Pieter Espeel

Additive-Free Clicking for Polymer Functionalization and Coupling by Tetrazine–Norbornene Chemistry

Herein we report the use of a tetrazine-norbornene inverse electron demand Diels-Alder conjugation applied to polymer end-functionalization and polymer-polymer coupling. The reaction was found to be applicable to polymer-polymer coupling, as judged by SEC, DOSY NMR, and LCxSEC analyses, giving diblock copolymers by merely mixing the constituent homopolymers together under ambient conditions, using no catalyst, additive, or external stimulus.

One-pot multistep reactions based on thiolactones: extending the realm of thiol-ene chemistry in polymer synthesis.

The in situ generation of thiols by nucleophilic ring-opening of a thiolactone with amines, followed by a UV-initiated radical thiol-ene reaction in a one-pot fashion, has been evaluated as an accelerated and versatile protocol for the synthesis of several types of polymeric architectures. After elaboration of a model amine-thiol-ene conjugation reaction, a number of routes based on readily available thiolactone-containing structures have been developed to successfully assemble functional, linear polymers and networks via a mild and facile radical photopolymerization process.

Multifunctionalized Sequence‐Defined Oligomers from a Single Building Block

Two decades of progress in the field of living and controlled polymerizations, combined with the elaboration of efficient conjugation reactions, greatly contributed to the elegant preparation of functionalized macromolecular architectures. However, these state-of-the-art methodologies, while providing a high degree of structural and topological control, are inadequate tools for controlling the polymer microstructure. Crucial parameters like primary structure (i.e. monomer sequence) and tacticity largely remain unmastered by current man-made approaches. Expectations for the next generation synthetic polymers include their performance as single chains, ability to fold and self-regulate, and to sense specific molecules and/or catalyze reactions. These precisely functionalized linear polymers should exhibit sharply defined and tailored structure-activity relationships, analogous to Nature’s delicately engineered macromolecules. Therefore, progress towards reliable sequence-controlled polymerization, enabling preprogrammed distribution of multiple functional groups along the backbone, is drawing attention in a growing number of research groups worldwide. Pioneering efforts to control the primary structure of functionalized polymers have been based on several approaches, such as different reactivity ratios of vinyl monomers, spatial prearrangement of monomers on a (macromolecular) template or, as recently demonstrated, the action of a small-molecule machine. Other attempts use (automated) sequential addition of building blocks on a solid or liquid support, leading to sequence control as a result of iterative coupling steps, thereby omitting the need for pre-organization. These protocols, established for peptide and oligonucleotide synthesis, present considerable drawbacks for sequence-controlled polymerization: they generally require the use of protecting groups and the restricted number of readily available building blocks (‘monomer alphabet’) equipped with the appropriate functional handle can further hamper the preparation of tailor-made functionalized sequences. The development of new chemical protocols for chain elongation, often on a solid support, resulting in sequence-defined (macro)molecular structures with unique backbones and side chain functionalities, or fragments thereof that could be combined to obtain sequence controlled polymers, is therefore highly desirable. We here report on a new coupling strategy for the controlled generation of sequence-defined multi-functionalized oligomers on solid support in a protecting group-free approach, inspired by the ‘submonomer’ synthetic protocol for the preparation of functionalized peptoids, via thiolactone-based chemistry. While the generated oligomers are small in size, reconstitution approaches could further allow the synthesis of larger chains, featuring designed and repetitive display of carefully selected and well-positioned functional entities.

Thiol-ene and thiol-yne chemistry in microfluidics: a straightforward method towards macroporous and nonporous functional polymer beads

Thiol-ene and thiol-yne reactions are explored as efficient pathways towards rapid production of diverse monodisperse macroporous and nonporous functional beads. In a straightforward method, polymer beads containing amine, hydroxyl and carboxyl groups have been prepared by reacting a tetrafunctional thiol with a range of mono and/or multifunctional -enes/-ynes containing the desired functional groups. The thiol-ene and thiol-yne reactions have been performed in a simple home-made microfluidic device utilizing thiol and ene/yne monomers at a 1 : 1 ratio of thiol to π-bond. The porous functional beads were prepared making use of a porogen in combination with a photoinitiator. The optical and scanning electron microscopy images demonstrated monodispersity of the beads with a spherical shape ranging in size from 210 to 600 μm. The beads were characterized in terms of glass transition temperature, surface area measurement and composition. The accessible amine and hydroxyl loading in the beads ranges from 0.23 to 0.69 mmol g−1 and 0.24 to 0.64 mmol g−1 respectively, as determined by the Fmoc method. This work demonstrates the applicability of thiol-ene and thiol-yne reactions in microfluidics as a powerful tool for the rapid design of functional beads for diverse applications.

Straightforward synthesis of functionalized cyclic polymers in high yield via RAFT and thiolactone–disulfide chemistry

An efficient synthetic pathway toward cyclic polymers based on the combination of thiolactone and disulfide chemistry has been developed. First, heterotelechelic linear polystyrene (PS) containing an α-thiolactone (TLa) and an ω-dithiobenzoate group was synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization, employing a newly designed TLa-bearing chain transfer agent (CTA). The subsequent reaction of this heterotelechelic polymer with an amine, which acts as a nucleophile for both the TLa and dithiobenzoate units, generated the α,ω-thiol-telechelic PS under ambient conditions without the need for any catalyst or other additives. The arrangement of thiols under a high dilution afforded single cyclic PS (c-PS) through an oxidative disulfide linkage. The cyclic PS (c-PS) disulfide ring formation was evidenced by SEC, MALDI-TOF MS and 1H-NMR characterization. Moreover, we demonstrated a controlled ring opening via either disulfide reduction or thiol–disulfide exchange to enable easy and clean topology transformation. Furthermore, to illustrate the broad utility of this synthetic methodology, different amines including functional ones were employed, allowing for the one-step preparation of functionalized cyclic polymers with high yields.

