Andrea V. Bordoni
,
M. Verónica Lombardo and
Alejandro Wolosiuk*
Gerencia Química – Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, CONICET, Av. Gral. Paz 1499, B1650KNA San Martín, Buenos Aires, Argentina. E-mail: wolosiuk@cnea.gov.ar
First published on 3rd August 2016
Although known for more than 40 years in the polymer chemistry field, the photochemical radical thiol–ene addition (PRTEA) has been recently recognized as a chemical reaction with click characteristics. Photoinitiation enables spatial and temporal control of this highly efficient reaction, bridging simple organic chemistry with high-end materials synthesis and surfaces functionalization. In this minireview, we focus on the latest contributions based on the PRTEA for the synthesis of chemical precursors for silica and transition metal oxides (TMO) based materials. We summarize the mechanism of the PRTEA, the development of new families of photoinitiators and how this extremely simple approach has spilled over into the materials science arena with clear success. In particular, PRTEA adds to the collective efforts for building a reliable and straightforward chemical toolbox for surface modification and the production of sol–gel precursors, nanoparticles and thin films. The excellent perspectives for simple molecular and supramolecular building block synthesis opens up a rational synthetic route for the design and integration of these components in multipurpose platforms.
Organoalkoxysilanes are molecules with the general formula R′nSi(OR)4−n that have revolutionized the manufacture of everyday materials and are key intermediates in sol–gel processing, as molecular precursors for building blocks or for the chemical functionalization of oxide materials.11,12 The hydrolysis of the R group (i.e. methoxy, ethoxy) leads to a Si–O–Si polycondensed network that can form strong covalent bonds to hydroxylated surfaces, such as SiO2 and transition metal oxides (TMO), making them particularly useful for connecting and bridging inorganic and organic components. The non-hydrolyzable organofunctional group R′ (i.e. amino, cyano, methyl or vinyl groups) integrates to the Si–O–Si framework, either on its surface or within the SiO2 or TMO based structure. In the case of surface functionalization, this advantageous characteristic allows keeping the texture of the supporting material (particles, powders, plain surfaces) while their bulk properties (density, refractive index, magnetism) remain intact. Alternatively, these chemical moieties can blend on the molecular scale, resulting in hybrid materials and nanocomposites with tailored properties and applications. In fact, SiO2 based materials hold interesting promise for smart coatings, encapsulation, biomedical applications, photonics and as platforms for the synthesis of fine chemicals. In order to satisfy these requirements, the production of a versatile organo-alkoxysilanes library of chemical precursors needs a simple and effective coupling chemistry.13–18
Among the “click-toolbox”, the photochemical radical thiol–ene addition (PRTEA) has attracted much interest, as it is easy to perform, is versatile in the availability of reactants and the mild reaction conditions required make it compatible with most functional groups.23 This reaction, known from the late 70s, has the following characteristics: (a) is orthogonal to most organic functional groups (–COOH, –NH2, –CH2OH), (b) does not require O2 free or anhydrous conditions, (c) benefits from the vast commercial availability of both thiol compounds, aimed at Au surfaces functionalization, and –ene based molecules, for olefin polymer synthesis, (d) the photochemical initiation of the reaction is highly attractive for tailored patterned surface modification and (e) solvents can be minimized, where reactions are carried under neat conditions.24,25
In this context, we will address click-derived approaches, based on the PRTEA reaction, for the simple chemical modification of a variety of inorganic oxide materials (i.e. SiO2 and Fe3O4) and surfaces, that may not satisfy all click requirements, but, open a new venue for tailoring surfaces and materials in a direct and simple manner.
