Temporal Control of Thiol-Click Chemistry

Abstract

A chemical clock protocol that enables enhanced temporal control over the onset of two base-catalyzed ‘click’ reactions, the thiol-Michael addition reaction, and the thiol-isocyanate reaction, is described and used in polymerization reactions. Initiating protocols with predictable induction times for both click reactions are developed and characterized using a pair consisting of an electron deficient vinylic species and a nucleophile with an acid. The approach was successfully demonstrated such that the reaction onset is effectively and predictably delayed by up to 20 min, with rapid complete reaction following the controllable induction period. By implementing initiation systems with varying relative concentrations of the electron deficient vinyl, nucleophile, and acid, this approach to formulating a comprehensive initiator system affords a previously unavailable degree of temporal control that is extremely useful for designing and processing cross-linked polymers and other thiol-Michael and thiol-isocyanate polymerizations.

Mechanistic Kinetic Modeling of Thiol–Michael Addition Photopolymerizations via Photocaged “Superbase” Generators: An Analytical Approach

“…This kinetic prediction appears to differ from that of the nucleophile-catalyzed thiol–Michael addition reaction using TPP/MsOH initiator system as time-lapse mechanism, where the reaction rate was found to remain largely unchanged regardless of the length of the induction period tested. 26 Nevertheless, similar inhibition kinetics would be expected to develop for nucleophile-driven thiol–Michael additions despite the distinct initiation mechanisms promoted by the two catalysts. The initial amount of acidic impurities can be estimated by plotting experimental data according to Figure 5d while applying the expression $${false[\text{HA}false]}_0=\chi {false[\text{PB}false]}_0=f{false[\text{PB}false]}_{0}false(1-{\mathrm{e}}^{-\text{slope}·{\phi }_{\mathrm{i}}}false)$$The theoretical analysis presented here clearly foretells the emergent need for a tight control of the reacting monomers purity and photoinitiation conditions in thiol–Michael addition reactions so that the “click” character associated with this chemistry is not altered when applied to photopolymerization systems that require rapid curing kinetics.…”

“…In step 2, the magnitude of the dynamic equilibrium established between the thiol and base catalyst is dictated by the difference in acidities between the thiol and the conjugate acid $$\mathrm{normal\Delta }\mathrm{normalp}{K}_{\mathrm{a}}=\mathrm{normalp}{K}_{\mathrm{normala}false(\text{RSH}false)}-\mathrm{normalp}{K}_{\mathrm{normala}false({\text{HB}}^{+}false)}$$assuming full dissociation of the intermediate ion-pair into free ions: 26,40–42 $$K_{\text{eq}}=\frac{k_{\mathrm{normalf}}}{k_{\mathrm{normalr}}}=\frac{{false[{\text{RS}}^{-}false]}_{\text{eq}}{false[{\text{HB}}^{+}false]}_{\text{eq}}}{{false[\text{RSH}false]}_{\text{eq}}{false[\mathrm{normalB}false]}_{\text{eq}}}={10}^{\mathrm{normal\Delta }\mathrm{normalp}{K}_{\mathrm{a}}}$$Efficient deprotonation will thus occur when very acidic thiols (i.e., with low p K a values) are combined with exceptionally strong bases such as TMG. Integration of eq 1 leads to the following explicit analytical solution describing the production of base $$false[{\mathrm{normalB}false]}_t=f{false[\text{PB}false]}_{0}false(1-{\mathrm{e}}^{-z_{\mathrm{i}}t}false)$$Accounting for an equilibrium constant, K eq ≫ 1 in step 2, 31 any quantity of base that is formed from photoinitiation is thus assumed to be immediately converted into an equivalent amount of the conjugate acid (or analogously, [RS − ] formed ≈ [B] consumed ), so that the net balance in base concentration remains very close to zero throughout the reaction.…”

Combined, independent small molecule release and shape memory via nanogel-coated thiourethane polymer networks

“…Step-growth thiourethane networks were created by adapting a previously described method 40 . Nucleophile-catalyzed thiol-isocyanate reactions can occur rapidly with gelation in less than 30 s, so a TPP/MsOH initiator/inhibitor system was prepared to allow for sufficient working time.…”

“…However, the thiol-isocyanate reaction is traditionally extremely rapid with little to no temporal control, making processing and handling challenging 39 and consequently has received less attention in the development of new functional materials. A recent study described a great improvement in controlling the onset of the thiol-isocyanate reaction by combining a phosphine and methanesulfonic acid to form an initiator/inhibitor “chemical clock” that can delay gelation by several minutes, which presents an opportunity for increased exploration into crosslinked thiourethane networks as functional materials 40 .…”

Development of fluorescent cholesterol derivatives for the exogenous introduction of proteins to the plasma membrane

“…83 In contrast, the weaker electrophile vinylsulfone is less reactive toward nucleophiles, but its thiol addition is significantly faster than the amine addition that results in higher chemoselectivity between pH 7.5 and 9.0. 182,183 Furthermore, maleimides can hydrolyze under mild basic conditions to maleic acid that is disadvantageous when a longer reaction time is required for capturing of the cholesterol anchor to a protein with a sterically hindered C-terminus. When a prolonged reaction time is necessary, the vinylsulfone containing anchor is to be the choice because it was found to be stable for days at pH 9.…”