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High Rates of Quinone-Alkyne Cycloaddition Reactions are Dictated by Entropic Factors
Johannes A M Damen1, Jorge Escorihuela2, Han Zuilhof1,3,4
1Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, Wageningen, 6807 WE, the Netherlands.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|March 21, 2023
Summary
Strained cycloalkynes react significantly faster than cycloalkenes in click reactions with 1,2-quinone. This study quantifies reaction rates and thermodynamic parameters, advancing understanding of these rapid chemical transformations.
Area of Science:
- Organic Chemistry
- Chemical Kinetics
- Computational Chemistry
Background:
- Cycloaddition reactions are crucial in synthetic chemistry, with click chemistry offering efficient and reliable methods.
- Strained cycloalkynes and cycloalkenes are increasingly utilized as reactive partners in click reactions.
- Understanding the kinetics and thermodynamics of these reactions is essential for optimizing their application.
Purpose of the Study:
- To quantify the reaction rates of strained cycloalkynes and cycloalkenes with 1,2-quinone.
- To determine the thermodynamic activation parameters governing these cycloaddition reactions.
- To compare the reactivity of different strained cyclic systems and the effect of derivatization on reaction rates.
Main Methods:
- Stopped-flow UV-Vis spectroscopy was employed to measure reaction kinetics.
- Computational analysis was used to support experimental findings and calculate activation parameters.
- The linearized Eyring equation was applied to determine thermodynamic parameters (ΔH≠, ΔS≠, ΔG≠).
Main Results:
- Strained cycloalkynes, such as BCN-OH 3, exhibit significantly faster reaction rates (>150 times) with 1,2-quinone compared to strained cycloalkenes like TCO-OH 5.
- The 8-membered strained alkyne BCN-OH 3 reacts 16 times faster than the more strained 7-membered THS 2.
- Derivatization with a carbamate group can reduce the rate constant of strained alkynes.
- Experimentally determined activation parameters (ΔG≠) for SPOCQ reactions were 13.1 kcal/mol for BCN-OH 3 and 14.8 kcal/mol for THS 2.
- Computational analysis corroborated the experimental findings, yielding calculated ΔG≠ values of 14.7 kcal/mol (BCN-OH 3) and 15.6 kcal/mol (THS 2).
Conclusions:
- Strained cycloalkynes are highly reactive dienophiles in SPOCQ reactions with 1,2-quinone.
- The study provides key thermodynamic data that contribute to a fundamental understanding of rapid click reactions.
- Kinetic and computational data offer insights into the factors governing the efficiency of these cycloaddition reactions.
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