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

Nature volume 499, pages 192–196 (2013)Cite this article

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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 molecules1,2,3,4,5,6. 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 reaction7. 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 required8,9,10,11,12,13. 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.

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Figure 1: Proposed diradical activation leading to aryl C–H oxidation through a reverse-rebound mechanism or a rebound mechanism.
Figure 2: Reaction of 1,3,5-trimethylbenzene with phthaloyl peroxide (1) and hydrolysis.
Figure 3: Phthaloyl peroxide (1)-mediated hydroxylation of arenes.
Figure 4: Hydroxylation of (+)-δ-tocopherol, dehydroabietylamine and clovanemagnolol derivatives.
Figure 5: Experimental results and computed free-energy surfaces for the functionalization of aromatic and benzylic C–H bonds of mesitylene.
Figure 6: Structures involved in the reverse-rebound mechanism.

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Data deposits

Supplementary crystallographic data for compound 2a–int have been deposited at the Cambridge Crystallographic Data Centre under accession number CCDC903297. These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

Financial support from the University of Texas at Austin, the Welch Foundation (F-1694 to D.S.), and the US National Science Foundation (CHE-1059084 to K.N.H.) are gratefully acknowledged. Calculations were performed on the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the US National Science Foundation (OCI-1053575).

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, 78712, Texas, USA

    Changxia Yuan, Taylor Hernandez, Adrian Berriochoa & Dionicio Siegel

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, California, USA

    Yong Liang & Kendall N. Houk

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Contributions

C.Y. designed experiments; C.Y., T.H. and A.B. carried out experiments; Y.L. and K.N.H. carried out computational analyses; C.Y., Y.L., K.N.H. and D.S. analysed data; K.N.H. and D.S. supervised research; C.Y., Y.L., K.N.H. and D.S. wrote the paper.

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Correspondence to Dionicio Siegel.

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Supplementary information

Supplementary Information

This file contains Supplementary Text and Data sections 1-10 – see contents page for details. The Supplementary Information was amended to include a new safety protocol on 24 September 2013 (PDF 13448 kb)

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Yuan, C., Liang, Y., Hernandez, T. et al. Metal-free oxidation of aromatic carbon–hydrogen bonds through a reverse-rebound mechanism. Nature 499, 192–196 (2013). https://doi.org/10.1038/nature12284

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