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A more detailed mechanistic analysis is depicted in Scheme 1: (i) the reaction is initiated thermally or photochemically after H abstraction from a thiol molecule using a radical initiator; this generates a highly reactive thiyl radical (R1S˙) that efficiently attacks alkene molecules (R2CH2CH); (ii) the generated carbon-centered radical (R1SCH2C˙HR2) is also able to abstract a H from a R1SH molecule. This last step can be considered as an amplification stage, where a single thiyl radical causes a cascade of chemical attacks, similar to chain-growth free radical polymerizations. From a historical perspective, this characteristic, in addition to a fast kinetic reaction, has been fuelling the research on thiol–ene polymerizations for more than 70 years.26
The rate of the radical thiol–ene addition is highly dependent on molecular characteristics such as electron density of the alkene, the S–H bond strength and the hydrogen abstraction ability of the intermediate carbon-centered radical. To date, alkene structure has been extensively studied related to the kinetic parameters of the reaction;27 as a rule of thumb, the following reactivity order applies: norbornene > vinyl ether > propenyl > alkene > vinyl ester > n-vinyl amides > allyl ether > allyltriazine > n-vinylamides > allylether > allyltriazine > allylisocyanurate > acrylate > unsaturated ester > n-substituted maleimide > acrylonitrile > methacrylate > styrene > conjugated dienes.26 On the other side, when analyzing thiol reactivity, the electrophilicity of the thiyl radicals is essential.23 Nonetheless, alkyl-3-thiolpropionates and alkylthioglycolates (i.e. thiol glycolate) stand out as multifunctional reactants for thiol–ene polymerizations. Apparently, these molecules react faster than alkylthiols because of the weakening of the S–H bond, due to hydrogen bonding with the carbonyl group.26
Despite the apparent simplicity of this reaction, it is very important to differentiate the potential pathway reactions that the thiol–ene addition can take. An overlooked fact, that may bring confusion to beginners, is to distinguish between thiol–ene Michael addition and radical thiol–ene reactions. Both transformations involve hydrothiolation of the –ene bond, differing in the mechanism and the chemical nature of the intermediate species. The Michael addition involves the heterolytic cleavage of the –SH bond, forming a negatively charged nucleophile (–S−). In this context, as thiols are acid–base groups too, they can produce thiolate species that can act as soft nucleophiles. Considering the rich chemistry of the SH group, it is fundamental to control the reaction conditions according to the thiol structure, as this will favour one mechanism over the other.23,28 Obviously, the thiol–ene Michael addition expands the library of thiol/alkene compounds and complements the possible shortcomings of the radical thiol–ene reaction. For nucleophilic/base thiol–ene addition, we suggest that the reader check other reviews that illustrate the use and applications of the thiol–ene Michael addition.29
As a final note, we must emphasize that contrary to what is observed in most radical-induced crosslinking processes, the thiol–ene radical reaction is not inhibited by oxygen. The peroxyl radicals (PO2) formed by O2 scavenging, can also react with the thiol and contribute to the propagation of the chain reaction.30 This has been stressed as one of the major advantages of the radical thiol–ene click reaction and definitively impacts at the industrial scale for mass production, simplifying the experimental lab setup.
The mechanism for the photochemically initiated thiol–ene reactions is the same as for their thermal radical counterpart, involving the addition of a thiol across an alkene to give a thioether.23 However, the distinctive feature of this approach is the use of light for thiyl production, which can be highly localized in time and space. There are several methods for RS˙ production, which we will review below.
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Scheme 2 Mechanism for the photoinitiation of a cleavage-type photoinitiator (DMPA) and H-transfer photoinitiator (BP). Adapted from ref. 26. |
Although UV photoinitiation is the standard procedure for thiyl production, shifting the excitation wavelength to lower energies brings the possibility to use safer excitation sources. Several groups have directed their efforts to synthesizing novel molecules, with red-shifted excitation wavelengths, motivated by the widespread availability of light emitting diodes (LED) technologies.37–41 Recently, Tehfe et al. generated thiyl radicals using chalcone derivatives (Scheme 3), evidenced by ESR spin trapping, and produced by means of a LED diode laser at 457 nm, a blue LED bulb at 462 nm, and a halogen lamp or sunlight.42 Shifting to longer wavelengths is promising for the immobilization of biologically derived molecules. Although this subject is in the early stages of development, it is expected to have a beneficial impact on PRTEA processes that require “soft” radical initiation.43
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Scheme 3 Chalcone derivatives photoinitiators.42 |
Visible light photoredox catalysis is another recent strategy that enables “green” organic transformations at ambient temperatures and using low energy photons.44,45 Ruthenium complex redox initiators, such as Ru(bpy)32+, are commonly employed because they show amphoteric redox activity in the form of reductive or oxidative cycles.44,46,47 As shown in Scheme 4, the excitation of Ru(bpy)32+ ions with visible light generates a [Ru(bpy)32+]* photoexcited state, through metal-to-ligand charge transfer (MLCT), that is further converted to [Ru(bpy)3]+ with the aid of a reductant (i.e. an electron donor like sodium ascorbate). The generated [Ru(bpy)3]+ can be oxidized again to Ru(bpy)32+ through an electron acceptor such as bromotrichloromethane.46 Then, the produced trichloromethyl radical initiates the thioether bond formation by hydrogen atom abstraction from the thiol molecule. Subsequent capture of the electrophilic thiyl radical by an alkene produces a carbon-centered radical that, upon H-atom abstraction from another thiol molecule, propagates the radical chain process.
Xu et al. used a blue LED (λmax = 461 nm), a Ru based complex, and p-toluidine for thiyl production as presented in Scheme 5.47 Linear polymers were synthesized in a few minutes by step-growth addition reactions using 25 ppm photocatalyst relative to alkene concentration. The authors claim that this will have important industrial implications, as mild reaction conditions are required and it can be easily scaled-up.
