Salicylic acid Kolbes reaction

Current Methods. The general outline of the Kolbe-Schmitt reaction, as it is employed in the 1990s, is as follows. In the first step, phenol and hot aqueous caustic are mixed to produce the sodium phenate which is taken to dryness. Next, the phenate and dry carbon dioxide are introduced into the carbonator. Air is excluded to minimize oxidation and the formation of colored compounds. The gas—solid mixture is agitated and heated, first at low temperature, followed by several hours at higher temperatures, to complete the formation of sodium salicylate. Variations of this reaction have been noted in the literature and are still being investigated (10,11). One reported scheme produces salicylic acid or substituted salicylic acids by reaction of a granulated alkali metal salt of the respective phenolic compound with C02 in a fluidized bed at 20—130°C until at least 50—80% of the metal salt has been converted to... 

Salicylic acid. The preparation of salicylic acid by passing carbon dioxide into dry sodium phenoxide at 170-190° is the classical example of the Kolbe-Schmltt reaction. The latter is a method for introducing a carboxyl group directly into a phenol nucleus. 

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... 

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... 

Carbon dioxide reacts with phenolates 1 to yield salicylate 2 with less reactive mono-phenolates, the application of high pressure may be necessary in order to obtain high yields. This reaction, which is of importance for the large scale synthesis of salicylic acid, is called the Kolbe-Schmitt reaction ... 

The Kolbe-Schmitt reaction is limited to phenol, substituted phenols and certain heteroaromatics. The classical procedure is carried out by application of high pressure using carbon dioxide without solvent yields are often only moderate. In contrast to the minor importance on laboratory scale, the large scale process for the synthesis of salicylic acid is of great importance in the pharmaceutical industry. 

KOH plants, environmental awareness in, 20 634. See also Potassium hydroxide KOH solution, 12 215 meta-Koksowy coal grade (Poland), 6 713t Kolbe-Schmidt reaction, 2 208 of salicylic acid synthesis, 22 7-8 Kolmogoroff microscale, 16 697 Konica Dry Color System, 19 348 Konjac glucomannan, 4 7241... 

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). 

A large number of salts of salicylic acid have been prepared and evaluated for therapeutic or other commercial use. Table 7 lists those most frequently referenced. Sodium salicylate has analgesic, antiinflammatory, and antipyretic activities and was used extensively in the sixteenth and seventeenth centuries as a remedy, prepared from natural sources, for arthritis and rheumatism. In the 1990s the salt can be obtained directly from Kolbe-Schmitt carboxylation or by the reaction of salicylic acid with either aqueous sodium bicarbonate or sodium carbonate. The resulting mixture is heated until effervescence stops the salt is then isolated by filtration and evaporation to dryness at low temperatures. Generally, the solution must be kept slightly acidic so that a white product is obtained if the mixture is basic, a colored product results. The USP product contains 99.5—100.5% NaC H503 (anhydrous). The May 1996 price was 8.15/kg (18). 

It may also have been unfortunate for Couper that he was an excellent experimentalist, because his greater skill in the laboratory unwittingly gave ammunition to his opponents. In his early work that culminated in stmctural theory, he reported the formation of a cyclic compound from the reaction between phosphoms pentachloride and salicylic acid (57). Both Kekule (56) and Kolbe (57) attempted to reproduce his reaction without success, and used their failure to duplicate his results to cast doubt on his other claims. It was not until a better experimentalist, Richard Anschutz, repeated Couper s work exactly as he had set out in his paper that his skill as an experimentalist was confirmed, and his... 

Carbonation Kolbe reaction Treatment of a salt of a phenol with CO2 replaces a ring hydrogen with a carboxyl group. This reaction is applied in the conversion of phenol itself into ort/io-hydroxybenzoic acid, known as salicylic acid. Acetylation of salicylic acid produces acetylsalicylic acid (aspirin), which is the most popular painkiller in use today. 

