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Room-temperature synthesis of m-benzyne

Nature Synthesis volume 3, pages 1083–1090 (2024)Cite this article

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Abstract

For over a century, scientists have been fascinated by the unique electronic, structural and bonding properties of the three isomers of benzyne, a highly reactive organic intermediate derived from benzene by removing two hydrogen atoms. Although o- and p-benzynes have been extensively studied following the establishment of reliable synthetic methods to prepare them, m-benzyne in the ground state has remained experimentally inaccessible. We report herein the room-temperature and atmospheric-pressure synthesis of m-benzyne in solution. Experimental and theoretical investigations revealed that owing to the inner bond inside the benzene ring between C1 and C3 atoms, m-benzyne behaves as a potent electrophile with a Mayr’s electrophilicity parameter E of around −2 but shows weak free-radical character. The bonding appears similar to the inverted σ-bond, the so-called charge-shift bond, in [1.1.1]propellane. By utilizing the unique bonding character of m-benzyne, we established halogenations and C–N and C–C coupling reactions, as well as a successive m-benzyne generation and trapping sequence that provides access to 1,3,5-trisubstituted benzenes.

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Fig. 1: Background of benzyne chemistry.
Fig. 2: m-Benzyne and inverted σ-bonded species.
Fig. 3: Preparation of precursor and generation of m-benzyne.
Fig. 4: Generation of m-aryne and its reactivity towards chloride ion.
Fig. 5: Trapping experiments of m-benzyne 2 with nitrogen nucleophiles.
Fig. 6: Trapping experiments of m-benzyne 2 with carbon nucleophiles.

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Data availability

The data that support the findings of this study are available in this article and the Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2061582 (8a), CCDC 2268762 (8b), CCDC 2268732 (8c) and CCDC 2061583 (25). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

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Acknowledgements

This research was supported in part by Grants-in-Aid for Scientific Research (Nos. 17H03017 and 20H02720 to K.M., and Nos. 17H06173, 22H00320 and JP22H05125 to M.U.) from Japan Society for the Promotion of Science (JSPS) (Japan), Research Fellowships for Young Scientists (No. 21J21600 to K.K.) from JSPS (Japan), Core Research for Evolutionary Science and Technology (CREST) (No. JPMJCR19R2 to M.U.) from Japan Science and Technology Agency (Japan), NAGASE Science Technology Foundation, Naito Foundation, Chugai Foundation and Uehara Memorial Foundation (to M.U.).

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Kenta Koyamada, Kazunori Miyamoto & Masanobu Uchiyama

  2. Faculty of Pharmacy, Keio University, Tokyo, Japan

    Kazunori Miyamoto

  3. Research Initiative for Supra-Materials (RISM), Shinshu University, Ueda, Japan

    Masanobu Uchiyama

Authors
  1. Kenta Koyamada
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  2. Kazunori Miyamoto
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  3. Masanobu Uchiyama
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Contributions

K.K. and K.M. carried out the experimental work. K.K. carried out computational studies and performed X-ray crystal structure analyses of diaryl-λ3-iodanes and compound 25. K.M. and M.U. designed, advised and directed the project, and wrote the paper. All authors edited the paper.

Corresponding authors

Correspondence to Kazunori Miyamoto or Masanobu Uchiyama.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Wolfram Sander and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Experimental details, Supplementary Figs. 1–5 and Tables 1–3.

Supplementary Data 1

X-Ray crystallographic data for compound 8a, CCDC 2061582.

Supplementary Data 2

X-Ray crystallographic data for compound 8b, CCDC 2268762.

Supplementary Data 3

X-Ray crystallographic data for compound 8c, CCDC 2268732.

Supplementary Data 4

X-Ray crystallographic data for compound 25, CCDC 2061583.

Source data

Source Data Fig. 4 (download XLSX )

Source data for the graphs in Fig. 4b.

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Koyamada, K., Miyamoto, K. & Uchiyama, M. Room-temperature synthesis of m-benzyne. Nat. Synth 3, 1083–1090 (2024). https://doi.org/10.1038/s44160-024-00572-y

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