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 (Keq) of these reactions. Herein we report how sterics can be used to enhance the Keq of these rt dynamic bonds. A series of benzalcyanoacetate, benzalcyanoacetamide, and benzalisoxazolone-based Michael acceptors with varying substituents in the ortho-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 Keq. By modulating the size of the ortho-substituent, the magnitude of Keq could be increased by 1.3 to 6.8 times relative to their para-substituted counterparts. The ortho-substituted acceptors could still be tuned electronically through the para-position, allowing access to r.t., dynamic covalent bonds whose Keq could be tuned from 10 to 1.8 × 106 M–1 across the three acceptor families.