Phenol hydroxylation catechol/hydroquinone

Starting from Benzene. In the direct oxidation of benzene [71-43-2] to phenol, formation of hydroquinone and catechol is observed (64). Ways to favor the formation of dihydroxybenzenes have been explored, hence CuCl in aqueous sulfuric acid medium catalyzes the hydroxylation of benzene to phenol (24%) and hydroquinone (8%) (65). The same effect can also be observed with Cu(II)—Cu(0) as a catalytic system (66). Efforts are now directed toward the use of Pd° on a support and Cu in aqueous acid and in the presence of a reducing agent such as CO, H2, or ethylene (67). Aromatic... 

Other Methods. A variety of other methods have been studied, including phenol hydroxylation by N2O with HZSM-5 as catalyst (69), selective access to resorcinol from 5-methyloxohexanoate in the presence of Pd/C (70), cyclotrimerization of carbon monoxide and ethylene to form hydroquinone in the presence of rhodium catalysts (71), the electrochemical oxidation of benzene to hydroquinone and -benzoquinone (72), the air oxidation of phenol to catechol in the presence of a stoichiometric CuCl and Cu(0) catalyst (73), and the isomerization of dihydroxybenzenes on HZSM-5 catalysts (74). 

An interesting observation reported in Table XLIX is the increase in the hydroquinone/catechol ratio from 1.44 to 1.99 when the dielectric constant of the medium is decreased from 58.9 to 39.2 by addition of methanol to water. A similar increase in the hydroquinone/catechol ratios was also observed in phenol hydroxylation catalyzed by TS-1 (266) in dioxane-water and tert-butyl alcohol-water mixtures. The para/ortho ratio increased nearly 10-fold when 10% dioxane was added to water. Similarly, the para/ortho ratio more than doubled (1.3-3.0) when 10% tert-butyl alcohol was added to water. An opposite trend, namely, a decrease in the para/ortho ratio from 1.4 to 0.6, was observed when 10% formamide (s = 108) was added to water. Because of geometric constraints in the MFI pores, catechol is expected to be formed more easily on the external surface of TS-1 crystallites than in the pores (91). Hydroquinone, less spatially demanding, can form in the TS-1 channels. A greater coverage of the hydrophobic... 

Cytochrome P4502E1, also microsomally located, catalyzes the hydroxylation of phenol to form hydroquinone (and to a much lesser extent catechol), which is then acted upon by the phase II enzymes (Benet et al. 1995 Campbell et al. 1987 Gut et al. 1996 McFadden et al. 1996). All three enzyme systems are found in multiple tissues and there is competition among them not only for phenol but for subsequent oxidative products, like hydroquinone. As a consequence, the relative amount of the products formed can vary based on species, dose and route of administration. In vivo, the gastrointestinal tract, liver, lung, and kidney appear to be the major sites of phenol sulfate and glucuronide conjugation of simple phenols (Cassidy and Houston 1984 Powell et al. 1974 Quebbemann and Anders 1973 ... 

Figure 11. The influence of residual H2O2 on the reaction testing of phenol hydroxylation to catechol (CAT), hydroquinone (HQ), and para-benzoquinone (BQ) [61], Reaction conditions 4 g phenol 50 mL water solvent 0.2 g a-Fe203 catalyst inner standard ethanol reaction temperature 70°C. Aliquots were sampled at different times and analyzed by (a) HPLC and (b) GC to determine the conversions of PHE (A) and yields of CAT + HQ + BQ ( ), CAT ( ), and BQ (T). Aliquots were also analyzed by (c) iodometric titration to determine the conversion of H2O2 (o). [Reproduced by permission of Elsevier from Ma, N. Ma, Z. Yue, Y. H. Gao, Z. J. Mol. Catal. A 2002, 184, 361-370.]...