Recently, Ma et al. reported the use of a fac-Ir(ppy)3 photoredox catalyst for the α,ω-divinyl linear telechelic polythiolether oligomers between 1,4-benzenedimethanethiol (BDMT) to diethylene glycol divinyl ether (DEGVE) after excitation at 380 nm.48
A very interesting recent application of heterogeneous photoredox catalysts is the use of nanoparticles for thiyl generation. Greaney's group used Aeroxide® P25 TiO2 nanoparticles for producing photoexcited electron/hole pairs that lead to thiyl radicals.51 They suggest that O2 must be present in solution to act as a sacrificial electron acceptor, after photo-excitation of electrons to the conduction band of the TiO2 catalyst. Simultaneously, the hole in the valence band of TiO2 forms a thiyl cation (RSH˙+) that is further converted into a radical molecule, as portrayed in Scheme 6. Some thiol/alkene combinations resulted in high yields and definitively, this work presents an interesting perspective on RS˙ generation from dispersed nanoparticles. In a similar work, Bi2O3 photocatalyst powders were used; again, BrCCl3 was used to generate trichloromethyl radicals for thiyl radical production.52 Nonetheless, in both cases, mechanistic studies of these chemical transformations involving nanoparticles are still missing and represent an exciting field of research.
In a seminal work, Garrell et al. introduced a series of alkoxysilanes synthesized under UV light, using neat mixtures of 3-mercaptopropyltrialkoxysilane and an allyl/terminal alkene, or a thiol and allyltrialkoxysilane, in the presence of 2 mol% of DMPA (Irgacure® 651) as a photoinitiator, shown in Scheme 7.63
As a characteristic feature of thiol–ene addition reactions, 1H-NMR vinyl carbons signals from unreacted alkenes (δ ∼ 6.5–5.8 ppm) are non-existent or extremely weak, pointing to almost complete conversions of the CC bond into thioether. Typical conversions lie in the 94% to >99% range, while the purity of the obtained silanes is well above 90%, as seen in Table 1.
Moreover, these authors provide a cost analysis for the synthesis of specific precursors, finding that it is possible to lower the retail price of silane derivatives from usual chemical suppliers to 1/13. Although they do not provide information related to scaling-up energetic costs (i.e. UV), the simplicity for getting tailored alkoxysilanes stands out as a remarkable feature of the PRTEA reaction.
Based on this work, we introduced a general approach for anchoring carboxylic groups on SiO2 materials, an elusive chemical group in silica modification (see Scheme 8).64,65 The 1H-NMR of crude PRTEA reactions of mercaptosuccinic acid, mercaptoundecanoic acid and mercaptoacetic acid with vinyltrimethoxysilane show the appearance of a signal at high fields (δ ∼ 0.9 ppm), due to methylene protons bonded to Si (–Si–CH2–CH2–S–CH2) after the formation of a thioether bond.
Along this line, Bloemen et al. described the use of the PRTEA click chemistry to synthesize various different siloxanes with protected functional groups. The SiO– bonds anchor to the surface of iron oxide NPs and are deprotected later on. In this way, they solve the issues of colloidal stability and wrong ligand orientations (i.e. Fe3O4 has affinity for –COOH groups) as represented in Scheme 9.66 Fine chemical tuning of the SiO2/magnetic oxides interface is extremely important when aiming for imaging biomedical applications.15
In a recent example, Carron et al. used this strategy for developing bimodal contrast agents for MRI and optical imaging. They reacted a macrocyclic allyl derivative of DO3A-tri-t-butyl ester with the modified surface of ultra-small Fe3O4 nanoparticles with 3-mercaptopropyltrialkoxysilane. The DO3A organic moiety anchored on the Fe3O4 surface entrapped Eu(III) ions; characterization of the relaxometric and optical properties of the bimodal system was conducted. This work demonstrates the usefulness of PTREA in the synthesis of complex organic siloxane-coating precursors with simple building blocks.67
The generation of biocompatible surfaces for medical applications requires the anchoring molecules with high affinity for bio-membranes. Phosphorylcholine (PC) is a major component of eukaryotic cell membranes; PC derivatives show high affinity for living organs and present an excellent perspective as antifouling surface modifiers for medical applications.68 Starting from allylphosphorylcholine, Liu et al. synthesized trimethoxy-, triethoxy-, dimethylethoxy- and methyldiethoxy-silane precursors and concluded that the thioether linkage provides less steric effects, therefore higher loading rates on SiO2 surfaces, when compared with the CuAAC reaction, involving bulkier triazole moieties.
