Computational Studies of Reactions of 1,2,4,5-Tetrazines with Enamines in MeOH and HFIP

Pengchen Ma; Dennis Svatunek; Zixi Zhu; Dale L Boger; Xin-Hua Duan; K N Houk

doi:10.1021/jacs.4c06067

Computational Studies of Reactions of 1,2,4,5-Tetrazines with Enamines in MeOH and HFIP

J Am Chem Soc. 2024 Jul 10;146(27):18706-18713. doi: 10.1021/jacs.4c06067. Epub 2024 Jun 28.

Authors

Pengchen Ma^{1

2}, Dennis Svatunek^{2

3}, Zixi Zhu⁴, Dale L Boger⁴, Xin-Hua Duan¹, K N Houk²

Affiliations

¹ Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, China.
² Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States.
³ Institute of Applied Synthetic Chemistry, TU Wien, 1060 Vienna, Austria.
⁴ Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.

PMID: 38941192
DOI: 10.1021/jacs.4c06067

Abstract

The reaction between 1,2,4,5-tetrazines and alkenes in polar solvents proceeds through a Diels-Alder cycloaddition along the C-C axis (C3/C6 cycloaddition) of the tetrazine, followed by dinitrogen loss. By contrast, the reactions of 1,2,4,5-tetrazines with enamines in hexafluoroisopropanol (HFIP) give 1,2,4-triazine products stemming from a formal Diels-Alder addition across the N-N axis (N1/N4 cycloaddition). We explored the mechanism of this interesting solvent effect through DFT calculations in detail and revealed a novel reaction pathway characterized by C-N bond formation, deprotonation, and a 3,3-sigmatropic rearrangement. The participation of an HFIP molecule was found to be crucial to the N1/N4 selectivity over C3/C6 due to the more favored initial C-N bond formation than C-C bond formation.