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Computational analysis of modular diazotransfer reactions for the development of predictive reactivity models and diazotransfer reagents

Nature Synthesis (2024)Cite this article

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Abstract

The development of the sulfur(VI)–fluoride exchange (SuFEx) and modular diazotransfer (MoDAT) reactions represent important milestones in the evolution of click chemistry. However, their reactivity profiles, chemoselectivity origins and underlying mechanisms remain unclear. Here we report a computational study of the MoDAT and SuFEx pathways, focusing on the reaction between the diazotransfer reagent fluorosulfuryl azide and primary amines. Our calculations reveal that the MoDAT reaction possesses a small kinetic barrier and a strong driving force, making it kinetically and thermodynamically more favourable than the SuFEx reaction. Through mechanistic scrutiny and structure–activity relationship studies, we have formulated predictive models for the reactivity and selectivity of the MoDAT reaction. Leveraging these insights, an easy-to-prepare and easily handled diazotransfer reagent with excellent reactivity has been developed, which holds broad promise for applications in chemistry and biology.

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Fig. 1: Click reactions.
Fig. 2: Mechanisms of the MoDAT and SuFEx reactions.
Fig. 3: Predictive models for the selectivity and reactivity of primary amines in the MoDAT reaction.
Fig. 4: Predictive models for the reactivity of diazotransfer reagents.
Fig. 5: Design and preparation of diazotransfer reagents.
Fig. 6: Isolated azide products prepared from the corresponding primary amines.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 2336497 (PSIA-II). These data can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the Ministry of Science and Technology of China (2021YFF0701700 to X.-S.X.), the National Natural Science Foundation of China (grant numbers 22122104, 22193012 and 21933004 to X.-S.X.), the CAS Project for Young Scientists in Basic Research (grant numbers YSBR-095 and YSBR-052 to X.-S.X.) and the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB0590000 to X.-S.X.). We thank F. Zhang and P. Ji for their inspiring discussions and comments.

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  1. These authors contributed equally: Meng-Meng Zheng, Liu Cai.

Authors and Affiliations

  1. Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Meng-Meng Zheng, Liu Cai, Hao-Dong Tan, Xiaoyu Lai & Xiao-Song Xue

  2. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Meng-Meng Zheng & Xiao-Song Xue

  3. School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China

    Tiancheng Ma & Jiajia Dong

  4. Institute of Translational Medicine, National Facility for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China

    Jiajia Dong

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Contributions

X.-S.X. conceived and directed the project. M.-M.Z. and H.-D.T. conducted the DFT calculations. L.C., T.M. and X.L. performed the experiments. M.-M.Z., L.C., J.D. and X.-S.X. discussed the results. M.-M.Z., L.C. and X.-S.X. wrote the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to Jiajia Dong or Xiao-Song Xue.

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Competing interests

X.-S.X., L.C. and M.-M.Z. have filed a patent application lodged with Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (reference number CN2024103608309) based on this work. T.M., H.-D.T., X.L. and J.D. declare no competing interests.

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Nature Synthesis thanks Trevor Hamlin, Patrick Melvin and Han Zuilhof for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–30, Table 1, computational details, reagent development and characterization data.

Supplementary Data 1

Crystallographic data for compound PSIA-II, CCDC 2336497

Supplementary Data 2

Computational data

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Zheng, MM., Cai, L., Ma, T. et al. Computational analysis of modular diazotransfer reactions for the development of predictive reactivity models and diazotransfer reagents. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00633-2

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