The UV irradiation of phenol in the presence of nitrite (pH around neutrality) yields 4-nitrosophenol, catechol, hydroquinone, 1,4-benzoquinone, 2-nitrophenol and 4-nitrophenol [44,62,78,79]. It is interesting to observe that nitrophenols do not form in appreciable amount upon irradiation of 1.0 x 10-3 M phenol and nitrite, while relevant nitrophenol formation can be observed for [N02 ] > 1.0 x 10-3 M [44,79]. The formation of catechol, hydroquinone and 1,4-benzoquinone is most likely due to the photoinduced generation of hydroxyl (reactions 17 and 18). The relevant processes are initiated by hydroxyl attack on phenol (H-Ph-OH) in the presence of oxygen ([78,79] HO - Ph - OH catechol or hydroquinone, O = Ph = O 1,4-benzoquinone) ... 

Hydroxyl radical generated from hydrogen peroxide in the presence of iron(II) salts hydroxylates most aromatic centres, and indeed a phenol hydroxylation process based on this chemistry was operated for nearly a decade.471 The process ran at similar conversions to the acid-catalysed route mentioned above, however selectivity to dihydroxybenzenes was somewhat lower, and some resorcinol was formed along with catechol and hydroquinone. 

In phenol hydroxylation, remarkable selectivities to single products have been achieved using vanadium heteropolyacid catalysts.485 The use of the ZSM-5 titanium silicalite (TS-1)483 permits the oxidation of phenol to catechol and hydroquinone to be carried out on an industrial scale with a higher selectivity at a greater conversion of substrate that was not previously possible with strong acid catalysts. 

The discovery of TS 1 led rapidly to the development of a process for phenol hydroxylation (25). This process has numerous advantages over the previous processes using peracid or Co2+, Fe2+ as catalysts higher conversion of phenol (30% instead of 5-9%) requiring less phenol separation/recycle steps, comparable or higher yields relative to both hydrogen peroxide and phenol, wider range of catechol/hydroquinone ratio (0.5-1.3 instead of 1.2-1.5 or 2.0-2.3) (24, 26). 

The hydroxylation of phenol to catechol and hydroquinone with H2O2, introduced in the 1970s, represented a major advance over earlier methods of production, which utilized the alkaline fusion of o-chlorophenol (catechol) and the stoichiometric oxidation of aniline with manganese dioxide (hydroquinone). The inorganic and organic wastes in both processes were of the order of several kg per kg of product. However, the hydroxylation of phenol too is not free of drawbacks one is the co-production of two chemicals, destined for two... 

TS-1 is a good catalyst for the hydroxylation of benzene when it is used in a highly polar medium, such as sulfolane. This promotes the fast desorption of the product thus hindering its further oxidation (Annex 2). The selectivity of 94% to phenol (plus 6% hydroquinone and catechol), obtained at 9% benzene conversion, is comparable to the per-pass yield of the cumene process. 

V.D). When the electron density in the ring is high (as in polyalkyl phenols) and the ortho- and/or para position (with respect to the OH group) is vacant, the formation of ortho- or para-benzoquinone also occurs. Indeed, in the hydroxylation of phenol to catechol and hydroquinone, one of the major side products (and the main cause of the tar formation) is the formation of benzo-quinones and products derived from them. The benzoquinones of polyalkyl-benzenes are starting materials for many products in the photographic and fine chemicals industries. Trukhan et al. 234) reported the oxidation of 2,3,-... 

The ionized dihydroxybenzenes 39" behave similarly (Scheme 17). Note that, in this series, one of the phenolic hydroxyl groups acts as a hydrogen acceptor and the other as an H donor. The El mass spectrum of catechol (o-39) exhibits a significant ortho effect. While the intensity of the [M — H20]" peak in the El spectrum of o-39 is no greater than ca 15%B, the spectra of resorcinol (m-39) and hydroquinone (p-39) both show negligibly smah [M — H20] + peaks ( 2%B). It is likely that water loss from the intermediate 47 generates again bicyclic [M — H20]" ions, i.e. ionized benzoxirene 48. And, notably, the CO losses does not parallel the ortho effect of the water elimination in this series, as it is the most pronounced ion the case of m-2>9. 

