Kolbe-Schmitt carboxylation reaction

The first step in the industrial synthesis of aspirin is known as the Kolbe-Schmitt carboxylation reaction. The phenolate ion reacts with carbon dioxide under pressure to form o-hydroxybenzoic acid, also known as salicylic acid. Acetylation of salicylic acid with acetic acid forms acetylsalicylic acid (aspirin). 

Kolbe-Schmitt carboxylation reaction a reaction that uses CO to carboxylate phenol. 

A large number of salts of sahcyhc acid have been prepared and evaluated for therapeutic or other commercial use. Table 7 hsts those most frequently referenced. Sodium sahcylate 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 sahcyhc 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 H O (anhydrous). The May 1996 price was 8.15/kg (18). 

The enzymes catalyzing the Kolbe-Schmitt carboxylation seem to occur ubiquitously. Some of them, such as 2,6-dihydroxybenzoate decarboxylase and pyrrole-2-carboxylate decarboxylase, catalyze efficiently the reverse carboxylation reaction and accumulate high concentration of 2,6-dihydroxybenzoate from 1,3-dihydroxybenzene and pyrrole-2-carboxylate from pyrrole, respectively, in the... 

Tommasi et al. recently reported the carboxylation of l,3-dialkyHmidazoHum-2-carboxylates, which can be seen as a remarkable variant of the Kolbe-Schmitt synthesis [27]. In this case, it was shown that l,3-dialkyBmidazolium-2-carboxylates could be synthesized from 1,3-diaIkylimidazolium chlorides and C02 via a Kolbe-Schmitt-type reaction (actually, this was more of a Marasse variant, run in solution). The starting compounds were carboxylated in anhydrous dimeth-ylformamide (DMF) under approximately 5 MPa C02, at temperatures ranging from 353 to 408 K and with Na2C03/C02 as a catalyst, according to Scheme 5.4. 

CARBOXYLATION OF PHENOLS ASPIRIN AND THE KOLBE-SCHMITT REACTION... 

Carboxylation of Phenols Aspirin and the Kolbe-Schmitt Reaction... 

Sodium phenoxides can be carboxylated, mostly in the ortho position, by carbon dioxide (the Kolbe-Schmitt reaction). The mechanism is not clearly understood, but... 

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-Schmitt reaction. The latter is a method for introducing a carboxyl group directly into a phenol nucleus. 

Kolbe hydrocarbon synthesis orgchem The production of an alkane by the electrolysis of a water-soluble salt of a carboxylic acid. kol-bo. hT-dro kar-bon, sin-th3-s3s Kolbe-Schmitt synthesis org chem The reaction of carbon dioxide with sodium phenoxide at 125°C to give salicyclic acid. kol-bo shmit, sin-th3-s3s Konowaioff ruie phys chem An empirical rule which states that in the vapor over a liquid mixture there is a higher proportion of that component which, when added to the liquid, raises its vapor pressure, than of other components., k6-n9 va-lof, rul ... 

Carboxylation with Carbon Dioxide. The Kolbe-Schmitt Reaction Carboxylation or Carboxy-de-hydrogenation... 

The Kolbe-Schmitt reaction produces O- and C-carboxylation through the reaction of carbon dioxide with sodium benzenolate at 125° ... 

The Kolbe-Schmitt reaction is related to enzymatic carboxylations as of D-ribulose 1,5-diphosphate with carbon dioxide, a key step in photosynthesis (Section 20-9). The overall result is C—C bond formation by addition of C02 to an enolate salt or its enamine equivalent. 

Both, the Kolbe-Schmitt reaction and the dialkyl carbonate route may be beneficial, notably when taking into account the former syntheses used to produce these carboxylato derivatives. Prior to the study of Tommasi et al., the formation of imi-dazolium carboxylates via highly reactive N-heterocydic carbenes (NHC) had been reported, although this rather challenging synthesis could not be extended to an industrial scale. The synthesis of l,3-diisopropyl-4,5-dimethyl-imidazohum-... 

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. 

Carboxylation reactions based on carbon dioxide have a great interest as the direct introduction of the carboxylic functionality represents, wth respect to the conventional synthetic methodologies, a way for both saving energy and reducing the production of wastes. Despite such aspects, that have a positive environmental impact, the only "direct carboxylation" process exploited at the industrial level is the more-than-one-hundred-years old Kolbe-Schmitt reaction. This process converts phenol (in the form of a Group 1 element salt) and carbon dioxide into a mixture of o- and p-OH-benzoic acid. The major product depends on the reaction conditions and the metal used (Na or K, respectively). This reaction has been recently reviewed [4] by several research groups and extended to other substrates. 

