Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

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.

References

  1. Chen, M. S. & White, C. M. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007)

    Article  CAS  ADS  Google Scholar 

  2. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009)

    Article  CAS  ADS  Google Scholar 

  3. Chen, M. S. & White, C. M. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010)

    Article  CAS  ADS  Google Scholar 

  4. Gutekunst, W. R. & Baran, P. S. C–H functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011)

    Article  CAS  Google Scholar 

  5. Simmons, E. M. & Hartwig, J. F. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012)

    Article  CAS  ADS  Google Scholar 

  6. Roizen, J. L., Harvey, M. E. & Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C–H bonds. Acc. Chem. Res. 45, 911–922 (2012)

    Article  CAS  Google Scholar 

  7. Rappoport, Z. The Chemistry of Phenols Vols 1 and 2, 395–490 (Wiley-VCH, 2003)

    Book  Google Scholar 

  8. Neufeldt, S. R. & Sanford, M. S. Controlling site selectivity in palladium-catalyzed C–H bond functionalization. Acc. Chem. Res. 45, 936–946 (2012)

    Article  CAS  Google Scholar 

  9. Emmert, M. H., Cook, A. K., Xie, Y. J. & Sanford, M. S. Remarkably high reactivity of Pd(OAc)2/pyridine catalysts: nondirected C–H oxygenation of arenes. Angew. Chem. Int. Ed. 50, 9409–9412 (2011)

    Article  CAS  Google Scholar 

  10. Zhang, Y.-H. & Yu, J.-Q. Pd(II)-catalyzed hydroxylation of arenes with 1 atm of O2 or air. J. Am. Chem. Soc. 131, 14654–14655 (2009)

    Article  CAS  Google Scholar 

  11. Huang, C., Ghavtadze, N., Chattopadhyay, B. & Gevorgyan, V. Synthesis of catechols from phenols via Pd-catalyzed silanol-directed C–H oxygenation. J. Am. Chem. Soc. 133, 17630–17633 (2011)

    Article  CAS  Google Scholar 

  12. Gulevich, A. V., Melkonyan, F. S., Sarkar, D. & Gevorgyan, V. Double-fold C–H oxygenation of arenes using PyrDipSi: a general and efficient traceless/modifiable silicon-tethered directing group. J. Am. Chem. Soc. 134, 5528–5531 (2012)

    Article  CAS  Google Scholar 

  13. Powers, D. C., Xiao, D. Y., Geibel, M. A. L. & Ritter, T. On the mechanism of palladium-catalyzed aromatic C–H oxidation. J. Am. Chem. Soc. 132, 14530–14536 (2010)

    Article  CAS  Google Scholar 

  14. Russell, K. E. The preparation of phthalyl peroxide and its decomposition in solution. J. Am. Chem. Soc. 77, 4814–4815 (1955)

    Article  CAS  Google Scholar 

  15. Greene, F. D. Cyclic diacyl peroxides. II. Reaction of phthaloyl peroxide with cis- and trans-stilbene. J. Am. Chem. Soc. 78, 2250–2254 (1956)

    Article  CAS  Google Scholar 

  16. Greene, F. D. & Rees, W. W. Cyclic diacyl peroxides. III. The reaction of phthaloyl peroxide with olefins. J. Am. Chem. Soc. 80, 3432–3437 (1958)

    Article  CAS  Google Scholar 

  17. Yuan, C., Axelrod, A., Varela, M., Danysh, L. & Siegel, D. Synthesis and reaction of phthaloyl peroxide derivatives, potential organocatalysts for the stereospecific dihydroxylation of alkenes. Tetrahedr. Lett. 52, 2540–2542 (2011)

    Article  CAS  Google Scholar 

  18. Fujimori, K., Oshibe, Y., Hirose, Y. & Oae, S. Thermal decomposition of diacyl peroxide. Part 11. 18O-scrambling in carbonyl-18O-labelled phthaloyl peroxide, a cyclic case III diacyl peroxide. Extremely large return of unescapable acyloxyl radical pair. J. Chem. Soc. Perkin Trans. 2 413–417 (1996)

  19. Ensing, B., Buda, F., Gribnau, M. C. M. & Baerends, E. J. Methane-to-methanol oxidation by the hydrated iron(IV) oxo species in aqueous solution: a combined DFT and Car-Parrinello molecular dynamics study. J. Am. Chem. Soc. 126, 4355–4365 (2004)

    Article  CAS  Google Scholar 

  20. Curci, R., D’Accolti, L. & Fusco, C. A novel approach to the efficient oxygenation of hydrocarbons under mild conditions. Superior oxo transfer selectivity using dioxiranes. Acc. Chem. Res. 39, 1–9 (2006)

    Article  CAS  Google Scholar 

  21. Shuklov, I. A., Dubrovina, N. V. & Börner, A. Fluorinated alcohols as solvents, cosolvents and additives in homogeneous catalysis. Synthesis 2925–2943. (2007)

  22. Virtamo, J. et al. Incidence of cancer and mortality following alpha-tocipherol and beta-carotene supplementation: a postintervention follow-up. J. Am. Med. Assoc. 3, 962–986 (2011)

    Google Scholar 

  23. Wilkerson, W. W., Galbraith, W., DeLucca, I. & Harris, R. R. Topical antiinflammatory dehydroabietylamine derivatives IV. Bioorg. Med. Chem. Lett. 3, 2087–2092 (1993)

    Article  CAS  Google Scholar 

  24. Malkowsky, I. M., Nieger, M., Kataeva, O. & Waldvogel, S. R. Synthesis and properties of optically pure phenols derived from (+)-dehydroabietylamine. Synthesis 773–778 (2007)

  25. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008)

    Article  CAS  Google Scholar 

  26. Cheng, X., Harzdorf, N. L., Shaw, T. & Siegel, D. Biomimetic syntheses of the neurotrophic natural products caryolanemagnolol and clovanemagnolol. Org. Lett. 12, 1304–1307 (2010)

    Article  CAS  Google Scholar 

  27. Frisch, M. J. et al. GAUSSIAN09, Revision C.01 (Gaussian, Inc., 2010)

  28. Jursic, B. S. & Martin, R. M. Calculation of bond dissociation energies for oxygen containing molecules by ab initio and density functional theory methods. Int. J. Quantum Chem. 59, 495–501 (1996)

    Article  CAS  Google Scholar 

  29. Wang, J., Tsuchiya, M., Tokumaru, K. & Sakuragi, H. Intramolecular hydrogen-atom transfer in 2-alkylbenzoyloxyl radicals as studied by transient absorption kinetics and product analyses on the photodecomposition of bis(2-alkylbenzoyl) peroxides. Bull. Chem. Soc. Jpn. 68, 1213–1219 (1995)

    Article  CAS  Google Scholar 

  30. Takahara, S. et al. The role of aroyloxyl radicals in the formation of solvent-derived products in photodecomposition of diaroyl peroxides. The reactivity of substituted cyclohexadienyl radicals and intermediacy of ipso intermediates. Bull. Chem. Soc. Jpn. 58, 688–697 (1985)

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Dionicio Siegel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12284

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing