Aspirin synthesis from phenol

The key compound in the synthesis of aspirin, 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 ... 

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. 

Problem 24.15 Aspirin is acetylsalicylic acid (o-acetoxybenzoic acid, 0-CH3COO-CftH4COOH) oH of wintergrcen is the ester, methyl salicylate. Outline the synthesis of these two compounds from phenol. 

Arylbismuth 671, 673 Arylboronic acid 671, 673 Arylbutenes, formation of 613 Aryl-2-cyclohexenones 653 Aryl ethers—see also AUyl aryl ethers. Diaryl ethers. Phenyl ethers, Propargyl aryl ethers formation from calixarenes 1387 Aryl haUdes, as phenol precursors 396, 397 Ai-Arylhydroxylamines, isomerization of 801-805 oxidation of 419 3-Arylindoles, synthesis of 1236 Aryl ketones, oxidation of 424, 425 Aryloxylium cations 179 Asatone, synthesis of 1178, 1179 Ash, from incineration of municipal waste, phenoUc compounds in 938 Aspersitin, synthesis of 1327, 1328 Aspirin 10, 11... 

During World War I, the American subsidiary of the Bayer Company bought as much phenol as it could from the international market, knowing that eventually all the phenol could be converted into aspirin. This left little phenol available for other countries to purchase for the synthesis of 2,4,6-trinitrophenol (TNT), a common explosive. 

The next example taken from the synthesis database is a reaction network for various routes to aspirin [57,58], Figures 9.22 through 9.24 show reaction networks for phenol, acetic anhydride, and aspirin, respectively. The digraph in Figure 9.25 shows the combination of two subnetworks for phenol and acetic anhydride that converge to produce the final target product. 

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