In general a phenol will undergo direct carboxylation of the nucleus when the dry sodium salt is heated under pressure with carbon dioxide (the Kolbe-Schmidt reaction). Addition of the weakly electrophilic carbon dioxide is promoted by electron release from the oxyanionic site. With phenol itself the ultimate product is salicylic acid (o-hydroxybenzoic acid) predominantly ortho attack may be attributable to stabilisation of the transition state through chelation. 

The carboxylation of phenols is a well established process for synthesis of salicylic acid according to the Kolbe-Schmitt method (Table 4, entry 39). The exothermic reaction is carried out at slightly elevated temperatures around 150 °C and pressures of approximately 5 bar. Batch processes are still mainly used. The main task is to exclude water from the reaction mixture, because this would release the alkali metal hydroxide from the phenoxide salt. 

The phenoxide ion is even more reactive towards electrophilic attack than phenol. It will even react with such weak electrophiles as carbon dioxide. This reaction, known as the Kolbe-Schmitt process, is used industrially to prepare salicylic acid, a precursor in making aspirin. 

Salicylic acid is prepared today exclusively by the Kolbe-Schmitt method, in which absolutely dry sodium phenolate is treated with dry carbon dioxide, first at ordinary temperature, then at 125° under a pressure of 4 to 7 atmospheres. The reaction proceeds quantitatively if the salt is completely dry and pulverized to a dust. This fine subdivision is achieved by drying and grinding in a vacuum. 

More active aromatic compounds, such as resorcinol and a-naphthol, are carboxylated in excellent yields by heating their alkali salts with carbon dioxide (Kolbe reaction). The carboxyl group of salicylic acid migrates to the para position when this compound is heated to 240° with potassium carbonate the p-hydroxybenzoic acid is obtained in 80% yield. ... 

The formation of the phenoxide anion enhances the reactivity of the ortho and para positions of the aromatic ring towards electrophilic reagents. The reaction of the phenoxide anion with carbon dioxide at 130 °C leads to ortho carboxylation (the Kolbe reactior. Thus phenol gives salicylic acid (4.4), the acetate of which is aspirin. The reaction is reversible and ortho phenolic acids undergo decarboxylation on heating. 

Treatment of the salt of a phenol with carbon dioxide brings about substitution of the carboxyl group, COOH, for hydrogen of the ring. This reaction is known as the Kolbe reaction its most important application is in the conversion of phenol itself into o-hydroxybcnzoic acid, known as salicylic acid. Although some p-hydroxybenzoic acid is formed as well, the separation of the two isomers can be... 

Kolbe-Schmitt reaction Synthesis of salicylic acid der. from phenols and CO2. 248... 

A phenoxide ion, therefore, might be expected to undergo certain reactions characteristic of carbanions at the ortho and para positions. One of the best-known examples of such a reaction is the Kolbe synthesis of salicylic acid in which the carbanion form of the phenoxide ion undergoes addition to the carbonyl group of carbon dioxide 49... 

The classical Kolbe-Schmidt reaction treats alkali metal phenoxides and carbon dioxide at higher than atmospheric pressure, giving salicylic acid. Hirao and Kato developed several modifications for industrial production ". Recently, phenol phosphate was enzymatically carboxylated, giving p-hydroxybenzoic acid ". As for related reactions, Sartori and coworkers conducted o-carbamoylation of aluminum or boron phenoxides with alkyl isocyanate ", and Adachi and Sugasawa o-cyanated phenols using methyl thioisocyanate in the presence of BCI3 (equation 54). ... 

An easier method of production of p-anisic acid is methy-lation of p-hydroxy benzoic acid obtained as a co-product during manufacture of o-hydroxy benzoic acid (salicylic acid) via Kolbe reaction of phenol and CO2... 

Enter obacter sp., S. aureus, S. agalactiae, and S. mar ce see ns (Rob son et al., 1982). At concentrations exceeding 90%, Dermaide inhibited E. coli, C. albicans, and S. pyogenes. It did not inhibit B. subtilis at any concentration. The aloe vera extract contained 3.6 mg/dL of salicylic acid. Other components, emodin, emolin, and barbaloin are converted to salicylic acid by the Kolbe reaction, perhaps explaining in part the anti-inflammatory activity of the extract (Robson et al., 1982). 

---