Effects of Thiol Substitution on the Kinetics and Efficiency of Thiol-Michael Reactions and Polymerizations

Abstract

The kinetic effects of the substitution and functionality of the thiol in thiol-Michael reactions were investigated using model monofunctional thiols and multifunctional thiols used in various cross-linking polymerizations. The differences in kinetic rates and final conversions were observed via Fourier transform infrared spectroscopy. The shelf life of these polymers and their mechanical properties were analyzed using a rheometer to measure viscosity changes over time. It was concluded that for monofunctional systems, the reaction rate is dependent on both electronic and steric interactions. For systems with a propagation rate-limiting step (propionate), the secondary thiol was faster than the primary thiol due to increased reactivity of the thiolate anion, by as much as much as a 60% increase in the rate. However, more sterically hindered internal alkenes resulted in primary and secondary rates about equal to each other. For systems with a chain transfer-limiting step (alkyl thiol), the rate was dependent on the pK a of the thiol and ease of deprotonation; in these cases, the primary thiol was the fastest. Though primary and secondary thiols had relatively mild differences in rates, reactions of tertiary thiols were slower than either of the others. For polymerizing systems using multifunctional thiols, the results varied depending on the substitution and functionality. When reacting with a difunctional alkene, the secondary thiol was 74–95% faster than the primary thiol, depending on the type of thiol assessed, and as the functionality of the alkene increased, the rates became more comparable. In the tetrafunctional alkene systems, the primary thiol was 57% faster than the secondary thiol. The shelf life of the systems produced varied results. Typically, in systems with the difunctional thiol, the primary thiol formulation was significantly less stable and gelled more rapidly than the resin with the corresponding secondary thiol. However, in the tetrafunctional thiol systems, the resin containing the secondary thiol gelled more rapidly than that containing the primary thiol. All systems typically gelled within 30 days regardless of substitution, although no additional formulation adjustments were made to stabilize any of these systems beyond changing the thiol structure.

Catch, Modify and Analyze: Methods of Chemoselective Modification of Cysteine-Containing Peptides

“…Maleimide and its derivatives have been used extensively to modify cysteine residues [ 5 , 25 ]. The advantage of cysteine modification by maleimide is its high selectivity and irreversibility [ 22 , 109 ]. However, in comparison to, for example methanethiosulfonate, the reaction is slower and the reaction of cysteine with maleimides requires the monitoring of pH.…”

“…Additionally, the reaction rate is influenced by the steric hindrance of the reactants; the presence of larger substituents in the α and β positions on the Michael acceptor can hamper the reaction [20,21]. Moreover, a high steric hindrance around the nucleophilic center decreases its reactivity to the Michael acceptor [22]. In 2004 Ren et al [23] developed a simple strategy for specifically targeting cysteinecontaining peptides in a tryptic digest.…”

Photopolymerizable Ionogel with Healable Properties Based on Dioxaborolane Vitrimer Chemistry

“…More precisely, these ionogels were obtained from the reaction of multifunctional thiols on diacrylate using thiol-ene Michael addition chemistry in the presence of ILs. The thiol-ene Michael addition is a reaction that involves a base- or nucleophile-catalyzed addition of a thiolate anion to electron-deficient alkenes such as maleimides, vinyl sulfones, acrylates, and methacrylates [ 7 ]. The sole difference between base- and nucleophile-catalyzed reactions lies in the way the thiolate anion is generated.…”

Substituted Thiols in Dynamic Thiol–Thioester Reactions

“…12,13 While substantial work has been done to characterize TTE for thiols common in materials synthesis, 5 the effect of substitution of the thiol on TTE has received little attention. Recently, the substitution of the thiol on various thiol−X processes has seen attention from Li and co-workers, who observed that increasingly substituted thiols have a longer shelf life and less odor than typical primary thiols, 14 and Long and co-workers, who have shown that secondary and tertiary thiols can be used in thiol-ene 15 and thiol−Michael addition 16 polymerizations with minimal detrimental effects on reaction kinetics or conversion at relevant polymerization conditions while resulting in the improved shelf life of the resin mixture. This outcome has important implications for many thiol−X materials that often cannot be premixed and stored as a monomer resin due to their high reactivity.…”