Peter J. Roth

RAFT polymerization and thiol chemistry: a complementary pairing for implementing modern macromolecular design.

Reversible addition fragmentation chain transfer (RAFT) polymerization is one of the most extensively studied reversible deactivation radical polymerization methods for the production of well-defined polymers. After polymerization, the RAFT agent end-group can easily be converted into a thiol, opening manifold opportunities for thiol modification reactions. This review is focused both on the introduction of functional end-groups using well-established methods, such as thiol-ene chemistry, as well as on creating bio-cleavable disulfide linkages via disulfide exchange reactions. We demonstrate that thiol modification is a highly attractive and efficient chemistry for modifying RAFT polymers.

Synthesis of Hetero-Telechelic α,ω Bio-Functionalized Polymers

Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize poly[diethylene glycol monomethylether methacrylate] (PDEGMA) (M(n) = 6250 g/mol, PDI = 1.14) with a pentafluorophenyl (PFP) activated ester and a dithioester end group. The hormone thyroxin (T4) was quantitatively attached to the PFP activated ester alpha end group via its amino group. The omega-terminal dithioester was not harmed by this reaction and was subsequently aminolyzed in the presence of N-biotinylaminoethyl methanethiosulfonate, yielding a polymer with a thyroxin and a biotin end group with very high heterotelechelic functionality. The polymer was characterized by (1)H, (13)C, and (19)F NMR, UV-vis, and IR spectroscopy and gel permeation chromatography. The thyroxin transport protein prealbumin with two thyroxin binding sites and streptavidin, which has four biotin binding sites, was conjugated using the biotarget labeled polymer, resulting in the formation of a protein-polymer network, confirming the heterotelechelic nature of the polymer. Polymer-protein microgel formation was observed with dynamic light scattering. To realize a directed protein assembly, prealbumin was immobilized onto a surface, exposing one of its two thyroxin binding groups and thus allowing the conjugation with the thyroxin alpha end group of the heterotelechelic polymer. The biotin omega end group of the attached polymer layer enabled the subsequent immobilization of streptavidin, yielding a defined multilayer system of two proteins connected with the synthetic polymer (efficiency of streptavidin immobilization 81% based on prealbumin). Without the polymer, no streptavidin immobilization occurred. The layer depositions were monitored by surface plasmon resonance. The synthetic approach of combining PFP activated esters with functional MTS reagents presents a powerful method for obtaining well-defined heterotelechelic (bio-) functionalized polymers.

UCST-type behavior of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) in aliphatic alcohols: solvent, co-solvent, molecular weight, and end group dependences

Poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) is shown to possess insoluble–soluble transitions (UCST-type phase behavior) in a large variety of aliphatic alcohols. Samples of different molecular weights ranging from 5 kg mol−1 to 23 kg mol−1 prepared by the RAFT process and featuring different end groups at each end were analyzed by cloud point measurements. Transitions occurred sharply and were fully reversible. The UCST was found to increase with an increasing molecular weight. Hydrophobic (alkyl chain) end groups were found to lower the critical temperature in isopropanol, while rigid aromatic end groups raised the transition temperature. In ternary mixtures of isopropanol/chloroform/POEGMA, the UCST decreased with an increasing chloroform concentration, with 10 vol% of chloroform accounting for a 30 °C drop. In mixtures of isopropanol/hexane/POEGMA, the cloud point increased significantly only with hexane concentrations above 30 vol%, at which level a 2 °C transition temperature increase was found. Addition of water to isopropanol solutions had a strong effect, with 1 vol% of water causing a decrease of the transition temperature of 12.5 °C. With an increasing chain length of the solvent, the cloud point increased, while a branching of the hydrocarbon chains lowered the cloud point. Samples of 23 kg mol−1POEGMA were for instance found to have cloud points of 22.0 °C in ethanol, 35.7 °C in isopentanol, and 75.4 °C in dodecanol.

