Journal Article

Metal-free oxidation of aromatic carbon–hydrogen bonds through a reverse-rebound mechanism

Yuan, Changxia, Berriochoa, Adrian, Liang, Yong, Hernandez, Taylor, Houk, Kendall N., Siegel, Dionicio

2013

Overview

Phthaloyl peroxide functions as a selective oxidant of C–H bonds in the transformation of arenes to phenols under mild conditions, in a reaction that is compatible with a wide array of functional groups. Phenol synthesis without the fuss The selective oxidation of the C–H bond is central to synthetic organic chemistry, both by producing the target functional molecule and in 'build-up' molecules on more complex syntheses. Here Dionicio Siegel and colleagues use computational analysis to develop a new method of transforming arenes to phenols that requires much milder conditions than most established routes. They use phthaloyl peroxide as a selective oxidant in a reaction that does not require a metal catalyst, is entropically favourable and has high tolerance for a variety of different functional groups. 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 1 , 2 , 3 , 4 , 5 , 6 . 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 7 . 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 8 , 9 , 10 , 11 , 12 , 13 . 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 –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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 639/638/403 / 639/638/403/933 / 639/638/563/606 / Benzene Derivatives - chemistry / Carbon / Carbon - chemistry / Catalysis / Chemical bonds / Chemical properties / Chemical research / Diterpenes, Abietane - chemistry / Humanities and Social Sciences / Hydrogen / Hydrogen - chemistry / Hydrogen Bonding / Hydrolysis / Hydroxylation / letter / Metals / Methods / multidisciplinary / Oxidants - chemistry / Oxidation / Oxidation-Reduction / Oxidation-reduction reaction / Oxidizing agents / Oxygen - chemistry / Peroxides - chemistry / Phenols / Phenols - chemistry / Quantum Theory / Science / Sesquiterpenes - chemistry / Tocopherols - chemistry