Double modular modification of thiolactone-containing polymers: towards polythiols and derived structures

A conceptual proof for the double modification (aminolysis and subsequent thiol-click modification) of thiolactone units, incorporated in linear polymer scaffolds, was elaborated. These polymers were prepared by either reversible addition–fragmentation chain transfer (RAFT) or nitroxide mediated radical polymerization (NMP) starting from a stable, readily available styrenic thiolactone monomer (St-TLa). Successful copolymerization of the latter with styrene (St) or methyl methacrylate (MMA) yielded linear polymers with varying thiolactone content (4–25%). Upon amine treatment, the ring-opening of the pendent thiolactones resulted in the formation of linear polythiols. Reaction conditions were optimized to avoid cross-linking via disulfide formation, thus preserving the linear nature of the polymer. Different primary amines (propylamine, benzylamine, ethanolamine and Jeffamine M-1000) were attached to the polymer backbone, while the PDIs remained low. The resulting polythiols are versatile scaffolds for further modification by various thiol-click reactions. In this respect, thiol–maleimide conjugation was used as a model reaction. NMR- and SEC-analyses revealed a near-quantitative double modification of thiolactone containing polystyrene (PS) and poly(methylmethacrylate) (PMMA) by subsequent treatment with propylamine and N-benzylmaleimide.

Synthesis of multi-functionalized hydrogels by a thiolactone-based synthetic protocol

We established a simplified synthetic protocol for the preparation of multiple functionalized hydrogels, which is potentially employable for the fabrication of adaptable sensors, using the recently introduced thiolactone chemistry. Thiolactone groups can be opened with a primary amine, through which a functional group is introduced, while at the same time a thiol is released, which is available for crosslinking or further functionalization. In this respect, a thiolactone functionalized poly(N-isopropylacryl amide) (p(NIPAAm-co-TlaAm)) precursor, obtained via RAFT, and 3-morpholinopropylamine or histamine as the ring opening amines are used to synthesize gels responding to CO2. The synthetic protocol relies on a newly discovered crosslinking mechanism involving the solvent dichloromethane as the crosslinking agent. We discuss the gel formation protocol in detail, including the crosslinking mechanism, and additionally demonstrate the response of the synthesized gels towards CO2. Finally, we show how the applied synthetic protocol can be used for the preparation of multiple functionalized gels, extending the concept to optical response type gels.

Poly(thiolactone) homo- and copolymers from maleimide thiolactone: synthesis and functionalization

We describe the synthesis of a thiolactone-functionalized maleimide (MITla), and its (co)polymerization into poly(thiolactone) homo- and copolymers via controlled or free radical polymerization (CRP or FRP) techniques. Homopolymers were synthesized using FRP whereas MITla was copolymerized with styrene and N-iso-propylacrylamide (NIPAAm) via RAFT. In that way, we were able to combine the properties of a maleimide with the possibility to use the thiolactone side chain functionality in subsequent double modification reactions. Thiolactones are susceptible to nucleophilic ring-opening in the presence of primary amines, releasing a thiol moiety that can be used for conjugate addition (nucleophilic thiol–ene) reactions afterwards. We synthesized and characterized copolymers of different compositions, followed by site-specific double modification reactions with a combination of n-butylamine and methyl acrylate.

From NMP to RAFT and Thiol-Ene Chemistry by In Situ Functionalization of Nitroxide Chain Ends

A straightforward, novel strategy based on the in situ functionalization of polymers prepared by nitroxide-mediated polymerization (NMP), for the use as an extension toward block copolymers and post-polymerization modifications, has been investigated. The nitroxide end group is exchanged for a thiocarbonylthio end group by a rapid transfer reaction with bis(thiobenzoyl) disulfide to generate in situ reversible addition-fragmentation chain transfer (RAFT) macroinitiators. Moreover, not only have these macroinitiators been used in chain extension and block copolymerization experiments by the RAFT process but also a thiol-terminated polymer is synthesized by aminolysis of the RAFT end group and subsequently reacted with dodecyl vinyl ether by thiol-ene chemistry.

Thiolactone chemistry and copper-mediated CRP for the development of well-defined amphiphilic dispersing agents

A straightforward synthetic pathway was developed for the synthesis of amphiphilic graft and toothbrush copolymers by combining copper-mediated controlled radical polymerization with the thiolactone-based amine–thiol–ene conjugation in a “grafting-onto approach”. First, a series of well-defined, thiolactone containing macromolecular backbones were synthesized via copolymerization with a thiolactone-containing monomer. Next, acrylate end-functionalized polymers were obtained in a post-polymerization modification procedure and coupled to the backbones. Furthermore, in-depth characterization of the different structures was performed by the use of SEC, NMR, MALDI-TOF and LCxSEC analysis. In order to demonstrate the amphiphilic behaviour of these graft and toothbrush copolymers, micelle formation tests were carried out and measured with DLS and TEM, while the dispersing features of these comb-like copolymers were evaluated by pigment stabilization tests.