The nmr chemical shifts of alkah metal ( K, Na etc.) phenoxide moved to down field upon formation of the complex, [ phenoxide-M CO2] with carbon dioxide in the Kolbe-Schmitt reaction. The complex formed under pressure of carbon dioxide showed more increments in weights and chemical shifts, as much as 0.72 ppm of (5 paia of potassium phenoxide at 5 MPa. The kinetic studies on the carboxylation of resorcinol in aqueous hydrogencarbonates with carbon dioxide revealed an equilibrium between resorcinol and the product or resorcylic acid. 

The Kolbe-Schmitt reaction[l] has long history related with aspirin and has been a name reaction used for the longest period in an industrial process. While the demand for the manufacturing aromatic hydroxycarboxyhc acids is still successively coming out today with a number of patents, the mechanism of the reaction has remained unsolved. The present nmr spectroscopic studies have proved a [substrate CO2] complex or an intermediate prior to the formation of carboxyhc acids. Another puzzling question about the unstable complex even to moisture, is why the carboxylation of polyhydroxybenzenes, such as resorcinol, should proceed in aqueous solutions. Herein also reported are kinetic studies on the carboxylation of resorcinol in aqueous solutions of alkali hydrogencarbonates. 

The Kolbe-Schmitt reactions of polyhydroxy phenols such as resorcinol, pyrogallol and phloroglucinol are exceptionally carried out in aqueous solution.[6] Any explanation has not yet been given to the reason of the exception. Kinetic studies on the carboxylation of resorcinol (ROH) with hydrogencarbonate (KHCO-O were carried out in aqueous solutions. 

The mechanism of the Kolbe-Schmitt reaction was investigated since the late 1800s, but the mechanism of the carboxylation could not be elucidated for more than 100 years. For a long time, the accepted mechanism was that the carbon dioxide initially forms an alkali metal phenoxide-C02 complex, which is then converted to the aromatic carboxylate at elevated temperature. The detailed mechanistic study conducted by Y. Kosugi et al. revealed that this complex is actually not an intermediate in the reaction, since the carefully prepared phenoxide-C02 complex started to decompose to afford phenoxide above 90 °C. They also demonstrated that the carboxylated products were thermally stable even at around 200 °C. The CO2 electrophile attacks the ring directly to afford the corresponding ortho- or para-substituted products. (When the counterion is large (e.g., cesium) the attack of CO2 at the ortho-position is hindered therefore, the para-substituted product is the major product.)... 

Phenols that have more than one hydroxyl group may be carboxylated with CO2 at atmospheric pressure under basic conditions. The research team of Y.-C. Gao synthesized 3,5-di-fert-butyl-y-resorcylic acid from 4,6-di-fert-butyl resorcinol using the Kolbe-Schmitt reaction under these conditions. The resorcylic acid derivative was needed in order to prepare ternary complexes of lanthanide(lll)-3,5-di-fert-butyl-Y-resorcylate with substituted pyridine-A/-oxide. 

B.S. Green and co-workers developed an improved preparation of the clathrate host compound tri-o-thymotide (TOT) and other trisalicylide derivatives. The synthesis began with the preparation of orfho-thymotic acid from thymol using the Kolbe-Schmitt reaction. The authors found that the yield of the product was dramatically increased when the reactants, solvents, and reagents were dried before use. Thus, thymol was dissolved in dry xylene, sodium metal was added and the temperature was kept at 130 °C for 20h in a dry carbon dioxide atmosphere. The desired carboxylated product was isolated in good yield. Finally, cyclodehydration with POCI3 afforded TOT in almost quantitative yield. 

The first enantioselective total synthesis of the fungal metabolite (+)-pulvilloric acid was accomplished by H. Gerlach et al. At the final stages of the synthetic effort the carboxylic acid moiety was installed via the Kolbe-Schmitt reaction using CO2 at atmospheric pressure. The final formylation and ring-closure were achieved with triethyl orthoformate. 

Kosugi, Y., Takahashi, K. Carboxylation reaction with carbon dioxide. Mechanistic studies on the Kolbe-Schmitt reaction. Stud. Surf. Sci. Catal. 1998, 114,487 90. 

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