Exploring thiol‐yne based monomers as low cytotoxic building blocks for radical photopolymerization

The last decade has seen a remarkable interest in the development of biocompatible monomers for the realization of patient specific medical devices by means of UV‐based additive manufacturing technologies. This contribution deals with the synthesis and investigation of novel thiol‐yne based monomers with a focus on their biocompatibility and also the mechanical properties in their cured state. It could be successfully shown that propargyl and but‐1‐yne‐4‐yl ether derivatives have a significant lower cytotoxicity than the corresponding (meth)acrylates with similar backbones. Together with appropriate thiol monomers, these compounds show reactivities in the range of (meth)acrylates and almost quantitative triple bond conversions. A particular highlight is the investigation of the network properties of photo cured alkynyl ether/thiol resins by means of low field solid state nuclear magnetic resonance spectroscopy. Additionally, dynamic mechanical analysis of those polymers revealed that monomers containing rigid backbones lead to moduli and glass transition temperatures (T_g's), sufficiently high for the fabrication of medical devices by UV based additive manufacturing methods. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3484–3494     

A novel polymerization approach via thiol‐yne addition

The ability of thiyl radicals to add to terminal unsaturations in an efficient way made them considered being one of the click reactions. Recently, thiol‐yne addition reactions have been used extensively for the synthesis of crosslinked networks and dendrimers and postpolymerization functionalization protocols. Herein, we report a novel step‐growth type reaction for highly functional linear polymers using a monoalkyne and dithiol compound. First, we investigated the model reaction between 1‐octyne and 1‐octanethiol as well as 1,4‐butanedithiol compounds, which were initiated via self‐, thermal‐, and UV‐initiation; the UV‐initiation was found to be the most efficient method and completed within 2‐h reaction time. The same conditions were applied for the polymerization of four different functional alkynes bearing different functional groups with two dithiol compounds. All polymerizations resulted in highly functional linear polymers with number averaged molecular weights ranging from 5 to 30 kDa, except for propargylic acid and its methyl ester, where only oligomers formed. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Heterofunctional RAFT‐derived PNIPAM via cascade trithiocarbonate removal and thiol‐yne coupling click reaction

An efficient one‐pot process to functionalize the α‐ and ω‐positions of RAFT‐derived poly(N‐isopropylacrylamide) (PNIPAM) by two inherently different mechanistic pathways is reported. The method relies on the RAFT polymerization of NIPAM using a new alkyne‐based RAFT agent, namely 2‐cyano‐5‐oxo‐5‐(prop‐2‐yn‐1‐ylamino)pentan‐2‐yl dodecyltrithiocarbonate (COPYDC) and the combination of thiol‐yne click chemistry and thiocarbonylthio chain‐end removal reactions. COPYDC was prepared in good yield and used as an efficient chain transfer agent during the RAFT polymerization of NIPAM. Well‐defined polymers with controlled molar masses ( = 7500–14,700 g.mol^?1) and narrow dispersities (? = 1.18–1.26) are thus obtained. Cascade thiol‐yne click reaction at the alkyne α‐chain end and trithiocarbonate removal at the ω‐chain end are successfully achieved using benzyl mercaptan and excess AIBN. The reported method provides a facile and mild route to heterofunctional telechelic RAFT polymers with predictable molar masses and low dispersities. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 3597–3606     

A versatile approach to the synthesis of polyphosphazene derivatives via the thiol–ene reaction

The thiol–ene radical addition reaction has been successfully used to synthesize polyphosphazene derivatives. Poly[bis(allylamino)phosphazene] with pendant allyl groups was reacted with different thiol reagents under UV irradiation. These thiol reagents include 1‐pentanethiol, 3‐mercaptopropionic acid, 3‐mercapto‐1,2‐propane‐diol, and 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D ‐glucopyranose. ¹H NMR analyses confirm that the allyl polyphosphazene can be quantitatively modified by the mercaptans. In total, 100% conversion of the allyl groups was reached in <60 min toward the first three mercaptans, whereas about 80% conversion of the allyl groups was reached after 120‐min reaction toward the thioglucose. This method is a facile route for the synthesis of functional polyphosphazenes without the needs for protection/deprotection procedures. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Facile synthesis of dendrimers combining aza‐Michael addition with Thiol‐yne click chemistry

We report a highly efficient approach to prepare dendrimers by taking advantage of the orthogonal characteristic of aza‐Michael addition and thiol‐yne reactions. A fifth generation dendrimer was synthesized within five steps without protection/activation procedures. The reactions proceed under benign conditions without byproducts, and the target products can be easily purified via extraction or precipitation without chromatography. The structure of each generation dendrimer was characterized using NMR spectroscopy, size exclusion chromatography, and mass spectrometry. The obtained dendrimers can have peripheral amine or alkyne groups. We demonstrated that these groups can be used for selective and specific conjugation with various functional groups. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Lipidic polyols using thiol‐ene/yne strategy for crosslinked polyurethanes

