Substituted Thiols in Dynamic Thiol–Thioester Reactions

Abstract

The thiol–thioester reaction has emerged as a promising method for developing covalent adaptable networks (CANs) due to its ability to exchange rapidly under low temperature conditions in a number of solvents, orthogonality among other functional groups, and tunability. Here, the effects of thiol substitution (i.e., primary vs secondary) were assessed with respect to their reactivity in two dynamic thioester reactions: the thiol–thioester exchange and the reversible thiol–anhydride addition. Model NMR experiments were conducted using small-molecule compounds to observe how polymers of similar components would behave in thiol–thioester exchange. It was determined that the K eq was near unity for mixtures of primary thiols and secondary thioesters, and vice versa, in both a polar solvent, DMSO-d 6, and at most slightly favors primary thioesters in a relatively nonpolar solvent, CDCl3. Dielectric spectroscopy and stress relaxation experiments were used to determine the relaxation times and activation energies of the two thioester-containing networks: Thiol-ene networks, which undergo thioester exchange, displayed activation energies of 73 and 71 kJ/mol from dielectric measurements and 36 and 53 kJ/mol from stress relaxation for the primary and secondary thiols, respectively. Thiol–anhydride-ene networks, which undergo both thioester exchange and reversible thiol–anhydride addition, displayed activation energies of 94 and 114 kJ/mol from dielectric and 111 and 139 kJ/mol from stress relaxation for primary and secondary thiols, respectively. In both types of networks, the secondary thioester-based networks demonstrated slower dynamics as compared to the same primary network by at least one order of magnitude. In the anhydride network, the secondary thiol also biased the dynamics toward reversible addition.

Thioester deprotection using a biomimetic NCL approach

“…Overall, the best conditions for 3 deprotection were achieved using 2 eq L-CysOEt at pH 8, during 2 h to give 1 in 90% yield (see Supplementary Table S1 ). Since the thiol−thioester exchange is an equilibrium ( Bongiardina et al, 2021 ), an excess of the deprotecting agent 5a is required to shift the equilibrium toward the desired product. The reactions performed at pH 5 and 6 provided the less favorable yields, even when using more equivalents of 2-aminothiol or longer reaction times.…”

Synthesis and Characterization of Multifunctional Secondary Thiol Hardeners Using 3-Mercaptobutanoic Acid and Their Thiol–Epoxy Curing Behavior

“…We prepared and characterized multifunctional sec -thiol hardeners (di-, tri-, and tetra-functional sec -thiols) using the synthesized 3-mercaptobutanoic acid. In previous reports, 19 − 23 sec -thiols used in the thiol–ene system provided a slow reaction rate as well as a less offensive odor. Despite these positive results for the thiol–ene system, little information has been provided about thiol–epoxy systems.…”

Degradable thioester core-crosslinked star-shaped polymers

“…[18][19][20] As a result, thioesters are more prone to hydrolysis, two orders of magnitude more reactive towards amidation, and have a lower activation barrier to undergo transthioesterification reactions compared to their oxoester analogues. [18][19][20][21][22][23] Bowman and co-workers have extensively investigated thiol-thioester exchange as an alternative to transesterification for use in covalent adaptable networks. 18,21,22 Transthioesterification was shown to be successful at room temperature, while transesterification of oxoester derivatives was slow even at temperatures above 200 °C.…”

“…[18][19][20][21][22][23] Bowman and co-workers have extensively investigated thiol-thioester exchange as an alternative to transesterification for use in covalent adaptable networks. 18,21,22 Transthioesterification was shown to be successful at room temperature, while transesterification of oxoester derivatives was slow even at temperatures above 200 °C. 18 The reaction between thioesters and primary amines (S → N acyl shift) is also a crucial step in native chemical ligation as it renders the overall process irreversible.…”

“…20,23,30,31 While amidation, hydrolysis, transthioesterification and oxidative hydrolysis have previously been reported for the complete and selective degradation of polymers containing thioesters in the backbone, they remain unexplored for the design of degradable core-crosslinked star-shaped polymers. 18,[21][22][23][30][31][32] Herein, we introduce thioester linkages into the crosslinked core of star-shaped polymers in order to exploit their more pronounced reactivity and degradability compared to ester derivatives. Core-crosslinked polymers were prepared from defined poly(methyl methacrylate) arms, obtained through RAFT polymerisation, upon the addition of a synthesised bi-functional thiomethacrylate crosslinker.…”