Interestingly, FT-IR Raman experiments suggest that some thiol moieties remain unreacted and susceptible for further modification; on the other hand, no vinyl alkene signals were detected. We hypothesize that as the alkene/thiol ratio used in their experiments is 1:
1.5, the excess thiol may become entrapped within the monolithic structure. Nonetheless, the vinyl-POSS linker thiol library was explored, shown in Scheme 10, and resulted in monoliths with variable degrees of hydrophobicity/hydrophilicity and mechanical properties (gels to rigid materials) (Fig. 1).70
Liu et al. explored the PRTEA reaction between monovinyl substituted POSS and a series of thiols bearing hydroxyl, carboxyl, ester and trialkoxysilane groups to produce the corresponding functionalized POSS monomers; yields ranged in the 85% to 99% using DMPA as a PI.71
As we have seen before, phosphorylcholine is a highly attractive chemical group for tissue engineering applications. With the perspective of the design of new biomedical POSS hybrids, phosphorylcholine-substituted silsesquioxanes were synthesized between octakis(3-mercaptopropyl)octasilsesquioxane (POSS-SH) with 2-methacryloyloxyethyl-phosphorylcholine or allyl-phosphorylcholine as depicted in Scheme 11 (yields >93%).72
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Scheme 11 Syntheses of phosphorylcholine-substituted silsesquioxanes via PRTEA. Reproduced with permission from Liu et al., Tetrahedron Lett. 2015, 56, 1562–1565. Copyright 2015 Elsevier B.V. |
In a nice example of in situ PRTEA synthesis of a sol–gel film, Zhang and co-workers, irradiated with evanescent UV light the surface of a U-bent poly(methyl methacrylate) optical fiber submerged in a solution containing vinyl-functionalized polyhedral oligomeric silsesquioxanes (POSS-V8), alkane dithiols, a fluorescent allylporphyrin and DMPA (Scheme 12).73 This resulted in a facile strategy to fabricate fluorescent porous oxide thin films for vapor phase sensing of TNT explosives.
Zhao and Xu, reported the synthesis of various POSS-SiO2 porous aerogels with potential applications in oil/water separation processes and sound absorption materials; vinyltrimethoxy-, vinyltriethoxy-, mercaptopropyltrimethoxy- and mercaptopropyltriethoxysilanes reacted in the presence of DMPA as PI.74
Han and co-workers synthesized regioisomeric Janus-type polyhedral POSS using two consecutive PRTEA.75 Starting from octavinyl-POSS and β-mercaptoethanol, they obtained a mixture of [2:
6] octakis-adducts, which were separated using flash chromatography.
Fang et al. introduced an interesting approach for the synthesis of inorganic–organic hybrid POSS fibers by integrating UV initiated thiol–ene polymerization and centrifugal fiber spinning.76 The authors remarked on the enhanced thermal and mechanical fiber properties due to the POSS cage structure.
In 2007, Gross and co-workers, reported the first application of PRTEA on a thiol-functionalized zirconium oxocluster with the purpose of a polymer-hybrid material. They showed that the organic–inorganic oxoclusters were well dispersed within the polymeric network, with no significant macroscopic agglomeration. Increasing the Zr oxoclusters content also increased Tg values, storage modulus in the rubbery region, and thermal stability of the polymeric hybrid material. XPS analysis and SIMS depth profile confirmed the homogeneous distribution of these clusters within the polymeric matrix.78 An ensuing paper reported two isostructural mercapto-functionalized zirconium- and hafnium-oxoclusters [M12(μ3-O)8(μ3-OH)8(MP)24·n(MPA), MPA = HS–(CH2)2–C(O)OH; MP = HS–(CH2)2–C(O)O–; M = Zr, Hf; n = 4 for Zr, n = 5 for Hf], which were included in a polymethacrylic matrix using PRTEA.79
Esquivel et al. synthesized a thiol functionalized bis-silane PMO precursor between 1,2-(E)-bis(triethoxysilyl)ethene and thioacetic acid (see Scheme 13).81 After aminolysis, the self-assembly process of the formed SH-precursor with Pluronic® P123, under acidic conditions, yielded a 2D-hexagonal (P6mm) mesostructured PMO with good structural ordering. In particular, co-condensation of this bis-silane within the SiO2 framework resulted in free thiols and disulphide bridges, as evidenced by 13C CP/MAS NMR and FT-Raman spectra. In a continuing work, this group oxidized the SH groups to SO3H for acid catalysis and found that not all thiol groups are accessible to oxidation, as usually observed when using the co-condensation approach of organoalkoxysilanes for mesoporous matrices chemical modification.82
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Scheme 13 Synthesis of 1-thiol-1,2-bis(triethoxysilyl)ethane (2) and its corresponding thiol periodic mesoporous silica material (SH-PMO). Reproduced from ref. 81 with permission from the Royal Society of Chemistry. |
Taking advantage of the immobilized ethylene bridges in the previous PMO framework, Ouwehand et al. obtained a series of acid–base catalysts.83 The PRTEA reaction allowed them to graft, in a simple manner, cysteamine and cysteine. In the latter case, antagonistic acid and base groups were incorporated into a single postgrafting step, without using protecting groups or several synthetic steps.