Oleic acid and α,ω‐diacid were converted into propargylic esters followed by thiol‐ene/yne coupling (TEC/TYC) functionalization in presence of mercaptoethanol. The multiradical addition on fatty esters leads to the formation of lipidic polyols (OH1 and OH2), as judged by ¹H NMR and mass spectroscopies as well as by size exclusion chromatography. The crosslinking reaction between TEC/TYC‐based polyols and 4,4′‐methylene bis(phenylisocyanate) isocyanate reactant was monitored by FTIR experiment and reaction parameters were optimized. By differential scanning calorimetry, relatively high glass transitions are measured corresponding to structure with little or without dangling chain. Moreover, the thermal stability of the resulting plant oil‐based polyurethane materials (PU1 and PU2) were found to be fully consistent with that of other lipidic PUs respecting a three‐step process. Thanks to TYC methodology, fatty α,ω‐diacid produces lipidic polyol without dangling chain and lipidic thermoset PU with relatively high T_g. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1597–1606     

Versatile functionalization of aromatic polysulfones via thiol‐ene click chemistry

A facile, efficient approach for preparation of functionalized aromatic polysulfones by postpolymerization modification with thiol‐ene click chemistry is described. The key synthetic strategy is to incorporate a pendant vinyl ether group into polysulfones as a reactive precursor with controlled degrees of functionalization. Synthetic utility of the pendant alkenyl group is demonstrated by generating diverse polymer derivatives using thiol‐ene functionalization including glycosylated polysulfone. The highly reactive alkene platform in the polymer affords convenient, metal‐free, and azide‐free click transformations to create diverse ranges of new functionalized polysulfones that could be applied in various applications. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3237–3243     

Evaluation of thiol‐ene click chemistry in functionalized polysiloxanes

Polysiloxanes are commonly used in a myriad of applications, and the “click” nature of the thiol‐ene reaction is well suited for introducing alternative functionalities or for crosslinking these ubiquitous polymers. As such, understanding of the thiol‐ene reaction in the presence of silicones is valuable and would lead to enhanced methodologies for modification and crosslinking. Here, the thiol‐ene reaction kinetics were investigated in functionalized oligosiloxanes having varying degrees of thiol functionalization (SH), π–π interactions (from diphenyls, DP), and ene types (C?C). In the ene‐functionalized oligomers, π–π interactions were controlled through the use of dioctyl repeats (DO). The polymerization rate and rate‐limiting steps were determined for all systems containing an allyl‐functionalized oligomer, and rates ranging from 0.10 to 0.54 mol L^?1 min^?1 were seen. The rate‐limiting step varied with the oligomer composition; examples of rate‐limited propagation (5:3:2 C?C:DP:DO/1:1 SH:DP) or chain transfer (5:3:2 C?C:DP:DO/3:1 SH:DP) were found in addition to cases with similar reaction rate constants (5:2:3 C?C:DP:DO/1:1 SH:DP). None of the siloxanes were found to exhibit autoacceleration despite their relatively high viscosities. Instead, the allyl‐, vinyl‐, and acrylate‐functionalized siloxanes were all found to undergo unimolecular termination based on their high α scaling values (0.98, 0.95, and 0.82, respectively) in the relation R_p ∝ R_i^α. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Synthesis of main chain polymeric benzophenone photoinitiator via thiol‐ene click chemistry and Its use in free radical polymerization

Main chain polymeric benzophenone photoinitiator (PBP) was synthesized by using “Thiol‐ene Click Chemistry” and characterized with ¹H NMR, FTIR, UV, and phosphorescence spectroscopies. PBP as a polymeric photoinitiator presented excellent absorption properties (ε₂₉₄ = 28,300 mol^?1L^?1cm^?1) compared to the molecular initiator BP (ε₂₅₂ = 16,600 mol^?1L^?1cm^?1). The triplet energy of PBP was obtained from the phosphorescence measurement in 2‐methyl tetrahydrofurane at 77 K as 298.3 kJ/mol and according to phosphorescence lifetime, the lowest triplet state of PBP has an n‐π* nature. Triplet–triplet absorption spectrum of PBP at 550 nm following laser excitation (355 nm) were recorded and triplet lifetime of PBP was found as 250 ns. The photoinitiation efficiency of PBP was determined for the polymerization of Hexanedioldiacrylate (HDDA) with PBP and BP in the presence of a coinitiator namely, N‐methyldiethanolamine (MDEA) by Photo‐DSC. The initiation efficiency of PBP for polymerization of HDDA is much higher than for the formulation consisting of BP. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Sequential thiol‐ene/thiol‐ene and thiol‐ene/thiol‐yne reactions as a route to well‐defined mono and bis end‐functionalized poly(N‐isopropylacrylamide)

