrolysis (two molecules of salicylic acid per molecule of the ester), the action of sahcylsalicylic acid is less prompt but more persistent than that of other salicylates. Other salicylates of interest include ethylene glycol mono salicylate [87-28-5], dipropylene glycol monomethylether salicylate, bomyl salicylate [560-88-3], and -acetamidophenyl salicylate [118-57-0]. 

Alkyl and aralkyl salicylates, are sensorially important phenolcarboxylates that are used in flavors and fragrances. The following salicylates are used in perfume and flavor compositions and can be prepared by esterification of salicylic acid. 

Since salicylic acid has both an alcohol functional group and a carboxylic acid functional group, it can undergo two different esterification reactions depending on which functional group reacts. For example, when treated with ethanoic acid (acetic acid), salicylic acid behaves as an alcohol and the ester produced is acetylsalicylic acid (aspirin). On the other hand, when reacted with methanol, salicylic acid behaves as an acid and the ester methyl salicylate (oil of wintergreen) is produced. Methyl salicylate is also an analgesic and part of the formulation of many liniments for sore muscles. What are the structures of acetylsalicylic acid and methyl salicylate ... 

Recently [43] Gao et al. applied a zeolite-fiOlled polyvinyl alcohol (PVA) membrane in esterification and acetalization reactions. Zeolites NaA, KA and CaA as well as NaX were loaded into PVA up to 27 wt% and the composites tested in selective water removal during reaction. A pervaporation cell with a membrane area of 22.9 cm was coimected to a collection system kept at a vacuum of 0.1 mm Hg. A sulfonated resin was used as Bronsted acid catalyst in the esterification mixture (120 ml). Figure 28 shows the progress of the esterification of salicylic acid and methanol at 60°C. The reaction is accelerated considerably as a result of the water removal. 

S, Methyl Salicylate. 2-Hydroxybenzoic acid methyl ester wintergreen oil betula oil sweet birch oil teaberry oil. C H,03 mol wt 152.14. C 63.15%, H 5.30%. O 31.55% Present in leaves of Oaultherta procumbent L-> Ericaceae, in the bark of Betula lenta L., Betulaceae, hut mostly prepd by esterification of salicylic acid with methanol. The product of commerce is about 99% pure. 

It may be prepared by the esterification of acetyl salicylic acid and paracetamol with the elimination of a mole of water. 

Methyl 2-hydroxybenzoate (methyl salicylate) has the odor of oil of wintergreen.This ester is prepared by the Fischer esterification of 2-hydroxybenzoic acid (salicylic acid) with methanol. Draw a structural formula of methyl 2-hydroxybenzoate. 

Gao, Yue, and Li (1996) studied the same reaction using a zeolite A-PVA composite membrane (at temperatures ranging from 20 to 50 °C). In this work, together with the pervaporation-aided catalytic esterification of acetic acid with ethanol, the reaction between salicylic acid with methanol was also treated. Among other results, it showed that the continuous removal of water from the system displaced the equilibrium limit (79%), making possible a 95% conversion, when using PVA, PVA -I- KA, and PVA -I- CaA membranes for 20.0, 11.3, and 10.0 h, respectively. 

Bochner, M., S. Gerber, W. Vieth A. Rodger (1%5) Ion exchange resin-catalyzed esterification of salicylic acid with methanol. Industrial Engineering Chemistry Fundamentals, 4, 314-317,ISSN 01%-4313. 

In this reaction, the hydroxyl group (—OH) on the benzene ring in salicylic acid reacts with acetic anhydride to form an ester functional group. Thus, the formation of acetylsalicylic acid is referred to as an esterification reaction. This reaction requires the presence of an acid catalyst, indicated by the above the equilibrium... 

Methyl salicylate will be prepared from salicylic acid, which is esterified at the carboxyl group with methanol. You should recall from your organic chemistry lecture course that esterification is an acid-catalyzed equilibrium reaction. The equilibrium does not lie far enough to the right to favor the formation of the ester in high yield. More product can be formed by increasing the concentrations of one of the reactants. In this experiment, a large excess of methanol will shift the equilibrium to favor a more complete formation of the ester. 

Write a mechanism for the acid-catalyzed esterification of salicylic acid with methanol. You may need to consult the chapter on carboxylic acids in your lecture textbook. 

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