Diels-Alder reactivities of cycloalkenediones with tetrazine

  • Brian J. Levandowski
  • Trevor A. Hamlin
  • Hannah J. Eckvahl
  • F. Matthias BickelhauptEmail author
  • K. N. HoukEmail author
Original Paper
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Quantum chemical calculations were used to investigate the Diels-Alder reactivities for a series of cycloalkenediones with tetrazine. We find that the reactivity trend of cycloalkenediones toward tetrazine is opposite to cycloalkenes. The electrostatic interactions between the cycloalkenediones and tetrazine become more stabilizing as the ring size of the cycloalkenediones increases, resulting in lower activation energies. The origin of the more favorable electrostatic interactions and the accelerated reactivities of larger cycloalkenediones result from a stabilizing CH/π interaction that is not present in the reaction of the 4-membered cycloalkenedione. The Diels-Alder reactivity trend of cycloalkenediones toward tetrazine is opposite that of cycloalkenes. The increased reactivity of the 5- and 6-membered cycloalkenediones relative to the 4-membered cycloalkenedione is attributed to a stabilizing electrostatic CH/π interaction that is not present in the reaction of the 4-membered cycloalkenedione.

Graphical abstract

The Diels-Alder reactivity trend of cycloalkenediones towards tetrazine is opposite of cycloalkenes. The increased reactivity of the 5- and 6-membered cycloalkenediones relative to the 4-membered cycloalkenedione is attributed to a stabilizing electrostatic CH/π interaction that is not present in the reaction of the 4-membered cycloalkenedione


Diels-Alder reaction Distortion/interaction-activation strain model Reactivity Electrostatic interactions Density functional theory 



We thank the National Science Foundation (NSF CHE-1361104), the National Institute of Health (NIH R01GM109078), and the Netherlands Organization for Scientific Research (NWO) for financial support. We thank Dennis Svatunek for helpful discussions and assistance in generating the ESP maps. Computer time was provided by the UCLA Institute for Digital Research and Education (IDRE) on the Hoffman2 supercomputer. We additionally thank SURFsara for use of the Cartesius supercomputer.

Supplementary material

894_2018_3909_MOESM1_ESM.docx (370 kb)
ESM 1 (DOCX 370 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Brian J. Levandowski
    • 1
  • Trevor A. Hamlin
    • 2
  • Hannah J. Eckvahl
    • 1
  • F. Matthias Bickelhaupt
    • 2
    • 3
    Email author
  • K. N. Houk
    • 1
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM)Vrije Universiteit AmsterdamDe Boelelaan 1083The Netherlands
  3. 3.Institute for Molecules and Materials (IMM)Radboud UniversityHeyendaalseweg 135The Netherlands

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