Sequential thiol‐ene/thiol‐ene and thiol‐ene/thiol‐yne reactions have been used as a facile and quantitative method for modifying end‐groups on an N‐isopropylacrylamide (NIPAm) homopolymer. A well‐defined precursor of polyNIPAm (PNIPAm) was prepared via reversible addition‐fragmentation chain transfer (RAFT) polymerization in DMF at 70 °C using the 1‐cyano‐1‐methylethyl dithiobenzoate/2,2′‐azobis(2‐methylpropionitrile) chain transfer agent/initiator combination yielding a homopolymer with an absolute molecular weight of 5880 and polydispersity index of 1.18. The dithiobenzoate end‐groups were modified in a one‐pot process via primary amine cleavage followed by phosphine‐mediated nucleophilic thiol‐ene click reactions with either allyl methacrylate or propargyl acrylate yielding ene and yne terminal PNIPAm homopolymers quantitatively. The ene and yne groups were then modified, quantitatively as determined by ¹H NMR spectroscopy, via radical thiol‐ene and radical thiol‐yne reactions with three representative commercially available thiols yielding the mono and bis end functional NIPAm homopolymers. This is the first time such sequential thiol‐ene/thiol‐ene and thiol‐ene/thiol‐yne reactions have been used in polymer synthesis/end‐group modification. The lower critical solution temperatures (LCST) were then determined for all PNIPAm homopolymers using a combination of optical measurements and dynamic light scattering. It is shown that the LCST varies depending on the chemical nature of the end‐groups with measured values lying in the range 26–35 °C. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3544–3557, 2009     

Photocaged pendent thiol polymer brush surfaces for postpolymerization modifications via thiol‐click chemistry

In this work, a postpolymerization surface modification approach is reported that provides pendent thiol functionality along the polymer brush backbone using the photolabile protection chemistry of both o‐nitrobenzyl and p‐methoxyphenacyl thioethers. Poly(2‐hydroxyethyl methacrylate) (pHEMA) brushes were synthesized via surface‐initiated atom transfer radical polymerization, after which the pHEMA hydroxyl groups were esterified with 3‐(2‐nitrobenzylthio)propanoic acid or 3‐(2‐(4‐methoxyphenyl)‐2‐oxoethylthio)propanoic acid to provide the photolabile protected pendent thiols. Addressing the protecting groups with light not only affords spatial control of reactive thiol functionality but enables a plethora of thiol‐mediated transformations with isocyanates and maleimides providing a modular route to create functional polymer surfaces. This concept was extended to block copolymer brush architectures enabling the modification of the chemical functionality of both the inner and outer blocks of the block copolymer surface. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

In situ photopolymerization of biomaterials by thiol-yne click chemistry

The thiol-yne click chemistry reaction has been used for the in situ photocrosslinking of an aliphatic hyperbranched polyester. The biocompatibility of the resulting networks has been studied and marked cytotoxicity was not found for HeLa (human cervical carcinoma) tumoral cells and COS7 fibroblasts. The photoinduced thiol-yne process allows the generation of patterned structures with different geometries in films by DLW and these materials can be used as substrates for cell adhesion. The influence of the substrate geometry on cell adhesion has been studied by culturing cells onto these substrates and a preference for the photopatterned polymeric material can be seen in some of the structures by contrast phase microscopy. Actin and vinculin fluorescent staining revealed different adhesion behavior for HeLa cells and COS7 fibroblasts and this could be assigned to the different motility of cells. The thiol-yne photoreaction has proven to be an attractive approach for the preparation of micropatterned biomaterials.     

Synthesis of a stationary phase based on silica modified with branched octadecyl groups by Michael addition and photoinduced thiol–yne click chemistry for the separation of basic compounds

A novel silica‐based stationary phase with branched octadecyl groups was prepared by the sequential employment of the Michael addition reaction and photoinduced thiol–yne click chemistry with 3‐aminopropyl‐functionalized silica microspheres as the initial material. The resulting stationary phase denoted as SiO₂‐N(C18)₄ was characterized by elemental analysis, FTIR spectroscopy and Raman spectroscopy, demonstrating the existence of branched octadecyl groups in silica microspheres. The separations of benzene homologous compounds, acid compounds and amine analogues were conducted, demonstrating mixed‐mode separation mechanism on SiO₂‐N(C18)₄. Baseline separation of basic drugs mixture was acquired with the mobile phase of acetonitrile/H₂O (5%, v/v). SiO₂‐N(C18)₄ was further applied to separate Corydalis yanhusuo Wang water extracts, and more baseline separation peaks were obtained for SiO₂‐N(C18)₄ than those on Atlantis dC18 column. It can be expected that this new silica‐based stationary phase will exhibit great potential in the analysis of basic compounds.     

