Phenols laboratory synthesis

Replacement of the Diazonium Group by Hydroxide Hydrolysis Hydrolysis takes place when the acidic solution of an arenediazonium salt is warmed. The hydroxyl group of water replaces N2, forming a phenol. This is a useful laboratory synthesis of phenols because (unlike nucleophilic aromatic substitution) it does not require strong electron-withdrawing substituents or powerful bases and nucleophiles. 

A laboratory synthesis of phenylated phenols has been developed by N. Kharasch and co-workers. They first introduced iodine in the 2-, 4- and/or 6-positions of phenol and then photolysed the iodophenols in the presence of benzene. Phenylated phenols in yields of 60-75% were found 57). 

Dipheny[amine (7) is prepared industrially either by heating aniline with aniline hydrochloride at 140 °C under pressure, or by heating aniline with phenol at 260 °C in the presence of zinc chloride. The most convenient laboratory synthesis uses the Ullmann reaction (Scheme 8.9) (see Chapter 10), in which acetanilide is refluxed with bromobenzene in the presence of potassium carbonate and copper powder in nitrobenzene solvent. Triphenylamine is similarly prepared from diphenylamine and iodobenzene. 

Outline a possible laboratory synthesis of each of the following compounds from alcohols and phenols ... 

Until recent years, the sole somce of /3-D-glucopyranosiduronic acids, and indeed of D-glucuronic acid itself, was the urine of animals fed with the appropriate aglycons, and in most instances the chemical synthesis in the laboratory has yet to be achieved. In some cases [for example, phenol-phthalein (mono-)j3-D-glucopyranosiduronic acid], laboratory synthesis still presents difficulties. 

The structure of thyroxine, a thyroid hormone that helps to regulate metabolic rate, was determined in part by comparison with a synthetic compound believed to have the same structure as natural thyroxine. The final step in the laboratory synthesis of thyroxine by Harington and Barger, shown helow, involves an electrophilic aromatic substitution. Draw a detailed mechanism for this step and explain why the iodine substitutions occur ortho to the phenolic hydroxyl and not ortho to the oxygen of the aryl ether. [One reason iodine is required in our diet (e.g., in iodized salt) is for the biosynthesis of thyroxine.]... 

The most important laboratory synthesis of phenols is by hydrolysis of arenediazonium salts (Section 20.7E). This method is highly versatile, and the conditions required for the diazotization step and the hydrolysis step are mild. This means that other groups present on the ring are unlikely to be affected. 

The most important laboratory synthesis of phenols is from amines by hydrolysis of their corresponding diazonium salts, as described in Section 21.17. 

Electrophilic aromatic substitution also plays a role in the 1927 laboratory synthesis of thyroxine by C. Harington and G. Barger. Their synthesis helped prove the structure of this important hormone by comparison of the synthetic material with natural thyroxine. Harington and Barger used electrophilic aromatic substitution to introduce the iodine atoms at the ortho positions in the phenol ring of thyroxine. They used a different reaction, however, to introduce the iodine atoms in the other ring of thyroxine (nucleophilic aromatic substitution—a reaction we shall study in Chapter 21.)... 

While the diazonium salt route is probably the most commonly used laboratory synthesis of phenols, phenol itself is manufactured from wo-propylbenzene, which has the common name cumene. Cumene is prepared by a Friedel-Crafts reaction between propene and benzene, in the presence of a strong acid such as H3PO4 (Figure 13.28). The key intermediate is the 2-propyl cation, formed by protonation of propene. 

Alternatively, thermal cracking of acetals or metal-catalyzed transvinylation can be employed. Vinyl acetate or MVE can be employed for transvinylation and several references illustrate the preparation especially of higher vinyl ethers by such laboratory techniques. Special catalysts and conditions are required for the synthesis of the phenol vinyl ethers to avoid resinous condensation products (6,7). Direct reaction of ethylene with alcohols has also been investigated (8). 

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. 

R. Antony, Synthesis, Characterization and Thermal Behaviour of Chemically Modified Phenolic and Substituted Phenolic Polymers, Ph.D thesis. Regional Research Laboratory, Trivandrum and Kerala University, Trivandrum, India (1993). 

Examples of PLC with autoradiography detection include the published studies on labeling of l- H-PAF-aceter [25] diazinon and related compounds from plant material [26] metabolic fate of triamcinolone acetonide in laboratory animals [27] synthesis of 4-S-cysteaminyl-[U- " C]phenol antimelanoma agent [28] radiolabeled... 

In a related approach from the same laboratory, the perfluorooctylsulfonyl tag was employed in a traceless strategy for the deoxygenation of phenols (Scheme 7.82) [94], These reactions were carried out in a toluene/acetone/water (4 4 1) solvent mixture, utilizing 5 equivalents of formic acid and potassium carbonate/[l,T-bis(diphe-nylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2] as the catalytic system. After 20 min of irradiation, the reaction mixture was subjected to fluorous solid-phase extraction (F-S PE) to afford the desired products in high yields. This new traceless fluorous tag has also been employed in the synthesis of pyrimidines and hydantoins. 

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 1987, the successful startup of a new process was announced for the production of 10,000 tons/year of catechol and hydroquinone by the selective oxidation of phenol with H202 catalyzed by TS-1 at the Enichem plant in Ravenna, Italy (Notari, 1988). Soon thereafter, it was disclosed that another new process for the production of cyclohexanone oxime from cyclohexanone, H202, and NH3 with TS-1 as the catalyst was being developed (Roffia et al., 1990).The fact that a material with unusual catalytic properties had been obtained was then finally recognized, and the interest in titanium-containing catalysts spread rapidly in the scientific community, especially in industrial research laboratories. In the meantime, the synthesis method was studied and described in more detail and when all the necessary precautions were taken, TS-1 was reproduced in other laboratories, as were the highly selective catalytic reactions. The subsequent work confirmed that Ti v can assume the tetrahedral coordination necessary for isomorphous substitution of SiIV and added valuable information about the structure, properties and catalytic performance of the material. New reactions catalyzed by TS-1 have been discovered, and new synthetic methods... 

---