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Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives

Nature volume 618, pages 748–754 (2023)Cite this article

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Abstract

Since 18251, compounds with the molecular formula C6H6—most notably benzene—have been the subject of rigorous scientific investigation2,3,4,5,6,7. Of these compounds, 1,2,3-cyclohexatriene has been largely overlooked. This strained isomer is substantially (approximately 100 kcal mol−1) higher in energy compared with benzene and, similar to its relatives benzyne and 1,2-cyclohexadiene, should undergo strain-promoted reactions. However, few experimental studies of 1,2,3-cyclohexatriene are known8,9,10,11,12. Here we demonstrate that 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes, including diverse cycloadditions, nucleophilic additions and σ-bond insertions. Experimental and computational studies of an unsymmetrical derivative of 1,2,3-cyclohexatriene demonstrate the potential for highly selective reactions of strained trienes despite their high reactivity and short lifetimes. Finally, the integration of 1,2,3-cyclohexatrienes into multistep syntheses demonstrates their use in rapidly assembling topologically and stereochemically complex molecules. Collectively, these efforts should enable further investigation of the strained C6H6 isomer 1,2,3-cyclohexatriene and its derivatives, as well as their application in the synthesis of important compounds.

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Fig. 1: Selected strained isomers of benzene (1) and comparison of reaction coordinate diagrams.
Fig. 2: Strained cyclic intermediates and overview of the current study.
Fig. 3: Structural analysis of benzene (1), 1,2,3-cyclohexatriene (5) and benzyne (20) and trapping reactions of strained triene 5.
Fig. 4: Preparation of a disubstituted cyclic triene precursor and scope of reactions.
Fig. 5: Structure and regioselective reactions of a monosubstituted cyclic triene.
Fig. 6: Strained 1,2,3-cyclohexatrienes in multistep synthesis.

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Data availability

Experimental procedures, characterization data, computational methods and computational data are provided in the Supplementary Information. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2238912 and 2239633 (neilgarg@chem.ucla.edu). Reprints and permissions information is available at www.nature.com/reprints.

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Acknowledgements

We thank the NIH-NIGMS (R35 GM139593 for N.K.G.), the NSF (DGE-2034835 for A.V.K. and A.S.B.), the Foote family (for A.V.K. and A.S.B.), the Stone family (for D.C.W.) and the Trueblood family (for N.K.G.). These studies were supported by shared instrumentation grants from the NSF (CHE-1048804), the NIH NCRR (S10RR025631), the NIH ORIP (S10OD028644) and the DOE (DE-FC03-02ER63421). Calculations were performed on the Hoffman2 cluster and the UCLA Institute of Digital Research and Education (IDRE) at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). We thank K. Houk (UCLA) for computational resources and valuable discussion, M. Ramirez (California Institute of Technology) and Joseph W. Treacy (UCLA) for computational assistance and D. Turner (UCLA) for experimental assistance.

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  1. These authors contributed equally: Andrew V. Kelleghan, Ana S. Bulger

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  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA

    Andrew V. Kelleghan, Ana S. Bulger, Dominick C. Witkowski & Neil K. Garg

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A.V.K., A.S.B. and D.C.W. designed and performed experiments and analysed experimental data. A.V.K. and D.C.W. designed, performed and analysed computational studies. N.K.G. directed the investigations and prepared the paper with contributions from all authors; all authors contributed to discussions.

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Correspondence to Neil K. Garg.

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Kelleghan, A.V., Bulger, A.S., Witkowski, D.C. et al. Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives. Nature 618, 748–754 (2023). https://doi.org/10.1038/s41586-023-06075-8

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