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

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.