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