Limitations of radical thiol‐ene reactions for polymer–polymer conjugation

Abstract

In the current work, we report our findings on the use of radical thiol-ene chemistry for polymerpolymer conjugation. The manuscript combines the results from the Preparative Macromolecular Chemistry group from Karlsruhe Institute of Technology (KIT) and the Polymer Chemistry Research group from Ghent University (UGent), which allowed for an investigation over a very broad range of reaction conditions. In particular, thermal and UV initiation methods for the 2 radical thiol-ene process were compared. In the KIT group, the process was studied as a tool for the synthesis of star polymers by coupling multi-functional thiol core molecules with poly(nbutyl acrylate) macromonomers (MM), employing thermally decomposing initiators. The product purity and thus reaction efficiency was assessed via electrospray ionization mass spectrometry. Although the reactions with 10 or 5 equivalents of thiol with respect to macromonomer were successful, the coupling reaction with a one-to-one ratio of MM to thiol yielded only a fraction of the targeted product, besides a number of side products. A systematic parameter study such as a variation of the concentration and nature of the initiator and the influence of thiol to ene ratio was carried out for a one-to-one ratio of MM to thiol content.Further experiments with poly(styrene) and poly(isobornyl acrylate) containing a vinylic end group confirmed that thermal thiol-ene conjugation is far from quantitative in terms of achieving macromolecular star formation. In parallel, the UGent group has been focusing on photo-initiated thiol-ene chemistry for the synthesis of functional polymers on the one hand and block copolymers consisting of poly(styrene) (PS) and poly(vinyl acetate) (PVAc) on the other hand.Various functionalization reactions showed an overall efficient thiol-ene process for conjugation reactions of polymers with low molecular weight compounds (~90% coupling yield). However, while SEC and FT-IR analysis of the conjugated PS-PVAc products indicated qualitative evidence for a successful polymer-polymer conjugation, 1 H NMR and elemental analysis revealed a low conjugation efficiency of about 23% for a thiol-to-ene ratio equal to one. Blank reactions using typical thiol-ene conditions indicated that bimolecular termination reactions 3 occur as competitive side reactions explaining why a molecular weight increase is observed even though the thiol-ene reaction was not successful. The extensive study of both research groups indicates that radical thiol-ene chemistry should not be proposed as a straightforward conjugation tool for polymer-polymer conjugation reactions. Head-to-head coupling is a major reaction pathway, which interrupts the propagation cycle of the thiol-ene process.

Use of a continuous-flow microreactor for thiol–ene functionalization of RAFT-derived poly(butyl acrylate)

“…This is an interesting observation, since with the same excess of a similar tetrathiol compound no double coupling with acrylates was observed in radical thiol-ene reactions. 16 The amount of this side product is, however, small and can be safely considered to be negligible, especially concerning the impurity of the starting material.…”

Functionalization of polyurethanes by incorporation of alkyne side-groups to oligodiols and subsequent thiol–yne post-modification

“…Hence, a sufficient amount of photoinitiator is necessary to achieve a high functionalization degree, as also noted earlier. 3,24,25 Besides, as side reactions such as disulfide bond formation or thiyl radical combination are inevitable in thiol-yne reactions, 2,3 the use of an excess amount of thiol was employed to obtain full conversion. Good agreement between conversion of alkyne groups and the amount of attached thiol was observed, which indicates that two thiol molecules reacted with one alkyne group.…”

Synthesis of heterotelechelic polymers with affinity to glutathione-S-transferase and biotin-tagged proteins by RAFT polymerization and thiol–ene reactions

“…the addition of thiols with a variety of non-activated carbon-carbon double bonds, has been described in numerous publications. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] The demonstrated efficiency of thiol-ene click chemistry has been widely used in polymer functionalization and conjugations. 29,30,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] In this study, thiolene reactions have been employed to functionalize PNIPAAm with a-GSH, u-biotin termini.…”