Kolbe-Schmitt process

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. 

Synthesis of salicylic acid by the Kolbe-Schmitt process (see above) is an example for the direct carboxylation of aromatics.34 At the same time, it is also an example for the limitations of such reactions. Formal insertion of C02 into a C-H bond can usually be achieved with compounds containing active hydrogens (such as phenolates), and perhaps more importantly, the product carboxylic acids have to be stabilized by salt formation. Liberation of the free acid from such carboxylates requires a mineral acid and produces 1 equiv of inorganic salt (waste) (Scheme 6.1). 

C02 in methanol synthesis, the synthesis of cyclic carbonates from C02 and epoxides, and the production of salicylic acid according to the Kolbe-Schmitt process. 

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... 

The Kolbe-Schmitt reaction is an equilibrium process governed by thermodynamic control The position of equilibrium favors formation of the weaker base (salicylate ion) at the expense of the stronger one (phenoxide ion) Thermodynamic control is also responsible for the pronounced bias toward ortho over para substitution Salicylate anion IS a weaker base than p hydroxybenzoate and predominates at equilibrium... 

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. 

Hessel V, Hofmann C, Lob P, Lohndorf J, Lowe H, Ziogas A (2005) Aqueous Kolbe-Schmitt synthesis using resorcinol in a microreactor laboratory rig under high-P,T conditions. Org Process Res Dev 9 479-489 Inoue T, Schmidt MA, Jensen KF (2007) Microfabricated multiphase reactors for the direct synthesis of hydrogen peroxide from hydrogen and oxygen. Ind Eng Chem Res 46 1153-1160... 

Using the high-p,T microreactor processing, the Kolbe-Schmitt synthesis was completed within less than 1 min at comparable yields, i.e., a reaction time reduced by a factor of approximately 2,000 was achieved (see Fig. 6). This corresponds to an increase in space-time yield by a factor of 440. 

Fig. 6. Process intensification of the aqueous Kolbe-Schmitt synthesis of resorcinol using high-p,T processing. (Courtesy of ACS)...

Hessel V, Lowe H, Muller A, Kolb G (2005d) Chemical micro process engineering—processing and plants. Wiley-VCH, Weinheim Hessel V, Hofmann C, Lob P, Lowe H, Parals M (2007) Micro-reactor processing for the aqueous Kolbe-Schmitt synthesis of hydroquinone and phloro-glucinol. Chem Eng Technol 31, (in press)... 

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 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. 

Phadtare, P. G., Doraiswamy, L. K. Kolbe-Schmitt carbonation of 2-naphthol. Confirmation of the mass transfer model and process optimization. Industrial Engineering Chemistry Process Design and Development 1969, 8, 165-173. 

Salicylates are a special class of carboxylates and can be described by the general structure below the alkyl hydrocarbon radical R typically varies from 12 to 30 carbon atoms. Salicylates are a combination of phenate and carboxylate chemical functions. The chemical process generally used to prepare these substrates is known as the Kolbe-Schmitt reaction and involves the high-temperature reaction of an alkali metal phenate and carbon dioxide [20] ... 

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. 

The Kolbe-Schmitt synthesis using resorcinol with water as solvent to give 2,4-dihydroxybenzoic acid (Scheme 6.9) is a very reactive example of such reachons, since resorcinol is electron rich as compared to other phenols [39, 40]. Although this allows one to circumvent the high-pressure autoclave process typically used, and to establish liquid-phase operahon under ambient pressure, reaction hmes of about 2 h are shU needed at 100 °C (reflux condihons). 

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