The high surface area/mass ratio of mesoporous materials is a valuable feature for adsorbents design. In this context, SBA-15 SiO2 powders are versatile frameworks for easy chemical modification. Qian et al. synthesized a Cs+ adsorbent using the PRTEA between thiol-modified SBA-15 and a pentacyano(4-vinylpyridine)ferrate complex, as shown in Scheme 14. The anchored Fe complex endured several recycling adsorption/desorption cycles, indicating the strength of the thioether bond.84
Bordoni et al. modified SBA-15 with COOH groups from PRTEA between mercaptosuccinic acid, mercaptoundecanoic acid, mercaptoacetic acid and vinyltrimethoxysilane keeping the original mesoporosity (see Fig. 2). All post-grafted groups were available for Cu2+ adsorption and chemically accessible as evidenced from COO− and COOH FTIR signals.64
Silica shells modulate magnetic interactions in superparamagnetic Fe3O4 NP and provide an ideal anchorage for covalent bonding of specific ligands.87,88 Bloemen and coworkers modified oleic-Fe3O4 nanoparticles with an heterobifunctional methoxysilane, for covalent Fe3O4 surface attachment, and with an iminodiacetic end group for Ni2+ chelation. This is a well-known strategy for recovering genetically engineered His tagged proteins from cell lysates.89 Moreover, adding a polyethyleneglycol chain (PEG) provided excellent colloidal stability of superparamagnetic particles in aqueous solutions (Scheme 15).
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Scheme 15 Synthetic steps for imidoacetic (IDA) PEGylated silane molecule. The functionalized ethanolamine (1) is covalently bonded to PEG via an ester bond forming an allyl-PEG-imidoacetic-tBu molecule (2). PRTEA between 2 and mercaptopropylsilane leads to an IDA siloxane precursor. Posterior hydrolysis of the ester groups in 3 results in a free IDA moiety. Reproduced from ref. 89 with permission from the Royal Society of Chemistry. |
When designing magnetically recoverable transition metal adsorbents, Fe3O4 surfaces represent a chemical challenge, as they are TMO themselves, sharing the same chemistry as SiO2 surfaces. For example, diphosphonic acid is a highly desirable ligand for heavy metals, lanthanides, and actinides separation (see Scheme 16); unfortunately, the diphosphonate moiety also possesses a high affinity for iron oxide surfaces. This limits the probability of having free phosphonate groups oriented to the solution. Warner and co-workers solved this issue by joining an allyl diphosphonic molecule to mercaptopropionic modified Fe3O4 NPs under UV light, using BP as photoinitiator.90 Also, in a recent publication, they used the same family of ligands for uranium extraction from seawater.91
Khoee et al. synthesized superparamagnetic iron oxide nanoparticles (SPIONs) for cancer drug delivery with balanced hydrophilic/hydrophobic surface energy.92 This group anchored (3-mercaptopropyl)-trimethoxysilane on the SPION surface, obtaining a thiol-decorated NP, which further reacted, via PRTEA, with an acrylated poly(caprolactone) (PCL, hydrophobic) and methoxy poly(ethylene glycol) (PEG, hydrophilic) as represented in Scheme 17. This resulted in two types of polymers on the surface of the SPIONs, which could be modeled by employing coarse grain methods. Tuning the surface ratio of the PEG and PCL improved drug loading, cellular internalization and colloidal stability.
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Scheme 17 Synthesis of PEG and PCL polymers on mercaptopropylsilane modified magnetite NPs. Reproduced from ref. 92 with permission from the Royal Society of Chemistry. |
Liang et al. combined the superparamagnetism of Fe3O4 nanoparticles and the electrocatalytic activity of ferrocene for developing a recyclable, magneto-controlled bioelectrocatalytic system for glucose oxidation.93 The switching of the biocatalytic activity and recyclable usage of the ferrocene functionalized NP by means of the external magnet could provide a simple, green and convenient strategy for bioelectrosensing. Thiol-terminated Fe3O4 nanoparticles were synthesized and further reacted with vinylferrocene under 365 nm UV.
Amici et al. synthesized poly(ethylene glycol) coated Fe3O4 nanoparticles using vinyltrimethoxysilane for surface oxide modification and further PRTEA with poly(ethylene glycol) dithiol with no photoinitiator.94 The obtained particles were well distributed and not aggregated, with an average size of about 20–50 nm, as shown by TEM and DLS analyses.
Georgiadou et al. synthesized CoFe2O4 NPs stabilized with oleylamine (OAm), which further reacted with free thiols of bovine serum albumin modified with fluorescein (FITC-BSA).95 The hydrophobic OAm-CoFe2O4 NP had to be phase transferred with CTAB for the PRTEA reaction with UV/DMPA.
Cheng et al. described the synthesis of fluorescent SiO2 nanoparticles with boronic moieties for labelling overexpressed sialic acid in tumorous cell surface glycan structures.96 Mercaptoboronic acid was covalently bound through a PRTEA to vinyl-modified SiO2 NP as exemplified in Scheme 18. The labelling specificity on living cells was investigated by flow cytometry and confocal laser scanning microscopy.
