Hydroxylation arenes

Several important aromatic compounds have more than one arene hydroxyl group. These most often are derivatives of the following dihydric and trihydric arenols, all of which have commonly used (but poorly descriptive) names ... 

Cu2+ ions, e.g. Cu(N03)2, catalyze the epoxication of alkenes by iodosylbenzene.664 Oxidation of alcohols to aldehydes can be effected by 02 in the presence of Cu2 ions and Tempo (2,2,6,6-tetramethylpiperidinyl 1-oxide).665 Arene hydroxylation of the binucleating ligand (206)... 

Phenylalanine Hydroxylase (EC 1.14.16.1). In arene hydroxylation of phenylalanine to produce tyrosine, mammalian phenylalanine hydroxylase (PAH) requires nonheme iron and tetrahydropterin cofactor. The role of the metal is... 

The consistent picture being painted for this arene hydroxylation is an electrophilic attack of the bound peroxo ligand. The k2 value observed for [Cu2(H—XYL—D)]2+ (10-D) is within experimental error of that seen for the -H parent compound (10) this lack of deuterium isotope effect is consistent with electrophilic attack on the arene substrate n system, which precludes C—H bond cleavage in the rate-determining step. 

The effect of zeolite porosity on the reaction rate was also well demonstrated in liquid-phase oxidation over titanium-containing molecular sieves. Indeed, the remarkable activity in many oxidations with aqueous H2O2 of titanium silicalite (TS-1) discovered by Enichem is claimed to be due to isolation of Ti(IV) active sites in the hydrophobic micropores of silicalite.[42,47,68 69] The hydrophobicity of this molecular sieve allows for the simultaneous adsorption within the micropores of both the hydrophobic substrate and the hydrophilic oxidant. The positive role of hydrophobicity in these oxidations, first demonstrated with titanium microporous glasses,[70] has been confirmed later with a series of titanium silicalites differing by their titanium content or their synthesis procedure.[71] The hydrophobicity index determined by the competitive adsorption of water and n-octane was shown to decrease linearly with the titanium content of the molecular sieve, hence with the content in polar Si-O-Ti bridges in the framework for Si/Al > 40.[71] This index can be correlated with the activity of the TS-1 samples in phenol hydroxylation with aqueous H2C>2.[71] The specific activity of Ti sites of Ti/Al-MOR[72] and BEA[73] molecular sieves in arene hydroxylation and olefin epoxidation, respectively, was also found to increase significantly with the Si/Al ratio and hence with the hydrophobicity of the framework. 

Sharpless and Flood682 observed reactions characteristic of monooxygenases, such as stereospecific epoxidation of olefins and arene hydroxylation, with oxotransition metal (M=0) oxidants. For example, Cr02X2 (X=C1, OAc) oxidized tritium labeled naphthalene to naphthoquinone accompanied by tritium migration. Rearrangement is suggestive of arene oxide transients. 

Hegg, E.L., Ho, R.YN., and Que, L. Jr. (1999) Oxygen activation and arene hydroxylation by functional mimics of a-keto acid-dependent iron(II) dioxygenases, /. Am, Chem. Soc. 121, 1972-1973 Heinen, U., Berthold, T., Kothe, G., Stavitski, E., Galili, T., Levanon, H., Wiederrecht, G., and Wasielewski, M.R. (2002) High time resolution Q-band EPR study of sequential electron transfer in a triad oriented in a liquid crystal, J. Phys. Chem. A 106, 1933-1937... 

Reversible 02-Binding and Mechanistic Insights into Cu(I)/02-Mediated Arene Hydroxylation and Amide Hydrolysis... 

Figure 6. Scheme showing the nature of products (i.e., 9, PY2, formaldehyde and Me-PY2) obtained during the oxygenation of methyl-substituted xylyl ligand complexes [Cu2(R-XYL-Me)]2+ (6, X = Me). The proposed mechanism of copper mediated arene hydroxylation and NIH shift (1,2-migration) reactions is also outlined. 

W. Ando and Y. Moro-oka, Role of Oxygen in Chemistry and Biochemistry , Elsevier, Amsterdam, 1988. Includes chapters on (a) Cation-Radical Chain Catalyzed Oxygenation of Alkenes, by S. F. Nelsen, et al. (b) Photooxygenation of Organic Compounds via Thieir Radical Ions, by K. Mizono and Y. Otsuji (c) Triphenylpyrylium Sensitized Oxygenations, by K. Tokumaru a al. (d) Catalytic Oxidation of Metiiylarenes to Benzaldehydes, by R. A. Shddon and N. de Heij (e) Oxidation of Arylamines with Horseradish Peroxidase, 1 Fujimori et al. (f) Arene Hydroxylation by Cytochrome P-4S0, by M. Tsuda et al., and marry others. 

System Athene epoxidation S NS Alkane hydroxylation S NS Arene hydroxylation NIH shift Athene ketonization R s. 

This chapter describes computational strategies for investigating the species in the catalytic cycle of the enzyme cjdochrome P450, and the mechanisms of its main processes alkane hydroxylation, alkene epoxidation, arene hydroxylation, and sulfoxidation. The methods reviewed are molecular mechanical (MM)-based approaches (used e.g., to study substrate docking), quantum mechanical (QM) and QM/MM calculations (used to study electronic structure and mechanism). 

The polarity of the pocket and hydrogenbonding machinery were found to increase the dominance of the LS reactivity in arene hydroxylation and the HS reactivity in sulfoxidation. Similarly, these factors will have a strong impact on the appearance of cationic intermediates during hydroxylation and epoxidation. More intriguing is the result that these properties of the protein pocket have a major impact on the regioselectivity of C-H hydroxylation versus C=C epoxidation as well as on the stereospecificity of both processes. Time will show whether these are generalities or isolated findings. 

This stage is analogous to the crucial step in arene hydroxylation in living cells under the action of cytochrome P450. 

X-ray analysis of both copper(I) (e.g. 9) and copper(II) complexes, independent synthesis, and ammonolysis to the free ligands 35 and 36, confirmed the hydroxylation pathway.42 02-binding and hydroxylation in complex 10 were shown to be sensitive to electronic effects of the para-substituent (X = OMe, Me, C02Me, N02>. Tyrosinase, which contains a dinuclear copper active site strongly resembling the hemocyanine active site, binds O2 reversibly and activates O2 for arene hydroxylation (stoichiometry Cu O2 = 2 These are key features observed in the dinuclear copper complexes shown in... 

However, Karlin et al." found arene hydroxylation in 38 (R = Me), which is accompanied by 1,2-migration of the methyl group. Apparently attack of an electrophilic i-... 

An arene hydroxylation has been observed upon exposure of the dicopper(I) complex 19 to dioxygen in dry DMF or CH CN [72]. The ligand... 

Many binuclear model complexes of tyrosinase have been synthesized and studied in the last two decades. Karlin and co-workers showed the first example of arene hydroxylation by a well-defined jf-peroxo-dicopper(II) complex (54-57). The intramolecular reaction has been demonstrated to proceed by an electrophilic oxidative mechanism, according to extensive kinetic, Hammett correlation, and resonance Raman studies on the parent ligand complex and analogs (Fig. 2) (57). 

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]. 

---