title: Metal-free oxidation of aromatic carbon-hydrogen bonds through a reverse-rebound mechanism.
abstract: Methods for carbon-hydrogen (C-H) bond oxidation have a fundamental role in synthetic organic chemistry, providing functionality that is required in the final target molecule or facilitating subsequent chemical transformations. Several approaches to oxidizing aliphatic C-H bonds have been described, drastically simplifying the synthesis of complex molecules. However, the selective oxidation of aromatic C-H bonds under mild conditions, especially in the context of substituted arenes with diverse functional groups, remains a challenge. The direct hydroxylation of arenes was initially achieved through the use of strong Brønsted or Lewis acids to mediate electrophilic aromatic substitution reactions with super-stoichiometric equivalents of oxidants, significantly limiting the scope of the reaction. Because the products of these reactions are more reactive than the starting materials, over-oxidation is frequently a competitive process. Transition-metal-catalysed C-H oxidation of arenes with or without directing groups has been developed, improving on the acid-mediated process; however, precious metals are required. Here we demonstrate that phthaloyl peroxide functions as a selective oxidant for the transformation of arenes to phenols under mild conditions. Although the reaction proceeds through a radical mechanism, aromatic C-H bonds are selectively oxidized in preference to activated Csp3-H bonds. Notably, a wide array of functional groups are compatible with this reaction, and this method is therefore well suited for late-stage transformations of advanced synthetic intermediates. Quantum mechanical calculations indicate that this transformation proceeds through a novel addition-abstraction mechanism, a kind of 'reverse-rebound' mechanism as distinct from the common oxygen-rebound mechanism observed for metal-oxo oxidants. These calculations also identify the origins of the experimentally observed aryl selectivity.
authors.affiliation: Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Changxia
authors.initials: C
authors.lastname: Yuan
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
authors.forename: Taylor
authors.initials: T
authors.lastname: Hernandez
authors.forename: Adrian
authors.initials: A
authors.lastname: Berriochoa
authors.forename: Kendall N
authors.initials: KN
authors.lastname: Houk
authors.forename: Dionicio
authors.initials: D
authors.lastname: Siegel
mesh_terms: D045784:Abietanes / Q000737:chemistry; D001555:Benzene Derivatives / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D006859:Hydrogen / Q000737:chemistry*; D006860:Hydrogen Bonding; D006868:Hydrolysis; D006900:Hydroxylation; D008670:Metals; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D010545:Peroxides / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D011789:Quantum Theory; D012717:Sesquiterpenes / Q000737:chemistry; D024505:Tocopherols / Q000737:chemistry
chemical_list: D045784:Abietanes; D001555:Benzene Derivatives; D008670:Metals; D016877:Oxidants; D010545:Peroxides; D010636:Phenols; D012717:Sesquiterpenes; C549996:clovanemagnolol; D002244:Carbon; D006859:Hydrogen; C010219:mesitylene; D024505:Tocopherols; D010100:Oxygen