Sodium phenolate Salicylic acid

BIS(ACETATO)TRIHYDROXYTRILEAD (6080-56-4) Contact with acids forms acetic acid. Incompatible with bases, alkylene oxides, ammonia, amines, bromates, cresols, epichlorohydrin, hydrozoic acid, isocyanates, methyl isocyanoacetate, phenols, salicylic acid sodium salicylate, sodium peroxyborate, strong oxidizers, sulfites, trinitrobenzoic acid, urea nitrate. 

When the phenol contains a carboxylic acid group, e.g., m- or p-hydroxy-benzoic acid, the acetylated derivative will of course remain in solution as the sodium salt, but is precipitated when the solution is subsequently acidified. Salicylic acid, however, cannot be acetylated under these conditions. 

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. 

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... 

Phenolic resins were the first totally synthetic plastics invented. They were commercialized by 1910 [I]. Their history begins before the development of the structural theory of chemistry and even before Kekule had his famous dreams of snakes biting their tails. It commences with Gerhardt s 1853 observations of insoluble resin formation while dehydrating sodium salicylate [2]. These were followed by similar reports on the behavior of salicylic acid derivatives under a variety of reaction conditions by Schroder et al. (1869), Baeyer (1872), Velden (1877), Doebner (1896 and 1898), Speyer (1897) and Baekeland (1909-1912) [3-17]. Many of these early reports appear to involve the formation of phenolic polyesters rather than the phenol-aldehyde resins that we think of today. For... 

The key compound in the synthesis of aspir in, salicylic acid, is prepared from phenol by a process discovered in 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 subsequently acidified to yield salicylic acid ... 

Perhaps the most widely known compound prepared from phenol is aspirin. If phenol, sodium hydroxide, and carbon dioxide are heated together under pressure, salicylic acid is formed (as the sodium salt) ... 

An additional useful test is to distil the acid or its sodium salt with soda lime. Heat 0.5 g. of the acid or its sodium salt with 0 2 g. of soda lime in an ignition tube to make certain that there is no explosion. Then grind together 0 5 g. of the acid with 3 g. of soda lime, place the mixture in a Pyrex test-tube and cover it with an equal bulk of soda hme. Fit a wide dehvery tube dipping into an empty test-tube. Clamp the tube near the mouth. Heat the soda lime first and then the mixture gradually to a dull-red heat. Examine the product this may consist of aromatic hydrocarbons or derivatives, e.g., phenol from salicylic acid, anisole firom anisic acid, toluene from toluic acid, etc. 

Dicoumarol Dicoumarol, 3,3 -methylene-bis(4-hydroxycoumarin) (24.1.8), is synthesized from 4-hydroxycoumarine (24.1.7), which is in turn synthesized from salicylic acid methyl ester by cyclization to a chromone derivative using sodium or sodium methoxide or from o-oxyacetophenone by reacting it with diethylcarbonate in the presence of sodium ethoxide. Condensation of the resulting 4-hydroxycoumarin with formaldehyde as a phenol component gives dicoumarol [6-9],... 

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). 

Current Methods. The general outline of the Kolbe-Schmitt reaction, as it is employed in the 1990s, is as follows. In the first step, phenol and hot aqueous caustic are mixed to produce the sodium phenate which is taken to dryness. Next, the phenate and dry carbon dioxide are introduced into the carbonator. Air is excluded to minimize oxidation and the formation of colored compounds. The gas—solid mixture is agitated and heated, first at low temperature, followed by several hours at higher temperatures, to complete the formation of sodium salicylate. Variations of this reaction have been noted in the literature and are still being investigated (10,11). One reported scheme produces salicylic acid or substituted salicylic acids by reaction of a granulated alkali metal salt of the respective phenolic compound with C02 in a fluidized bed at 20—130°C until at least 50—80% of the metal salt has been converted to... 

Amino salicylic acid and its salts have been used in the treatment of tuberculosis. />-Amino s alicylic acid can be prepared by the carboxylation of, w-amino phenol (32). Aminosalicylic acid USP assays not less than 98.5% and not more than 100.5%, calculated on the anhydrous basis. The antitubercular agents are likely to be used as the more tolerated salts calcium [133-15-3], potassium [133-09-5], sodium [133-10-8], and the ethyl [6069-17-2] and phenyl [133-11-9] esters of aminosalicylic acid. 

Numerous methods for the synthesis of salicyl alcohol exist. These involve the reduction of salicylaldehyde or of salicylic acid and its derivatives. The alcohol can be prepared in almost theoretical yield by the reduction of salicylaldehyde with sodium amalgam, sodium borohydride, or lithium aluminum hydride by catalytic hydrogenation over platinum black or Raney nickel or by hydrogenation over platinum and ferrous chloride in alcohol. The electrolytic reduction of salicylaldehyde in sodium bicarbonate solution at a mercury cathode with carbon dioxide passed into the mixture also yields saligenin. It is formed by the electrolytic reduction at lead electrodes of salicylic acids in aqueous alcoholic solution or sodium salicylate in the presence of boric acid and sodium sulfate. Salicylamide in aqueous alcohol solution acidified with acetic acid is reduced to salicyl alcohol by sodium amalgam in 63% yield. Salicyl alcohol forms along with -hydroxybenzyl alcohol by the action of formaldehyde on phenol in the presence of sodium hydroxide or calcium oxide. High yields of salicyl alcohol from phenol and formaldehyde in the presence of a molar equivalent of ether additives have been reported (60). Phenyl metaborate prepared from phenol and boric acid yields salicyl alcohol after treatment with formaldehyde and hydrolysis (61). 

It will have been noted that in the formation of salicylic acid, only one half of the phenol is converted the rest is obtained unchanged. Schmitt (Dingier s Polyteehnisches Journal, 255, 259) succeeded in modifying the synthesis to obviate this defect, and his is the method always used industrially, although the other is more convenient in the laboratory. In Schmitt s synthesis sodium phenyl carbonate is prepared by heating up to 120°—140° dry sodium phenolate with carbon dioxide in autoclaves under pressure. Complete transformation of the intermediate sodium phenyl carbonate to mono-sodium salicylate then occurs on further heating. The carbon dioxide may be led in from a cylinder under pressure, or liquid or solid carbon dioxide may be mixed directly with the sodium phenolate in the autoclave. If preferred, the sodium phenyl carbonate can be prepared at ordinary pressures at 110° and then heated under pressure at 140°. 

In the industrial process used today to manufacture salicylic acid, dry sodium phenoxide obtained from phenol and soda is contacted with C02 under 0.5 MPa and at temperatures around 373 K. After absorption of approximately one molar equivalent of C02, the temperature is raised and held at 423—433 K for several hours to fulfill the reaction [16]. The final technical-grade salicylic acid is obtained after successive purification steps and, eventually, upon acidification with sulfuric or hydrochloric acid (Figure 5.1). 

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 manufacture of aspirin is based on the synthesis of salicylic acid from phenol. Reaction of carbon dioxide with sodium phenoxide is an electrophilic aromatic substitution on the ortho, para-directing phenoxy ring. The ortho isomer is steam distilled away from the para isomer. 

The manufacture of salicylic acid follows carboxylation of sodium phe-nolate (Fig. 1). The sodium phenolate must be finely divided and exposed to the action of the carbon dioxide under pressure and heat in a heated ball... 

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