Processing Kolbe-Schmitt synthesis

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)... 

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). 

Lowe, H., Parals, M., Micro-reactor processing for the aqueous Kolbe-Schmitt synthesis of hydroquinone and phlorogludnol, Chem. Eng. Technol. 30(3)... 

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. 

The aqueous Kolbe-Schmitt synthesis with resorcinol needs about 2h to achieve a 50% yield of the product under typical batch conditions with reflux of the solvent water (100 °C) [42]. In a setup with a minitube reactor and microcooler for quenching the reaction, high-temperature conditions at high pressures can be easily realized. Operation up to 200 °C at pressures of 40-70 bar allows a reduction of the reaction time to about 1 min or below with maximum yields of 45%. Similar findings were made for the phloroglucinol-based Kolbe-Schmitt synthesis [43]. Here, decarboxylation is more pronounced at lower temperature, which decreases the yield so that the operating temperature window is smaller, which also shows the limits of the applicability of the novel process window. 

V. Hessel, C. Hofmann, P. Lob, J. Ldhndorf, H. Lowe, A. Ziogas, Aqueous Kolbe-Schmitt synthesis using resorcinol in a micro-reactor laboratory rig under high-p,Tconditions. Org. Process Res. Dev., 2005, 9, 479-489. 

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 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. 

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. 

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). 

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