Ruizendaal et al. introduced a PRTEA procedure for obtaining ultra-small silicon nanoparticles (SiNP, radius < 5 nm) with tailored chemical groups.97 Thiol–ene chemistry performed on these surfaces allowed having functional SiNPs terminated with thioacetic acid, mercaptoethanol, ethylene glycol, and carboxylic acid. In addition to their nontoxicity, Si NPs have optical properties comparable to conventional quantum dots.
Silver-free antibacterial surfaces are promising environmentally friendly materials for controlling adhesion and the growth of pathogenic microorganisms. Gehring et al. obtained highly porous thiol-functionalized nanoparticles that were modified with vinyl-derivatized Rose Bengal using PRTEA and NO anchoring through forming a S-nitrosothiol bond.98 Sunlight triggered both the production of singlet O2 and the release of NO, having a synergistic effect for biocidal activity.
Although there is a wide library of alkene-derived and thiol simple molecules, highly designed polymeric materials constitute interesting modular building blocks for nanoparticle and plain surface modification. Polymer chemical diversity provides another way for tuning the physicochemical properties of various interfaces, an extremely important feature when designing stimuli-responsive surfaces, sensors and supramolecular delivery systems.
There are considerable efforts in the polymer science area focused on PRTEA as a synthetic technique for obtaining new thioether-based monomers that are susceptible to (co)polymerisation by a range of established methods, as well as a method for the modification of proper side- or end-group (co)polymers.23,59 For instance, reversible addition–fragmentation chain transfer (RAFT) polymerization processes involve the use of dithioesters, trithioesters and thiolcarbonyl as chain transfer agents. These chemical groups are readily converted into thiol moieties under mild reductive aqueous conditions, opening the possibility to be combined with PRTEA.99 Moreover, atom transfer radical polymerization (ATRP) is another preferred method as thiol functional groups can be introduced, modifying the halide end groups of the ATRP polymer.100
Mai et al. combined PRTEA and “activators regenerated by electron transfer atom transfer radical polymerization” (ARGET ATRP) for developing a thermo-responsive core–shell nanosystem based on poly(N-isopropylacrylamide) (PNIPAm) and SiO2 nanoparticles. ARGET ATRP was used as a reaction key for building the clickable precursor of PNIPAm (alkene counterpart), thiol functionalized silica nanoparticles were also synthesized as the complementary part and PRTEA was used for clicking the two blocks, as depicted in Scheme 19. The PNIPAmSiO2 nanoparticles showed thermo-responsive behaviour and may be useful for developing future stimuli-responsive delivery systems.101
Recently, Wu et al. obtained hyperbranched polymer-functionalized powders combining SiO2 nanoparticles treated with 3-mercaptopropyl trimethoxysilane to introduce mercapto groups, and successive trimethylolpropane triacrylate (TMPTA) and trimethylolpropane tris 3-mercaptopropionate (Trithol) using the PRTEA reaction.102 Although the reaction scheme is interesting and resembled a dendronized surface, no precautions were taken in order to avoid SiO2 nanoparticle agglomeration.
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Scheme 20 Schematic of “ene–thiol” (A) and “thiol–ene” reaction (B) proposed by Laaniste et al.104 Adapted from ref. 104. |
As an example of a rational material design approach, Laaniste et al. obtained a reversed-phase SiO2 monolithic column with high permeability when they reacted 1-octadecanethiol with the vinyl pre-functionalized silica monolith surface.104 This same group developed a multimodal biphasic monolithic column using successive photografting reactions with a UV-mask to localize different surface chemistries. Using different thiol monomers (octadecanethiol, cysteine and sodium mercaptoethanesulfonate), they prepared capillary columns with multiple chromatographic modes (reversed-phase, hydrophilic interaction and strong cation exchange) that were able to preconcentrate and separate β-blocker molecules.105 Moreover, they designed an aptamer-photoclicked silica monolith for in-line enrichment and purification of ochratoxin A, a suspected carcinogenic mycotoxin.106 In particular, a vinyl spacer was used for PRTEA anchoring of 5′-SH-modified oligonucleotide aptamers under irradiation at 365 nm for five minutes. Photografting allowed the confinement of the binding reaction to the desired silica monolithic segment, while the rest of the monolith was used for capillary electrophoresis. Both instances constitute good examples of anchoring and localizing specific chemical groups for molecular separation and detection (Fig. 3).
Cheng et al. carried out the PRTEA between 3-mercaptopropyltriethoxysilane (MPTES) and diethyl vinylphosphonate (DEVP) for nucleoside separations as shown in Scheme 21.107 The modified SiO2 colloidal particles were packed and employed in both reversed-phase liquid chromatography (RPLC) mode and hydrophilic interaction liquid chromatography (HILIC) mode.
