Phenol other routes

During the 1980s few innovations were disclosed in the Hterature. The hydroxylation of phenol by hydrogen peroxide has been extensively studied in order to improve the catalytic system as well as to master the ratio of hydroquinone to catechol. Other routes, targeting a selective access to one of the dihydroxyben2enes, have appeared. World production capacities according to countries and process types are presented in Table 1. 

This versatile synthetic route has been used extensively with a great variety of phenols and thiophenols to estabUsh structure—activity relationships for thyromimetic activity. Other routes can be summarized as follows (13). 

Other routes for the preparation of phenol are under development and include the Dow process based on toluene. In this process a mixture of toluene, air and catalyst are reacted at moderate temperature and pressure to give benzoic acid. This is then purified and decarboxylated, in the presence of air, to phenol (Figure 23.5). 

Cumene processes are currently the major source for phenol and coproduct acetone. Chapter 8 notes other routes for producing acetone. 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

No studies were located regarding distribution of phenol in humans after exposure by other routes. 

Interroute extrapolation. This model concerned itself primarily with the injection route of exposure, although the use of several injection sites was intended to simulate various distribution routes for orally ingested phenol. Extrapolation to other routes was not done. 

Other routes. Alternate process technologies for making phenol avoid the cumene route. A few plants have used toluene as a feed, oxidizing it over a cobalt catalyst to give benzoic acid. That is followed by a reduction (removal of oxygen atom) to give phenol and carbon dioxide. 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

There are essentially two mechanisms to be considered for these orthofurylation reactions. First, a direct nucleophilic addition of furan, to the acylquinone at the 2-position is postulated, which is probably catalyzed by traces of acid (route A). The other leads through a Diels-Alder addition, and the adduct yields a stable hydroquinone by a dienone-phenol rearrangement (route B). 

Global production of adipic acid is put at around 2.9 Mt/a and its consumption grows at around 3% per year. More than 90% of the production is achieved by oxidation of eyelohexane whieh, in turn, is obtained by hydrogenation of benzene or, in mueh smaller amounts, from the naphtha fraction of crude oil. Other routes to adipie aeid are based on benzene via cyclohexanol, obtained by partial hydrogenation to eyelohexene and subsequent hydration) or on phenol (through its hydrogenation to cyclohexanol, eyclohexanone or a mixture of both). 

Only one other synthesis from this review, the aldol self-condensation of cyclohexanone, followed by dehydrogenation of the initial products, is of preparative importance. It has even been used in the large scale industrial syntheses of 2,6-diphenyl-phenol (see 2.4). All the other routes mentioned in this account, are primarily of scientific interest and are not useful for larger scale preparative work. They ate, however, of interest insofar as they emphasize differences between the chemical properties of alkyl and aryl substituted phenols. 

The compounds described here are an analogue of the 4-t-butylcalix[n]arenes, 4-f-butyloxacalix[3]arene (28), and a variant, 4-phenyloxacalix[3]arene (30, Figures 3.17 and 3.18) containing a deep aromatic cavity. 4-r-Butyloxacalix[3J-arene is best prepared by Gutsche s original method [2] despite the more recent publication of several other routes. Syntheses of the respective bis(hydroxy-methyl)phenols (27 and 29) are also described although the methods are quite general and can be applied to prepare a variety of bis(hydroxymethyl)phenols from 4-substituted phenols. 

Discovery of the dienone-phenol rearrangement of quinol acetates has made possible the synthesis of dihydric phenols that were difficult of access by other routes. The starting materials are obtained from phenols and lead tetraacetate, and with acetic anhydride and sulfuric acid (Thiele acetylation) or with boron trifluoride in ether they give, respectively, di- and mono-acetyl derivatives of resorcinol or hydroquinone.309 When treated with lN-sodium hydroxide, 0-quinol acetates of type (1) undergo nucleophilic addition of an OH" ion, giving resorcinol derivatives (2).310 Occurrence of the reaction is considered... 

In summary, Sorensen completed a concise synthesis of FR901483 (16 steps from methyl ester of O-methyltyrosine, 1.5% overall yield) by a strategy that for the first time featured an oxidative cyclization of a phenolic secondary amine (obtained by a reductive coupling of two tyrosine units). The other notable aspect of his synthesis is the one-step conversion of a hydroxyl group to a phosphate unit with an inversion of configuration that shortens the global sequence in comparison with other routes. 

Aryl triflates have been used to generate arynes via other routes than metal-halogen exchange. For example, fluoride ion displacement of the trimethylsilyl group in 26 provides a convenient route to benzyne under mild conditions. The required benzyne precursor 26 was prepared from o-trimethylsilylphenoxytrimethylsilane by sequential treatment with BuLi and (Tf)20. Analogous aryne precursors have also been prepared less directly, as in the case of amide benzyne 31. Examples of 32 include various methylfurans, diphenylsobenzofuran and tetraphenylcyclopentadienone. Examples of nucleophiles include methanol, phenol, lithium thiophenoxide and others. 

The effect of administration route on drug action is discussed in some detail by Benet (19) and by Rowland (20). Oral administration forces a first-pass route through the liver, subjecting the toxicant to enhanced metabolism. Other routes are weaker metabolically, though in some cases, skin can display up to 80% or more of liver metabolite activity. In the rat, for example, skin is more efficient than liver in degrading aryl carbamates. Our results support this thesis in terms of mean Log MW/LD50 values for phenol toxicity but not for carbamate toxicity. 

The key step of the other synthesis was C-acetylation of aryl propanones like 72, which are readily accessible from the corresponding benzaldehydes 71. This aryl propanone route was very effective for the synthesis of /sphenolic diketones like 70 (X = OR), thus ideally complementing the other route. Both methods also allowed the synthesis of the free diketone 31 (70, R = H, X = OH) with two unprotected phenol functions in the aromatic ring, which could not be prepared by 0-dealkylation of the hydroxyethyl ether 58, as obtained in the biomimetic syntheses. 

Note that by-products can have a major influence on the economics of a chemical process. Phenol manufacture provides a striking example of this. The original route, the benzenesulphonic acid route, has become obsolete because demand for its by-product sodium sulphite (2.2 tonnes/1 tonne phenol) has dried up. Its recovery and disposal will therefore be an additional charge on the process, thus increasing the cost of the phenol. In contrast the cumene route owes its economic advantage over all the other routes to the strong demand for the by-product acetone (0.6 tonnes/1 tonne phenol). The sale of this therefore reduces the net cost of the phenol. 

It will be noted that the cumene process is based only on materials derived from petroleum in contrast to many other routes there is no substantial requirement of heavy inorganic chemicals. The economics of the process are bound up with the value of the co-product, acetone. The first cumene-phenol plant came on stream in 1952 and since this time the cumene process has become increasingly dominant. 

Phenol carboxylic acids. It should be mentioned that these can also be obtained by other routes branching off from, for example, shikimic acid, 5-dehydroshikimic acid or quinic acid. However, this means of forming phenol carboxylic acids seems to be less important in higher plants (cf. page 128). 

---