Electron transfer oxidation of 4-methoxyphenol using wjeio-tetraphenylporphyrin as the electron acceptor brings about dehydrodimerization of the phenol to yield 5. The presence of the radical cation of the phenol has been detected by CIDNP techniques. The same product is obtained by irradiation of the tetraphenylporphyrin/benzoquinone/p-methoxyphenol system . Pyrimidinopteridine Af-oxide has been used as a sensitizer to effect the hydroxylation of phenols, also involving the radical cation of the phenol. Thus phenol can be converted to catechol and hydroquinone while cresol yields 4-methyl-catechol . Hydroquinone can itself be oxidized by the cobalt azide complex in aqueous... 

Aromatic hydroxylation such as that depicted in figure 4,3 for the simplest aromatic system, benzene, is an extremely important biotransformation. The major products of aromatic hydroxylation are phenols, but catechols and quinols may also be formed, arising by further metabolism. One of the toxic effects of benzene is to cause aplastic anaemia, which is believed to be due to an intermediate metabolite, possibly hydroquinone. As a result of further metabolism of epoxide intermediates (see below), other metabolites such as diols and glutathione conjugates can also... 

A special case is the hydroxylation of benzene with nitrous oxide as oxidant, for which commercialization has been announced [55]. The reaction occurs on Fe-silicalite-1, in the gas phase, at temperatures close to 400 °C, producing molecular nitrogen as by-product. Other zeolites and supported metals and metal oxides are less satisfactory catalysts. Toluene, chlorobenzene, and fluorobenzene are similarly hydroxylated, yielding all three possible isomers. Phenol produces catechol and hydroquinone. 

Table 13 summarizes the activity of fresh hydroialcite catalysts studied for phenol hydroxylation carried out at 65"C using a substrateroxidant mole ratio of 2.0. On all the catalysts, catechol and hydroquinone were formed as major products. The conversion increased with an increase in the reaction temperature up to 65 C, except for CuCoFc-HT, and decreased with a further increase in temperature, may be due to competitive thermal decomposition of H20> at higher temperatures w iihout being involved in the reaction. 

Phenol hydroxylation over CoNiAl ternary fresh hydrotalcites yielded catechol and hydroquinionc with a preference to catechol. No other products were observed by GC indicating no transitory formation of p-bcnzoquinonc. This is in contrast to the results we have earlier reported for copper containing hydrotalcites (87, 105] where we observed both catechol and hydroquinone to significant levels, suggesting the nature of cations in the brucite-likc sheets in influencing the course of the reaction. Although both nickel and cobalt separately in a binary hydrotalcite with aluminum as trivalent cation showed no conversion of... 

Hydroxylation of phenol and anisole was investigated using TS-1, a silanised TS-1 and Al-free Ti-Beta. Pore geometry, solvent, external surface and substrate govern the selectivity of the hydroxylation reaction. In medium pore TS-1 the formation of hydroquinone in phenol hydroxylation is favoured due to the geometric constraint on the formation of catechol in the pores. A similar effect is observed for formation of ortho- and para hydroxy-anisoles in Al-free Ti-Beta. Solvents affect activity and selectivity of the hydroxylation reactions through adsorption and co-ordination to the titanium active site. The external surface of TS-1 plays a substantial role in hydroxylation reactions. 

With TS-1 as the catalyst, the oxidation products of phenol are hydro-quinone and catechol (para- and ort/to-hydroxyphenol), with minor yields of water and tar formed as by-products. Numerous early papers are concerned with this reaction (218), and patents (219) have been iiled. In the reaction catalyzed by TS-1, the conversion of phenol and the selectivity to dihydroxy products are significandy higher than achievable by either radical-initiated oxidation or acidic catalysts. The catechol/hydroquinone molar ratio is within the range of 0.5—1.3 and depends on the solvent. When the reaction occurs in aqueous acetone, the ratio is close to 1.3. It is believed that the product ratio is the result of restricted transition-state selectivity as well as mass transport shape selectivity associated with the different diffusivities of the ortho and para products. Hydroxylation at the para-position of phenol should be less hindered relative to that at the ortho-position, and hydroqui-none has a smaller kinetic diameter than catechol, facilitating diffusion. Tuel and Taarit (220) proposed that catechol is mainly produced at the external surface of TS-1 crystals. Thus, the different catechol/hydroquinone ratios obtained when methanol or acetone is used as a solvent could be explained by either rapid or very slow poisoning of external sites by organic deposits, respectively. Accordingly, the authors were able to show that tars were easily dissolved by acetone (i.e., external sites for catechol formation remained available in this solvent) while they were insoluble in methanol. 

Similar TS-1 films have been applied for phenol hydroxyl-ation reaction to dihydroxybenzenes (hydroquinone and catechol) [354] and catalytic oxidation of styrene to benzaldehyde and phenylacetaldehyde [355] with hydrogen peroxide as oxidant in batch-type membrane reactors. The dihydroxybenzenes and phenylacetaldehyde selectivity values increased with in-framework Ti content. In order to reduce the TS-1 membrane costs, Chen et al. [356] have successMly synthesized TS-1 on mullite tubes by replacing TPAOH with TPABr/EtjNH system (4% of the initial cost). The catalytic activity was tested in the probe reaction of isopropyl alcohol oxidation with hydrogen peroxide under pervaporation condition at 60°C. In general, future work on TS-1 film catalysts is required to improve mass transfer resistances and reaction conversion without compromising selectivity. 

The oxidation of phenols to catechols or hydroquinones by tyrosinase enzymes has been developed for biocatalysis. For example, the ortho-hydroxylation of L-tyrosine 162 (and also substituted variants) to give l-DOPA 163 has been extensively studied due to the importance of l-DOPA in the treatment of Parkinson s disease [92, 93]. An arene hydroxy lating enzyme having a broad substrate scope is 2-hydroxybiphenyl 3-monooxygenase from Pseudomonas azelaica, which is able to oxidize many ortho-substituted phenols 68 to the corresponding catechols 127 [94], as shown in Scheme 32.19. A notable example of an industrial biocatalytic arene hydroxylation that has been employed on very large scale (lOOm fermentation) is the pora-hydroxylation of R)-2-phenoxypropionic acid 164 by whole cells of Beauveria bassiana Lu 700 to give (R)-2-(4-hydroxyphenoxy)propionic acid 165, an important intermediate in herbicide manufacture [95]. 

In 1986, a new process for the phenol hydroxylation by hydrogen peroxide marked the first industrial application of the TS-1 catalyst. At that time, the chemical company of the Eni group was EniChem, which built a plant in Ravenna, Italy for producing 10,000 t/y of the catechol/hydroquinone nfixture. 

A one-pot reaction of hydroxylated phenols such as hydroquinone, resorcinol, catechol, and pyrogallol with DMAD in the presence of triphe-nylphosphine leads to the formation of the corresponding coumarins 50 following the same mechanism (Schemes 35 and 36) (01T7537). 

Conversely, nucleophilic molecules Nu) [Lewis bases e.g., catechols, hydroquinones, phenols, alcohols, and thiols (and their anions) aromatic hydrocarbons and amines (benzene, toluene, pyridine, bipyridine, etc.)] can be oxidized (1) by direct electron-transfer oxidation [Eq. (161)] [with the electron coming from the Highest-Occupied-Molecular-Orbital (HOMO)] or (2) by coupling with the oxidation product of H2O (or HO ), hydroxyl radical (HO ) [Eq. (162)]. 

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