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Scheme 21 Chromatographic phosphate ester-bonded silica stationary phase synthesis. Reproduced with permission from Cheng et al., J. Chromatogr. A, 2013, 1302, 81–87. Copyright 2015 Elsevier B.V. |
We have mentioned that is unusual to report the degree of monolith or surface modification after thiol–ene click-based reactions. However, Göbel et al. carried on a meticulous study on thiol-, vinyl- and allyl-modified mesoporous SiO2 monoliths.108 The alkene double bond content present in SiO2 monoliths were determined from iodine titrations and compared to 29Si solid-state NMR spectroscopy, elemental analysis and thermal gravimetric analysis. In particular, they found post-grafting efficiencies in the range of 25 to 50%, due to crowding of chemical groups on pore surfaces or non-accessible functional groups within the mesoporous structure.108 Demesmay and coworkers extended this analysis comparing reactions like bromination, radical initiated thiol–ene addition, PRTEA and radical initiated bisulfite reaction, observing a similar behaviour.109 Overall, for post-grafting mesopores chemical modification, there is a limit on the PRTEA ligation efficiency that depends on the following: (i) the steric constraints imposed by nanosized pore pockets and (ii) the unequal chemistry, according to which surface group is anchored (thiol–ene or ene–thiol).104,110
Escorihuela et al. developed a rapid strategy for the covalent immobilization of DNA onto silicon-based materials using the PRTEA.112 They demonstrated that thiol- and alkene-modified oligonucleotide probes were covalently attached in microarray format with immobilization densities of around 6 pmol cm−2, in 20 minutes, without the addition of photoinitiators.
Li et al. reported the generation of chemically hydrophilic micropatterns prepared on trichlorovinylsilane super-hydrophobic glass substrates using the PRTEA without PI.113
Han et al. also reported the use of fluorinated 1H,1H,2H-perfluoro-1-octene bonded to mercaptopropylsilane modified SiO2. X-ray photoelectron spectroscopy studies indicated the successful conversion of surface functionality.114
Köwitsch et al. demonstrated that glycosaminoglycans (GAG) on SiO2 glass slides resulted in a biocompatible surface for growing human fibroblasts.115 The authors reacted thiolated-GAG with 7-octenyldimethylchlorosilane modified SiO2 slides and proposed the applications of GAG modified surfaces for studies on cell adhesion and migration.
The photochemical reaction can be also employed for nanoparticle immobilization on planar surfaces. Aerosol bifunctional mesoporous nanoparticles, containing thiol and sulfonic acid groups, were anchored to allyltrimethoxysilane glass slides under direct UV illumination at 365 nm for 1 hour.116 The immobilized particles were solidly attached while the remaining SH groups immobilized within the pores, held Ag NPs with biocide activity.
Poly(ionic liquid)s (PILs) were anchored onto alkene modified SiO2 surfaces using DMPA as PI for 30 minutes.117 Clickable PILs were synthesized from styrenic imidazolium ionic liquid monomer through ATRP containing thiol terminal groups. PIL end groups are proposed for “smart” surfaces, anti-bacterial and anti-biofouling applications.
Tan et al. took on a rigorous study on the efficiency of the PRTEA compared to the corresponding thiol–yne reaction, analysing immobilized ATRP-generated polyglycidyl methacrylate (PGMA) polymer brushes on glass slides and Si wafers.118 PGMA surfaces were modified with various thiols (cysteamine, N-acetyl-L-cysteine, etc.) via direct photo-irradiation through a photomask and reactive microcontact printing. The density of the polymer brushes was found to confine functionalisation to its outermost surface, presumably due to restricted molecular diffusion.
Siloxane units and silica nanoparticles offer the opportunity to texturize glass slides with superhydrophobic properties.119 Uniform coatings obtained by spray-deposition of UV-curable hybrid inorganic–organic thiol–ene resins consisting of pentaerythritol tetra(3-mercaptopropionate) (PETMP), triallyl isocyanurate (TTT), 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane (TMTVSi), and hydrophobic fumed silica nanoparticles. In this particular case, the spray-deposition process and nanoparticle agglomeration/dispersion provided a surface with hierarchical structure with both micro- and nanoscale roughness. The surface photomodification was done under 6 minutes using a UV lamp. This same process was later adapted for the hydrophobization of a metallic mesh for oil/water separation.120
Chemtob et al. combined two photoinduced orthogonal reactions, PRTEA and alkoxysilyl sol–gel condensation using a photoacid generator, that converged in the fast formation of thioether–siloxane nanocomposite films.121 The formation of a rigid oxo-polymer siloxane network with high crosslink density coexists with the thiol–ene coupling, which imparts flexibility, elasticity and resistance to the cracking of the final material.
Silicon surfaces are interesting platforms for molecular-based electronics. Schulz et al. immobilized on highly doped p-type silicon (100), in a layer-by-layer approach, electroactive allyl-modified ferrocene (decaallyl-ferrocene, DAFc) with neat 1,4-butanedithiol utilizing thiol–ene click reaction conditions (see Scheme 22).122 Photoactivation was done using DMPA and a blue LED; the build-up of the redox system followed a linear growth.