Double Thermoresponsive Block Copolymers Featuring a Biotin End Group

A poly(oligo(ethylene glycol) monomethyl ether methacrylate)-block-poly(N-isopropyl methacrylamide) (POEGMA-b-PNIPMAM) block copolymer with a biotin end group on the PNIPMAM block as a biotarget was synthesized as a model system for temperature-controlled polymer immobilization. The synthesis was based on RAFT polymerization followed by postpolymerization modification of an activated ester precursor block and an exchange of the dithioester end group within one step. NMR, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and turbidimetry measurements were performed to investigate the stimulus-responsive properties. The double thermoresponsive POEGMA-b-PNIPMAM with biotin end group showed a temperature-dependent multistage assembly behavior as it was completely soluble in water at temperatures below the LCST of both blocks, formed micellar structures above the LCST of PNIPMAM but below the LCST of POEGMA, or precipitated from solution above the LCST of both blocks. At room temperature, the polymer could be immobilized onto a streptavidin surface via its biotin end group, as shown in surface plasmon resonance (SPR) experiments. At 50 °C, at which the block copolymer formed micelles trapping the biotin target within the PNIPMAM core, no immobilization was observed, showing that the biological binding ability of the model could be controlled via external stimuli.

End Group Reactions of RAFT-Prepared (Co)Polymers

This review highlights the chemistry of thiocarbonylthio groups with an emphasis on chemistry conducted at ω or α and ω chain-ends in copolymers prepared by reversible addition–fragmentation chain-transfer (RAFT) radical polymerization. We begin by giving a general overview of reactions associated with the thiocarbonylthio groups, followed by examples associated with macromolecular thiols.

Reactive surface coatings based on polysilsesquioxanes: controlled functionalization for specific protein immobilization.

The key designing in reliable biosensors is the preparation of thin films in which biomolecular functions may be immobilized and addressed in a controlled and reproducible manner. This requires the controlled preparation of specific binding sites on planar surfaces. Poly(methylsilsesquioxane)-poly(pentafluorophenyl acrylates) (PMSSQ-PFPA) are promising materials to produce stable and adherent thin reactive coatings on various substrates. Those reactive surface coatings could be applied onto various materials, for example, gold, polycarbonate (PC), poly(tetrafluoroethylene) (PTFE), and glass. By dipping those substrates in a solution of a desired amine, specific binding sites for protein adsorption could be immobilized on the surface. The versatile strategy allowed the attachment of various linkers, for example, biotin, l-thyroxine, and folic acid. The adsorption processes of streptavidin, pre-albumin, and folate-binding protein were monitored using surface plasmon resonance (SPR), Fourier transform infrared (FTIR) spectroscopy, fluorescence spectroscopy, and atomic force microscopy (AFM). The presented protein immobilization strategy, consisting of four steps (a) spin-coating of PMSSQ-PFPA hybrid polymer from tetrahydrofuran (THF) solution, (b) annealing at 130 degrees C for 2 h to induce thermal cross-linking of the PMSSQ part, (c) surface analogues reaction with different amino-functionalized specific binding sites for proteins, and (d) controlled assembly of proteins on the surface, may find various applications in future biosensor design.

Thiol-reactive Passerini-methacrylates and polymorphic surface functional soft matter nanoparticles via ethanolic RAFT dispersion polymerization and post-synthesis modification

RAFT dispersion polymerization (RAFTDP) is used to prepare reactive nanoparticles via the incorporation of Passerini-derived methacrylic comonomers containing pentafluorophenyl (PFP) groups. Copolymerization of 2-(dimethylamino)ethyl methacrylate with a Passerini comonomer gives copolymers suitable as macro-CTAs for ethanolic RAFTDP of 3-phenylpropyl methacrylate. Reaction of the PFP residues with functional thiols offers an approach for preparing surface modified nanoparticles.

