Sodium salicylate, synthesis

Since, in Kolbe s synthesis, as here described, the mono-sodium salicylate reacts to some extent with unchanged sodium phenoxide, producing the di-sodium salt, part of the phenol is liberated and excluded from the reaction. The reaction proceeds to completion if the sodium phenoxide is heated to about 150° for a long time, with carbon dioxide under pressure in the autoclave. This is the technical method of Schmitt. 

Hypersensitivity to salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs). Use extreme caution in patients with history of adverse reactions to salicylates. Cross-sensitivity may exist between aspirin and other NSAIDs that inhibit prostaglandin synthesis, and aspirin, and tartrazine. Aspirin cross-sensitivity does not appear to occur with sodium salicylate, salicylamide, or choline salicylate. Aspirin hypersensitivity is more prevalent in those with asthma, nasal polyposis, chronic urticaria. 

Early Synthesis. Reported by Kolbe in 1859, the synthetic route for preparing the acid was by treating phenol with carbon dioxide in the presence of metallic sodium (6). During this early period, the only practical route for large quantities of salicylic acid was the saponification of methyl salicylate obtained from the leaves of wintergreen or the bark of sweet birch. The first suitable commercial synthetic process was introduced by Kolbe 15 years later in 1874 and is the route most commonly used in the 1990s. In this process, dry sodium phenate reacts with carbon dioxide under pressure at elevated (180—200°C) temperature (7). There were limitations, however not only was the reaction reversible, but the best possible yield of salicylic acid was 50%. An improvement by Schmitt was the control of temperature, and the separation of the reaction into two parts. At lower (120—140°C) temperatures and under pressures of 500—700 kPa (5—7 atm), the absorption of carbon dioxide forms the intermediate phenyl carbonate almost quantitatively (8,9). The sodium phenyl carbonate rearranges predominately to the 07 0-isomer, sodium salicylate (eq. 8). 

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). 

It will have been noted that in the formation of salicylic acid, only one half of the phenol is converted the rest is obtained unchanged. Schmitt (Dingier s Polyteehnisches Journal, 255, 259) succeeded in modifying the synthesis to obviate this defect, and his is the method always used industrially, although the other is more convenient in the laboratory. In Schmitt s synthesis sodium phenyl carbonate is prepared by heating up to 120°—140° dry sodium phenolate with carbon dioxide in autoclaves under pressure. Complete transformation of the intermediate sodium phenyl carbonate to mono-sodium salicylate then occurs on further heating. The carbon dioxide may be led in from a cylinder under pressure, or liquid or solid carbon dioxide may be mixed directly with the sodium phenolate in the autoclave. If preferred, the sodium phenyl carbonate can be prepared at ordinary pressures at 110° and then heated under pressure at 140°. 

Both salicylic acid and sodium salicylate (its sodium salt) were widely used analgesics in the nineteenth century, but both had undesirable side effects. Salicylic acid irritated the mucous membranes of the mouth and stomach, and sodium salicylate was too sweet for most patients. Aspirin, a synthetic compound, was first sold in 1899 after Felix Hoffman, a German chemist at Bayer Company, developed a feasible commercial synthesis. Hoffman s work was motivated by personal reasons his father suffered from rheumatoid arthritis and was unable to tolerate the sweet taste of sodium salicylate. 

Acetic anhydride is produced by the direct oxidation of ethylene in the presence of air. The synthesis of salicylic acid involves the combination of several reactants. Sodium hydroxide (NaOH) reacts with phenol (CeHsOH) to give sodium phenolate and water. Sodium phenolate reacts with carbon dioxide (CO2) to obtain sodium salicylate. The subsequent acidification with H2SO4 leads to pure salicylic acid and sodium sulfate. 

