Phenols Kolbe carboxylation

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. 

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

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

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... 

Alkylphenols undergo a carboxylation reaction known as the Kolbe Schmidt reaction. In the following example, the phenolate anion of /)-nonylphenol (15) reacts with carbon dioxide under pressure. Neutralization generates a sahcyhc acid (16) (10). 

Manufacture. Several methods have been described for the preparation of -hydroxyben2oic acid. The commercial technique is similar to that of salicylic acid, ie, Kolbe-Schmitt carboxylation of phenol. The modification includes the use of potassium hydroxide in place of caustic (51). The dried potassium phenate is heated under pressure, 270 kPa (2.7 atm) or more, with dry carbon dioxide at 180—250°C. The potassium salt [16782-08-4] of Nhydroxyben2oic acid forms almost quantitatively and can be converted to free acid by using a mineral acid. 

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. 

This is Kolbe s synthesis of phenolic acids. It is capable of very wide application. In all cases the carboxyl group primarily seeks the or o-position if that is occupied, some condensation in the para-position occurs. The following are some examples. 

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... 

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 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... 

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 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. 

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. 

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-... 

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). ... 

There are many other approaches to industrial applications of flash chemistry, although available information is limited. Let us briefly touch on some examples. The Kolbe-Schmitt synthesis serves as a useful standard method to introduce a carboxyl group into phenols (Scheme 10.6). The Kolbe-Schmitt synthesis has been widely used in industry, and there are many variants of this transformation. Microflow systems can be used for conducting the Kolbe-Schmitt synthesis under aqueous high-pressure conditions.A decrease in reaction times by an order of magnitude (a few tens of seconds instead of minutes) and increase in space-time yields by orders of magnitude can be attained using a microflow system. For example, a microflow system composed of five parallel capillaries (inner volume 9 ml) has a productivity of 555 g/h, whereas the productivity of a macrobatch reactor (IL flask) is 28 g/h. 

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