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
Abstract
Abstract 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 ( k 2 1824 M −1 s −1 ) reacts >150 times faster than the strained alkene TCO‐OH 5 ( k 2 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 ( k 2 110.6 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 Δ H ≠ of 0.80 kcal/mol, Δ S ≠ =−46.8 cal/K⋅mol, and Δ G ≠ =14.8 kcal/mol (at 25 °C), whereas the same reaction with BCN−OH 3 is associated with, Δ H ≠ =2.25 kcal/mol, Δ S ≠ =−36.3 cal/K⋅mol, and Δ G ≠ =13.1 kcal/mol (at 25 °C). Computational analysis supported the values obtained by the stopped‐flow measurements, with calculated Δ G ≠ of 15.6 kcal/mol (in H 2 O) for the SPOCQ reaction with THS 2 , and with Δ G ≠ of 14.7 kcal/mol (in H 2 O) 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.