A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol

Abstract

Controlling product selectivity during the catalytic aerobic oxidation of phenols remains a significant challenge that hinders reaction development. This work provides a mechanistic picture of a Cu-catalyzed, aerobic functionalization of phenols that is selective for phenoxy-coupled ortho-quinones. We show that the immediate product of the reaction is a Cu(II)-semiquinone radical complex and reveal that ortho-oxygenation precedes oxidative coupling. This complex is the resting state of the Cu catalyst during turnover at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant. Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from Cu(I) and O2. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol.

Tyrosinase and catechol oxidase activity of copper(I) complexes supported by imidazole-based ligands: structure–reactivity correlations

“…These absorption features are similar to those described earlier for a purple Cu(II)-semiquinone radical complex, which was evidenced during the catalytic oxygenation of 4-tert-butylphenol mediated by a Cu(DBED) complex [25]. Importantly, this complex exhibits an absorption band at λ = 545 nm and a weaker one at λ ~900 nm.…”

“…In 2013, Herres-Pawlis et al presented catalytic copper(I) model systems supported by bis(pyrazolyl)methane ligands which exhibit room temperature stable peroxo intermediates [20]. More recently, Lumb et al demonstrated catalytic conversions of different monophenols to a variety of organic products [21][22][23][24][25][26]. During the last years our group published a number of new copper(I) complexes functioning as model systems for tyrosinase [2,19,[27][28][29][30][31][32][33][34].…”

Tyrosinase versus Catechol Oxidase: One Asparagine Makes the Difference

“…[15] Whereas originally an excess of triethylamine had to be employed to deprotonate phenolic substrates, [33,34] application of astoichiometric amount (or as light excess) of diamine ligand to achieve catalytic activity in these model systems has been shown only recently. [15,36] In summary,w eh ave demonstrated the dependence of tyrosinase activity on an asparagine which along with ag lutamate binds and activates ac onserved water molecule towards deprotonation of monophenolic substrates.T his result, which is supported by the first crystal structure of aplant tyrosinase (from walnut leaves) published recently, [37] provides ac onsistent understanding of the reactivities of type 3c opper systems on am olecular level as well as important structural insights for modifying or inhibiting these enzymes and applying them in biotechnology. [15,36] In summary,w eh ave demonstrated the dependence of tyrosinase activity on an asparagine which along with ag lutamate binds and activates ac onserved water molecule towards deprotonation of monophenolic substrates.T his result, which is supported by the first crystal structure of aplant tyrosinase (from walnut leaves) published recently, [37] provides ac onsistent understanding of the reactivities of type 3c opper systems on am olecular level as well as important structural insights for modifying or inhibiting these enzymes and applying them in biotechnology.…”

Catalytic aerobic oxidation of phenols to ortho-quinones with air-stable copper precatalysts

“…The crystal structure of 4 (Fig. 10 This suggests that the Cu IIpromoted reaction enters the same catalytic cycle as the Cu Ipromoted reaction, at least with non-coordinating counteranions. The 49°angle between the CuN 2 and CuO 2 planes likely results from the large steric demands of the tert-butyl substituents, as is the case in 3 † and other DBED-Cu II complexes.…”

“…While Cu II (OAc) 2 ·H 2 O is itself insoluble in CH 2 Cl 2 , addition of DBED creates a clear blue solution within a few minutes, i.e. 10,11,13 The conversion of 1 into 2 was monitored by UV-vis spectroscopy to probe for reaction intermediates. The soluble species is the discrete, neutral [Cu II (DBED)(AcO) 2 ] complex, 4, which is also an efficient precatalyst when preformed outside the reaction mixture (Table 1, entry 16).…”