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-1s-1) reacts >150 times faster than the strained alkene TCO-OH 5 (k2 11.56 M-1s-1). 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-1s-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 biogenic click reactions.