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.