Another type of micelle formation has also attracted the attention of researchers, a brief mention of which will be made below. Gravsholt [93], in an early work, reported viscoelasticity in highly diluted aqueous solutions of some cationic surfactants, namely, certain derivatives of the base structure of cetyltrimethylammonium bromide (CTAB), CTA-X (where X=salicylate, m-chlorobenzoate, p-chlorobenzoate). He came to the conclusion that the viscoelastic behavior indicates a micellar shape other than spheres and rods. Later it has been shown [e.g. 94] by fluorescence anisotropy using fluorescent probe molecules that CTAB and sodium p-toluenesulfonate, NapTS (with suitably weak fluorescence) in aqueous solution could produce long, threadlike micelles with network structure in which the cross-points had finite lifetime. Sodium salicylate was another useful additive for synthesis, but the intensity of its fluorescence was found unsuitable for examining the behavior of the probes. 

The presently dominant process for the production of salicylic acid is based on the Kolbe-Schmitt synthesis. Hermann Kolbe and E.Lautemann described the reaction of carbon dioxide with sodium phenolate to produce sodium salicylate and its subsequent reaction with sulfuric acid to yield salicylic acid, in 1860. However, as a result of the formation of di-sodium salicylate in this process, only half the phenol was converted into salicylic acid. Rudolf Schmitt modified the synthesis in 1884, by first bringing into contact carbon dioxide with cold, dry sodium phenolate, then heating the mixture under pressure to 120 to 140 °C. 

A working electrode made of a copper rod (5 mm diameter) and platinum disk (3 mm diameter) sealed in a Teflon holder using epoxy resin is realized. This electrode is polished with aqueous suspensions of alumina (1 pm) and then polarized at 1V vs. SCE. The polymerization medium is an aqueous solution containing the pyrrole monomer (0.5 M) and sodium salicylate (IM). PPy electrodeposition on copper is performed either potentiostatically (0.6 V) or galvanostatically (0.5 to 5 mA cm ) for 1 min. After the synthesis, the PPy film is rinsed with water and its electroactivity checked by cycling from —IV to -1-0.5 V in a monomer-free solution, with a pH adjusted to 6 by addition of salicylic acid or soda. 

Phenoxide ions react with carbon dioxide to give a carboxylic acid salt as shown by the industrial synthesis of salicylic acid, the starting material for the production of aspirin (Section 18.5B). Phenol is dissolved in aqueous NaOH, and this solution is then saturated with CO2 under pressure to give sodium salicylate. 

FIGURE 5.1 Examples of reactions involving carbon dioxide and leading to intermediates in industrial synthesis. Top The reaction of carbon dioxide with sodium phenolate to produce sodium salicylate. Bottom The reaction of carbon dioxide with an epoxide to make a cyclic organic carbonate. 

Some of the numerous adverse effects of aspirin on metabolism have been reviewed previously (136 ). Aspirin reduces the urinary excretion of prostaglandin metabolites, and may lower the serum calcium in patients with hypercalcaemia associated with malignancy (177). Sodium salicylate interferes with the synthesis of cartilage glycosamino-glycans and the question of long-term deleterious effects on articular cartilage has been raised (178). 

A French chemist, Gharles Frederic Gerhardt was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the s)mthesis and properties of various add anhydrides, he mixed acetyl chloride with sodium salicylate (Fig. 14.4). Since no structural theory existed at that time, Gerhardt assigned the compound he synthesised as salicylic-acetic anhydride. Six years later, in 1859, in Marburg, Kolbe successfully performed the structure elud-dation and synthesis of salicylic add. In the same year, von Gilm obtained analytically pure acetylsalicylic add... 

The key compound m the synthesis of aspirin salicylic acid is prepared from phe nol by a process discovered m the nineteenth century by the German chemist Hermann Kolbe In the Kolbe synthesis also known as the Kolbe—Schmitt reaction, sodium phen oxide IS heated with carbon dioxide under pressure and the reaction mixture is subse quently acidified to yield salicylic acid... 

Section 24 10 The Kolbe-Schmitt synthesis of salicylic acid is a vital step m the preparation of aspirin Phenols as their sodium salts undergo highly regioselective ortho carboxylation on treatment with carbon dioxide at elevated temperature and pressure... 

Kolbe-Schmitt reaction (Section 24 10) The high pressure re action of the sodium salt of a phenol with carbon dioxide to give an o hydroxybenzoic acid The Kolbe-Schmitt reac tion IS used to prepare salicylic acid in the synthesis of as pinn... 

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