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Why •CF2H is nucleophilic but •CF3 is electrophilic in reactions with heterocycles

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  • Meng Duan

    (University of California)

  • Qianzhen Shao

    (University of California)

  • Qingyang Zhou

    (University of California)

  • Phil S. Baran

    (Scripps Research)

  • K. N. Houk

    (University of California)

Abstract

Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF2H radical has a nucleophilic character similar to alkyl radicals, but the CF3 radical is electrophilic. While the difference between •CH3 and •CF3 is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF3 becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.

Suggested Citation

  • Meng Duan & Qianzhen Shao & Qingyang Zhou & Phil S. Baran & K. N. Houk, 2024. "Why •CF2H is nucleophilic but •CF3 is electrophilic in reactions with heterocycles," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48949-z
    DOI: 10.1038/s41467-024-48949-z
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    1. Yuta Fujiwara & Janice A. Dixon & Fionn O’Hara & Erik Daa Funder & Darryl D. Dixon & Rodrigo A. Rodriguez & Ryan D. Baxter & Bart Herlé & Neal Sach & Michael R. Collins & Yoshihiro Ishihara & Phil S. , 2012. "Practical and innate carbon–hydrogen functionalization of heterocycles," Nature, Nature, vol. 492(7427), pages 95-99, December.
    2. Joel W. Beatty & James J. Douglas & Kevin P. Cole & Corey R. J. Stephenson, 2015. "A scalable and operationally simple radical trifluoromethylation," Nature Communications, Nature, vol. 6(1), pages 1-6, November.
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