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Diels-Alder reactivities of cycloalkenediones with tetrazine

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Abstract

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.

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

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, CA, USA

    Brian J. Levandowski, Hannah J. Eckvahl & K. N. Houk

  2. Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands

    Trevor A. Hamlin & F. Matthias Bickelhaupt

  3. Institute for Molecules and Materials (IMM), Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

    F. Matthias Bickelhaupt

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  1. Brian J. Levandowski
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  2. Trevor A. Hamlin
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  3. Hannah J. Eckvahl
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  4. F. Matthias Bickelhaupt
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  5. K. N. Houk
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Correspondence to F. Matthias Bickelhaupt or K. N. Houk.

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Dedication: Dedicated to Tim Clark, computational chemist and friend, on the occasion of his 70th birthday.

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Levandowski, B.J., Hamlin, T.A., Eckvahl, H.J. et al. Diels-Alder reactivities of cycloalkenediones with tetrazine. J Mol Model 25, 33 (2019). https://doi.org/10.1007/s00894-018-3909-z

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