Salicylic acid Kolbe synthesis

Carbon dioxide is the most abundant heterocumulene on earth. The total amount of carbon dioxide in the atmosphere and in the oceans is estimated to represent lO tons of carbon. However its industrial use is currently not extensive. Examples of its industrial use include the production of urea, the Kolbe-Schmitt synthesis of salicylic acid, methanol synthesis and the synthesis of cyclic carbonates. Future industrial uses of carbon dioxide can be anticipated because it will become readily available by sequestering from the air. 

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... 

KOLBE - SCHMIDT Salicylic Acid Synthesis Caiboxylation (usually ortho) of phenols. Industrial method to obtain salicylic acid derivatives... 

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). 

The active principle was shown to be salicin by Buchner in 1828 but the bitter taste and damage to the gastric mucosa limited its use. Piria isolated salicylic acid from salicin in 1838. In 1859, Kolbe discovered the structure and synthesis of salicylic acid and in 1897 acetylsalicylic acid was synthesized by Hoffmann. Two years later, in 1899, acetylsalecylic acid, the first nonsteroidal antiinflammatory drug was registered under the name Aspirin (Fig. 2). 

It is an interesting fact that if potassium phenolate is used in the Kolbe synthesis para-hydroxy benzoic acid is obtained, especially at high temperatures. Potassium phenyl carbonate is first formed, and heated up to 150° yields salicylic acid, but if the temperature be further raised, the para-acidis produced in increasing quantities until at 220° potassium para-hydroxy-benzoic acid is the sole product. 

The use of C02 in chemistry normally requires its interaction with metal centers of catalysts one such example is the Kolbe-Schmitt carboxylation of phenol to produce salicylic acid. The potential of C02 as a raw material in the synthesis of carboxylates, carbonates, or carbamates is rather limited. A future aim is the economically attractive synthesis of carboxylic acids, or optically... 

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. 

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... 

A modification of the Kolbe synthesis which permits the immediate conversion of all the phenol into salicylic acid is known as Schmitt s synthesis. According to this method, as in the other, the sodium phenyl carbonate is first prepared this is then further heated in an... 

The Kolbe synthesis is capable of very common application, since from each mon-add phenol, a carbonic add may be obtained in the same way as that used above. The carboxyl group under these conditions primarily seeks the ortho position to the hydroxyl group. The derivatives of phenols, e.g. the three chlorphenols, yield chlorinated salicylic adds. With acid-ethers of poly-add phenols which still con-... 

Another active principle soon extracted from plants was salicylic acid. Salicin, extracted from the willow tree, has been launched in 1876 by a Scottish physician, Thomas John McLogan It was in extensive competition with Cinchona bark and quinine and never became a very popular treatment for fever or rheumatic symptoms. The Italian chemist Raffaele Piria, after having isolated salicylalde-hyde (1839) in Spireae species, prepared salicylic acid from salicin in Dumas laboratory in the Sorbonne, Paris. This acid was easier to use and was an ideal step before future syntheses. Its structure was closely related to benzoic acid, an effective preservative useful as an intestinal antiseptic for instance in typhoid fever. Acetylsalicylic acid has been first synthesized by Charles Frederic Gerhardt in 1853 and then, in a purer form, by Johann Kraut (1869). Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest. 

Thermodynamic analysis indicates that such reactions are on the whole unfavorable. Furthermore, the complexity and uncertainty of the mechanism by which such reactions may occur makes the choice of proper catalysts largely an empirical selection. However, it must not be overlooked that such reactions as the Kolbe-Schmitt synthesis of salicylic acid from dry sodium phenoxide and carbon dioxide represent processes, the success of which might point the direction to the solution of the problems attending the realization of the type reactions mentioned above. 

SCHEME 6.1 Kolbe-Schmitt synthesis of salicylic acid. 

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