Article | Published:

Charge-transfer-directed radical substitution enables para-selective C–H functionalization

Nature Chemistry volume 8, pages 810815 (2016) | Download Citation

Abstract

Efficient C–H functionalization requires selectivity for specific C–H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C–H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C–H functionalization reactions.

  • Compound

    1-(chloromethyl)-4-(4-fluorophenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(4-chlorophenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(p-tolyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(4-methoxyphenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(2-methoxyphenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(3-fluoro-4-methoxyphenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(9-oxo-9H-fluoren-2-yl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(2-methoxy-5-(methoxycarbonyl)phenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-(3-((3-chlorophenethyl)carbamoyl)-4-methylphenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    (S)-1-(chloromethyl)-4-(4-(2-(1,3-dioxoisoindolin-2-yl)-3-methoxy-3-oxopropyl)phenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(5-(4-chlorobenzoyl)-2-((1-isopropoxy-2-methyl-1-oxopropan-2-yl)oxy)phenyl)-4-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-phenylpiperazine

  • Compound

    1-(p-tolyl)piperazine

  • Compound

    1-(4-fluorophenyl)piperazine

  • Compound

    1-(4-chlorophenyl)piperazine

  • Compound

    1-(4-methoxyphenyl)piperazine

  • Compound

    1-(3,4-dimethylphenyl)piperazine

  • Compound

    1-(3-(tert-butyl)-4-methylphenyl)piperazine

  • Compound

    methyl 2-methoxy-5-(piperazin-1-yl)benzoate

  • Compound

    1-(3-fluoro-4-methoxyphenyl)piperazine

  • Compound

    1-(4-(benzyloxy)phenyl)piperazine

  • Compound

    2-methoxy-5-(piperazin-1-yl)benzonitrile

  • Compound

    methyl 4-methoxy-3-(piperazin-1-yl)benzoate

  • Compound

    2-(piperazin-1-yl)-9H-fluoren-9-one

  • Compound

    8-(piperazin-1-yl)quinoline

  • Compound

    1-(2-methoxypyridin-3-yl)piperazine

  • Compound

    2-(4-(piperazin-1-yl)phenyl)pyrimidine

  • Compound

    1-(4'-(trimethylsilyl)-[1,1'-biphenyl]-4-yl)piperazine

  • Compound

    1-([1,1'-biphenyl]-4-yl)piperazine

  • Compound

    1-(4-(4-fluorophenoxy)phenyl)piperazine

  • Compound

    methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(4-(piperazin-1-yl)phenyl)propanoate

  • Compound

    phenyl(5-(piperazin-1-yl)thiophen-2-yl)methanone

  • Compound

    ethyl 5-(piperazin-1-yl)thiophene-2-carboxylate

  • Compound

    isopropyl 2-(4-(4-chlorobenzoyl)-2-(piperazin-1-yl)phenoxy)-2-methylpropanoate

  • Compound

    1-(chloromethyl)-4-(2,5-dichlorophenyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(4-fluorophenyl)piperidine

  • Compound

    1-(3-fluorophenyl)piperidine

  • Compound

    1-(2-fluorophenyl)piperidine

  • Compound

    1-(5-chloro-2-methoxyphenyl)-4-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    1-(chloromethyl)-4-phenyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium

  • Compound

    4-fluoro-N,N,N-trimethylbenzenaminium iodide

  • Compound

    3-fluoro-N,N,N-trimethylbenzenaminium iodide

  • Compound

    2-fluoro-N,N,N-trimethylbenzenaminium iodide

  • Compound

    2-(2-fluorophenyl)isoindoline-1,3-dione

  • Compound

    2-(3-fluorophenyl)isoindoline-1,3-dione

  • Compound

    2-(4-fluorophenyl)isoindoline-1,3-dione

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Acknowledgements

The authors thank the National Institute of General Medical Sciences (GM088237), the National Institute of Biomedical Imaging and Bioengineering (EB013042), UCB Pharma and Kwanjeong Educational Foundation for funding. The authors further thank J. McClean (Harvard University) for helpful discussions.

Author information

Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA

    • Gregory B. Boursalian
    • , Won Seok Ham
    • , Anthony R. Mazzotti
    •  & Tobias Ritter
  2. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany

    • Gregory B. Boursalian
    •  & Tobias Ritter

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Contributions

G.B.B., W.S.H. and A.R.M. designed and performed the experiments and analysed the data. G.B.B. discovered the Ar–TEDA formation reaction and conceived the mechanistic proposal and explanation for the positional selectivity. A.R.M. discovered the reduction of Ar–TEDA compounds to aryl piperazines. G.B.B. and T.R. prepared the manuscript with input from W.S.H. and A.R.M.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tobias Ritter.

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DOI

https://doi.org/10.1038/nchem.2529

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