Bhairamadgi et al. compared thru XPS analysis the degree of Si surface functionalization for a wide range of thiol structures.123 Interestingly, they found that in a thiol–alkyne reaction, at least one thiol molecule reacted per alkyne group; on the other hand, for the PRTEA reaction, these values were lower: on average, 0.5 thiol molecules reacted per alkene moiety on an alkene-terminated monolayer. Only when anchoring a bulky functional group, such as the N-Fmoc-protected form of L-cysteine, did both photochemical thiol–ene and thiol–yne reactions modify the silicon substrate to an equal degree.
In conclusion, molecular crowding and steric repulsions on surfaces jeopardize highly efficient homogeneous chemical reactions; these molecular events reshape the click terminology, limiting the original concept.19,20
Several groups combined the PRTEA with μCP techniques on flat surfaces, obtaining low cost and highly reproducible biocompatible surfaces with a high throughput production.126–133 As a matter of fact, it has been shown that photochemical μCP yields dense monolayers of functional molecules under times as short as 30 s.126
Roling et al. demonstrated the immobilization of a microcontacted thiol-alkoxyamine nitroxide-mediated polymerization initiator on an undecenyl modified glass by PRTEA and combined surface-initiated nitroxide-mediated polymerization of polystyrene (SI-NMP), represented in Scheme 24.134 This resulted in patterned polystyrene (PS) and polyacrylate (PA) brushes for site-selective protein immobilization.
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Scheme 24 Synthesis of patterned PS and PA polymer brushes using PRTEA combined with μCP for immobilizing surface-initiated nitroxide-mediator for polymerization.134 Reproduced with permission from Roling et al., Macromolecules, 2014, 47, 2411–2419. Copyright 2014 American Chemical Society. |
Recently, Ravoo and co-workers patterned glucose oxidase and lactase enzymes on octenyltrichlorosilane or undecenyltrichlorosilane modified glass slides.135 Given that both enzymes have free thiol groups (cysteines) in their native structure, they achieved direct enzyme anchoring to the alkene-modified SiO2 surface without additional steps like enzyme modification or the use of coupling reagents (Scheme 25).
Despite the highly attractive features of the PRTEA as a “mix-and-use” reaction, some issues should be widened. For instance, fundamental studies have shown that the chemical diversity of the thiol group forces a careful analysis of reaction conditions in the “preclick” preparative steps.20,27 This same kind of analysis should be applied in the materials science area; the chemistry of the anchoring sites on the surfaces of porous and non-porous oxide materials can have a definite impact on either the kinetic or thermodynamic parameters of the reaction. Highly confined surfaces, as mesoporous oxide frameworks, deserve special attention as they can alter surface acid–base equilibria or impose steric constraints.136,137 Unfortunately, detailed studies and analysis of the PRTEA yields and stoichiometry on surfaces are scarce and rarely performed. These observations should be paired with theoretical calculations; quantum chemical studies of the PRTEA in solution have already described experimental results very well.27 We anticipate the combination of experimental and theoretical approaches in order to get a complete picture of the whole process.
PRTEA certainly accounts as a click metal-free alternative to CuAAC when it comes to biomedical and biomaterial applications. Triazole units, present in the CuAAC approach, are known to complex Cu, raising serious concerns for biological uses. As we have seen, several research groups have embraced the PRTEA approach as a safer alternative for labelling and conjugation of biomolecules (proteins, enzymes, carbohydrates, DNA). Nonetheless, this option suffers from an uncomfortable shortcoming because even after brief expositions, high-energy UV photons may compromise the molecular integrity of the biomolecules due to light induced side-reactions (i.e. variations in enzymatic parameters or denaturation). In this context, the use of long wavelength (low energy photons) PI represents an excellent perspective for “soft” radical initiation. Anyhow, the fate of PRTEA photoinitiators after materials synthesis and surface modification is still pending.
Light is an exceptional external trigger for initiating the catalytic process of the PRTEA; localized illumination, photomasks and very recently, the development of nanoparticle-based photoinitiators offer extraordinary opportunities for achieving extremely localized chemistry. It is highly likely that these features, in conjunction with surface immobilization techniques, will help the growing research on organic chemical reactions in microfluidic setups or flow reactors. Moreover, easy custom-made polymers with –ene or thiol end groups, obtained through reliable and well-established organic synthesis approaches (i.e. ATRP and RAFT), will expand the universe of macromolecular building blocks for producing high-end modified TMO surfaces through PRTEA, a relatively unexplored area.
In summary, PRTEA adds to the existing library for simple surface functionalization with molecules, nanomaterials synthesis and substrate chemical patterning. Evidently, this approach intertwines the design of molecular building blocks with well-defined chemical and physical properties, building up a multidisciplinary effort with a far-reaching impact in various technological and scientific applications.
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