The synthesis and aqueous solution properties of sulfobutylbetaine (co)polymers: comparison of synthetic routes and tuneable upper critical solution temperatures

Polysulfobutylbetaine (SBB) (co)polymers, zwitterionic species bearing ammonium and sulfonate groups separated by a butyl spacer in every repeat unit, were prepared through three different synthetic routes and their aqueous solution behaviour was studied. Postpolymerization quaternization of poly[2-(dimethylamino)ethyl methacrylate] with 1,4-butanesultone resulted in incomplete modification due to the low reactivity of this alkylating agent. RAFT radical polymerization of SBB-functional (meth)acrylate monomers and their copolymerization with a sulfopropylbetaine (SPB) methacrylate yielded well-defined (co)polymers with low dispersities 1.13 ≤ ĐM ≤ 1.23 at monomer conversions of 75–92%. For a series of SBB methacrylate homopolymers with increasing degrees of polymerization from 66–186 measured upper critical solution temperature (UCST) cloud points increased from 27–77 °C. Cloud points of statistical SPB-SBB copolymers with similar degrees of polymerization, but varying molar compositions, increased linearly with SBB content offering a simple means of UCST tuning. Additionally, novel SBB acrylamide homo- and copolymers were prepared by postpolymerization modification of poly(pentafluorophenyl acrylate) with an SBB-functional amine and in mixtures with benzylamine as a hydrophobic modifier. In all cases, the SBB (co)polymers had significantly higher UCSTs than their more common SPB counterparts, greatly extending the temperature range of tuneable UCST transitions and making the investigated SBB (co)polymers advantageous for exploiting their ‘smart’ behaviour. In this respect, combining SBB functionality with hydrophobic benzylacrylamide comonomers is presented as a simple means of increasing the maximum salt concentration at which UCST behaviour (which shows an antipolyelectrolyte effect) can be observed, enabling UCST transitions in aqueous solutions containing a physiological concentration (9 g L−1) of NaCl.

Synthesis and evaluation of N,S-compounds as chiral ligands for transfer hydrogenation of acetophenoneElectronic supplementary information (ESI) available: NMR spectra. See http://www.rsc.org/suppdata/ob/b2/b208907f/

New nitrogen- and sulfur-containing compounds, bicyclic and monocyclic, were prepared and evaluated as ligands in the transfer hydrogenation of acetophenone. Utilising [Ir(COD)Cl]2 as metal precursor the best result, 80% ee, was obtained using a bicyclic sulfoxide ligand.

Thiol-reactive functional poly(meth)acrylates: multicomponent monomer synthesis, RAFT (co)polymerization and highly efficient thiol–para-fluoro postpolymerization modification

A novel class of thiol-reactive (meth)acrylate monomers and the quantitative postpolymerization modification of their RAFT-made (co)polymers with aromatic, glycosidic, and aliphatic thiols are presented. A set of 6 different N-functional 2-(meth)acryloyloxy-2-(pentafluorophenyl)acetamide monomers bearing pentafluorophenyl groups was prepared by a Passerini three-component reaction of (meth)acrylic acid, 2,3,4,5,6-pentafluorobenzaldehyde, and various isocyanides in water in up to near-quantitative isolated yields. RAFT polymerization was used to produce well-defined homopolymers and copolymers with methyl methacrylate, tert-butyl methacrylate, poly(ethylene glycol) methyl ether (meth)acrylate, and pentafluorophenyl acrylate, with low polydispersity indices of generally ĐM ≤ 1.23. In the presence of base, (co)polymers underwent selective para-fluoro substitution reactions with thiols in the absence of any side reactions observable by 1H and 19F NMR spectroscopy and size exclusion chromatography. The selection of employed thiols included various alkanethiols, a thiolated glucose derivative, mercaptopropionic acid, L-cysteine and the drug captopril. 19F NMR kinetic measurements indicated quantitative thiol–para-fluoro substitutions after primary aliphatic > secondary aliphatic > tertiary aliphatic) and the choice of a suitable base (triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)). The versatility of thiol-reactive (meth)acrylate species is demonstrated by the examples of a thermoresponsive copolymer showing a thiol-sensitive lower critical solution temperature (LCST) and the selective sequential modification with thiols and amines of a doubly reactive copolymer containing activated pentafluorophenyl esters.