A Twist on Controlling the Equilibrium of Dynamic Thia-Michael Reactions.

The thia-Michael reaction, i.e., the addition of a thiol to an α,β-unsaturated carbonyl moiety, has recently gained significant attention within the field of dynamic covalent chemistry. Interestingly, including an additional electron-withdrawing group at the α-position of the Michael acceptor can result in room temperature (rt), catalyst-free dynamic thia-Michael reactions. Importantly, the electronic nature of the Michael acceptor can be used to tune the equilibrium constant () of these reactions. Herein we report how sterics can be used to enhance the of these rt dynamic bonds. A series of benzalcyanoacetate, benzalcyanoacetamide, and benzalisoxazolone-based Michael acceptors with varying substituents in the -position of their β-phenyl rings were investigated. By placing substituents in such a position, out-of-plane twisting was created between the β-phenyl ring and the α,β-unsaturated carbonyl, raising the overall energy of the reactants and leading to significant increases in . By modulating the size of the -substituent, the magnitude of could be increased by 1.3 to 6.8 times relative to their -substituted counterparts. The -substituted acceptors could still be tuned electronically through the -position, allowing access to r.t., dynamic covalent bonds whose could be tuned from 10 to 1.8 × 10 M across the three acceptor families.