High Rates of Quinone-Alkyne Cycloaddition Reactions are Dictated by Entropic Factors

Johannes A.M. Damen, Jorge Escorihuela, Han Zuilhof, Floris L. van Delft, Bauke Albada*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


Reaction rates of strained cycloalkynes and cycloalkenes with 1,2-quinone were quantified by stopped flow UV-Vis spectroscopy and computational analysis. We found that the strained alkyne BCN−OH 3 (k2 1824 M−1 s−1) reacts >150 times faster than the strained alkene TCO-OH 5 (k2 11.56 M−1 s−1), and that derivatization with a carbamate can lead to a reduction of the rate constant with almost half. Also, the 8-membered strained alkyne BCN−OH 3 reacts 16 times faster than the more strained 7-membered THS 2 (k2 110.6 M−1 s−1). Using the linearized Eyring equation we determined the thermodynamic activation parameters of these two strained alkynes, revealing that the SPOCQ reaction of quinone 1 with THS 2 is associated with ΔH of 0.80 kcal/mol, ΔS=−46.8 cal/K⋅mol, and ΔG=14.8 kcal/mol (at 25 °C), whereas the same reaction with BCN−OH 3 is associated with, ΔH=2.25 kcal/mol, ΔS=−36.3 cal/K⋅mol, and ΔG=13.1 kcal/mol (at 25 °C). Computational analysis supported the values obtained by the stopped-flow measurements, with calculated ΔG of 15.6 kcal/mol (in H2O) for the SPOCQ reaction with THS 2, and with ΔG of 14.7 kcal/mol (in H2O) for the SPOCQ reaction with BCN−OH 3. With these empirically determined thermodynamic parameters, we set an important step towards a more fundamental understanding of this set of rapid click reactions.

Original languageEnglish
Article numbere202300231
JournalChemistry - A European Journal
Issue number39
Publication statusPublished - 11 Jul 2023


  • eyring plot
  • secondary orbital interactions
  • thermodynamic reaction parameters


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