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.

The combination of RAFT chemistry and the hetero-Diels-Alder (HDA) cycloaddition was successfully utilized in the synthesis of poly(styrene) (PS) star polymers with up to 4 arms. This variant of the "coupling onto" method of star polymer synthesis was investigated for two different RAFT end groups (diethoxyphosphoryldithioformate and pyridin-2-yldithioformate) and coupling agents bearing 2, 3, or 4 diene functional groups. When a diethoxyphosphoryldithioformate terminated polymer was reacted with the 2-, 3-, and 4-fold functionalized coupling agents, the yields of 2-arm star, 3-arm star, and 4-arm star polymers were 81%, 77%, and 65%, respectively, and when a pyridin-2-yldithioformate terminated polymer was reacted with the same coupling agents, the yields of 2-arm star, 3-arm star and 4-arm star polymers were 91%, 86% and 82% respectively. The HDA coupling reaction was monitored via UV/vis spectroscopy from the perspective of the RAFT end group as well as by 1 H NMR spectroscopy from the perspective of the diene functionality. The results of these investigations indicated that the phosphoryldiethoxydithioformate terminated polymer achieves 92% conversion within a 24 h time frame and the pyridin-2-yldithioformate terminated polymer achieves 96% conversion in 10 h. The 4-arm star polymers were also subjected to high-temperature environments, and GPC measurements indicated that complete cleavage of all 4 arms from the core was achieved in 24 h at 160°C.

Blockcopolymere in Sekundenschnelle: Eine katalysatorfreie Klickkonjugation einzelner Polymerketten gelingt bei Raumtemperatur mithilfe neuer, durch ATRP hergestellter Polymere mit Cyclopentadienyl‐Endfunktionen. Dabei werden diese Polymere durch eine äußerst schnelle heterogene Diels‐Alder‐Cycloaddition mit durch RAFT hergestellten Makromolekülen umgesetzt, die elektronenarme Dithioester‐Endfunktionen aufweisen.

The establishment of advanced living/controlled polymerization protocols allows for engineering synthetic polymers in a precise fashion. Combining advanced living/controlled polymerization techniques with highly efficient coupling chemistries facilitates quantitative, modular, and orthogonal functionalization of synthetic polymer strands at their chain termini as well as side‐chain functionalization. The review highlights the current status of selected post‐functionalization techniques of polymers via orthogonal ligation chemistries, major characteristics of the specific transformation chemistry, as well as the characterization of the products.

The tendency of electron-deficient dithioesters to undergo hetero Diels-Alder cycloadditions is successfully used to generate polymer conjugates between a RAFT-polymerized poly(styrene) and a diene-terminated poly(epsilon-caprolactone).

The nitrile imine‐mediated tetrazole‐ene cycloaddition reaction (NITEC) is introduced as a powerful and versatile conjugation tool to covalently ligate macromolecules onto variable (bio)surfaces. The NITEC approach is initiated by UV irradiation and proceeds rapidly at ambient temperature yielding a highly fluorescent linkage. Initially, the formation of block copolymers by the NITEC methodology is studied to evidence its efficacy as a macromolecular conjugation tool. The grafting of polymers onto inorganic (silicon) and bioorganic (cellulose) surfaces is subsequently carried out employing the optimized reaction conditions obtained from the macromolecular ligation experiments and evidenced by surface characterization techniques, including X‐ray photoelectron spectroscopy and FT‐IR microscopy. In addition, the patterned immobilization of variable polymer chains onto profluorescent cellulose is achieved through a simple masking process during the irradiation.

A combination of reversible addition fragmentation chain transfer (RAFT) polymerization and hetero Diels‐Alder (HDA) chemistry has been utilized to successfully generate functional core‐shell microspheres. Initially, precipitation polymerization in conjunction with the RAFT technique has been employed to synthesize divinylbenzene (DVB) microspheres with surface expressed RAFT groups. Subsequently, HDA cycloaddition has been performed under mild reaction conditions (50 °C, 24 h) with a diene‐functionalized poly(ε‐caprolactone) (PCL). While the successful grafting is immediately evident by optical inspection of the microspheres (color change from purple to white), X‐ray photoelectron spectroscopy (XPS), and attenuated total reflectance spectroscopy (ATR) were additionally employed to characterize the chemical composition and surface functionalization of the microspheres. Further, confocal microscopy was used to confirm the presence of grafted PCL chains after labeling them with rhodamine B.magnified image

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