Postfunctionalization of polyoxanorbornene via sequential Michael addition and radical thiol‐ene click reactions

We demonstrated the successful postfunctionalization of poly(oxanorbornene imide) (PONB) with two types of double bonds using sequential orthogonal reactions, nucleophilic thiol‐ene coupling via Michael addition and radical thiol‐ene click reactions. First, the synthesis of PONB with side chain acrylate groups is carried out via ring‐opening metathesis polymerization and nitroxide radical coupling reaction, respectively. Subsequently, the resulting polymer having two different orthogonal functionalities, main chain vinyl and side chain acrylate, is selectively modified via two sequential thiol‐ene click reactions, nucleophilic thiol‐ene coupling via Michael addition and photoinduced radical thiol‐ene. The orthogonal reactivity of two diverse double bonds, vinyl and acrylate functionalities, for the abovementioned consecutive thiol‐ene click reactions was first demonstrated on the model compound. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Exploring Network Formation of Tough and Biocompatible Thiol‐yne Based Photopolymers

This work deals with the in‐depth investigation of thiol‐yne based network formation and its effect on thermomechanical properties and impact strength. The results show that the bifunctional alkyne monomer di(but‐1‐yne‐4‐yl)carbonate ( DBC ) provides significantly lower cytotoxicity than the comparable acrylate, 1,4‐butanediol diacrylate ( BDA ). Real‐time near infrared photorheology measurements reveal that gel formation is shifted to higher conversions for DBC /thiol resins leading to lower shrinkage stress and higher overall monomer conversion than BDA . Glass transition temperature (T_g), shrinkage stress, as well as network density determined by double quantum solid state NMR, increase proportionally with the thiol functionality. Most importantly, highly cross‐linked DBC /dipentaerythritol hexa(3‐mercaptopropionate) networks (T_g ≈ 61 °C) provide a 5.3 times higher impact strength than BDA , which is explained by the unique network homogeneity of thiol‐yne photopolymers.

     

Thiol‐yne Click Adamantane Monolithic Stationary Phase for Capillary Electrochromatography

A porous crosslinked organic polymer based on N‐acryloxysuccinimide (NAS) and ethylene dimethacrylate (EDMA) was prepared inside 75 µm i.d. fused silica capillary as functionalizable monolithic stationary phase for electrochromatographic applications. Succinimide groups on the monolith surface provide reactive sites able to react readily through standard electrophile‐nucleophile chemistry. Propargylamine was used to prepare alkyne functionalized poly(NAS‐co‐EDMA). Onto this thiol‐reactive polymer surface was grafted adamantane units via a photochemically‐driven addition reaction. Chemical characterization was performed in situ after each synthetic step by means of Raman spectroscopy and grafting kinetics was investigated to ensure quantitative grafting of 1‐adamantanethiol. The as‐designed monolithic stationary phase exhibited typical reversed‐phase separation mechanism as evidenced by the linear increase of the logarithm of retention factor of neutral aromatic solutes with the increase of the aqueous buffer content in the mobile phase.     

Silica/poly (N‐vinylimidazolium) nanospheres by combined RAFT polymerization and thiol‐ene click chemistry

We report a facile method that combined sol–gel reaction, reversible addition–fragmentation chain transfer (RAFT)/macromolecular design via interchange of the xanthates process and thiol‐ene click reaction to prepare monodisperse silica core‐poly(N‐vinylimidazole) (PVim) shell microspheres of 200 nm in average diameters. First, silica with C = C double bonds was prepared by the sol–gel reaction of 3‐(trimethoxysilyl)propyl methacrylates (MPS) with tetraethoxysilane in ethanol; SiO₂@PVim were subsequently prepared by grafting PVim chain (Mn = 9800 g/mol, polydispersity index = 1.22) to MPS‐SiO₂ via the thiol‐ene click chemisty. The obtained SiO₂@PVim microspheres show higher catalytic activity toward the hydrolysis of p‐nitrophenyl acetate compared with the PVim homopolymers. The as‐prepared composites have been characterized by scanning electron microscopy, transmission electron microscopy, thermal gravimetric analysis and Fourier transform infrared spectrometry analysis. Copyright © 2014 John Wiley & Sons, Ltd.     

Convenient Synthesis of Functionalized Bis‐ureidopyrimidinones Based on Thiol‐yne Reaction

The preparation of functionalized bis‐ureidopyrimidinones ( Bis‐UPy ) through the thiol‐yne reaction is described. Various Bis‐UPys with different functional groups were synthesized by using the readily available functionalized alkynes and UPy‐thiol to affirm the simplicity and versatility of the methodology.