Reversible Surface Engineering via Nitrone-Mediated Radical Coupling

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Reversible Surface Engineering via Nitrone-Mediated Radical Coupling Joachim Laun, Wouter Marchal, Vanessa Trouillet, Alexander Welle, An T. Hardy, Marlies K. Van Bael, Christopher Barner-Kowollik, and Tanja Junkers Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b03167 • Publication Date (Web): 19 Feb 2018 Downloaded from http://pubs.acs.org on February 21, 2018

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Reversible Surface Engineering via Nitrone-Mediated Radical Coupling Joachim Laun,# Wouter Marchal,¥ Vanessa Trouillet,†,± Alexander Welle,±,‡ An Hardy,¥,≠ Marlies K. Van Bael,¥,≠ Christopher Barner-Kowollik,§,+,×,* and Tanja Junkers#,≠,* #

¥

Polymer Reaction Design Group, Institute for Materials Research (IMO), Universiteit Hasselt, Martelarenlaan 42, 3500 Hasselt, Belgium Hasselt University, Institute for Materials Research, Inorganic and Physical Chemistry and IMEC - Division IMOMEC, Martelarenlaan 42,

3500 Hasselt, Belgium †

Institute for Applied Materials (IAM), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-

Leopoldshafen, Germany ±

Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-

Leopoldshafen, Germany ‡

Institute of Functional Interfaces, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen,

Germany §

School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George Street, QLD 4000,

Brisbane, Australia +

Macromolecular Architectures, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstraße

18, 76128 Karlsruhe, Germany ×

Institut für Biologische Grenzflächen (IBG), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-

Leopoldshafen, Germany ≠

IMEC associated lab IMOMEC, Wetenschapspark 1, 3590 Diepenbeek, Belgium

*E-mail: [email protected]; [email protected]; [email protected]

Abstract Efficient and simple polymer conjugation reactions are critical for introducing functionalities on surfaces. For polymer surface grafting, post polymerization modifications are often required, which can impose a significant synthetic hurdle. Here, we report two strategies that allow for reversible surface engineering via nitrone-mediated radical coupling (NMRC). Macroradicals stemming from activation of polymers generated by copper-mediated radical polymerization are grafted via radical trapping with a surface-immobilized nitrone or a solution-borne nitrone. Since the product of an NMRC coupling features an alkoxyamine linker, the grafting reactions can be reversed or chain insertions be performed via nitroxide mediated polymerization (NMP). Poly(n1 ACS Paragon Plus Environment

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butyl acrylate) (Mn=1570 g·mol-1, Ɖ = 1.12) with bromine terminus was reversibly grafted to planar silicon substrates or silica nanoparticles as successfully evidenced via X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry, and grazing angle attenuated total reflection Fourier-transform infrared spectroscopy (GAATR-FTIR). NMP chain insertions of styrene is evidenced via GAATR-FTIR. On silica nanoparticles, a NMRC grafting density of close to 0.21 chains per nm² was determined by dynamic light scattering and thermogravimetric analysis. Concomitantly, a simple way to decorate particles with nitroxide radicals with precise control over the radical concentration is introduced. Silica microparticles and zinc oxide, barium titanate, and silicon nanoparticles were successfully functionalized.

Introduction The need for polymer-coated surfaces with unique properties has remained unbroken over the past twenty years.1-4 There are two general methodologies to graft polymers onto a surface; ‘grafting-from’ and ‘grafting-to’.5-8 Grafting-from approaches allow for high grafting densities as small molecules are directly attached to the surface followed by chain growth, yet precise tuning of polymer properties is challenging since imperfections of the growth mechanism in the confined space on the surface are irreversibly encoded. Further, the full characterization of the grafted chains is challenging.9-10 In contrast, grafting-to approaches attach preformed chains to the surface. Therefore, these methods often rely on very efficient conjugation reactions such as (hetero) Diels-Alder, thiol-ene (Michael additions), nitrile imine tetrazole-ene cycloadditions,11 copper-catalyzed azide–alkyne cycloadditions,5 and oxime ligations12 to name a few prominent examples. Nevertheless, grafting densities are often below the respective grafting-from approaches due to steric congestion on the binding sites.10

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Living/controlled polymerizations such as living anionic polymerization, ring-opening polymerization and reversible-deactivation radical polymerizations generally allow for good control over the reaction with respect to chain length, dispersity and chemical functionality, and the selection of topology.13 With their simple protocols, reversible-deactivation radical polymerizations,

i.e.

nitroxide-mediated

polymerization

(NMP),14

reversible-addition

fragmentation transfer polymerization (RAFT),15 and atom transfer radical polymerization (ATRP)16 as the most prominent techniques, excellent control of molecular architectures and therefore material properties became accessible beyond the limitations of living anionic polymerization.13, 17 The broad range of usable monomers makes these techniques ideal for both design and synthesis of advanced macromolecular architectures in solution and on surfaces.13, 18 Grafting-to reactions rely on an efficient conjugation processes. However, these conjugation reactions in most cases require specific functional groups that are not a priori present in the target molecule and postpolymerization modifications might become necessary – either to introduce or to unprotect the required chemical functionality.19-20 The high end group fidelity of reversible deactivation radical polymerization hereby provides a good starting point for the introduction of the desired functionality.21-22 However, these modifications do not only require at least one other reaction step, yet may lead to unwanted side products and impurities.23 If the polymerization conditions and the target end group chemistry are orthogonal, the desired functionality can be readily attached to the initiator or chain-transfer agent, respectively.20 However, even the robust copper-catalyzed azide–alkyne cycloadditions are subject to a loss of orthogonality with many monomers during radical polymerization since monomers can slowly react with the azide moiety, especially at extended reaction times.24 While RAFT polymers in principle allow for direct hetero Diels-Alder reactions,25 ATRP polymers can be directly employed in radical-radical coupling reactions such as atom transfer radical coupling, nitroxide radical coupling or nitrone-mediated 3 ACS Paragon Plus Environment

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radical coupling (Scheme 1).26 Atom transfer radical coupling (ATRC) leads to the irreversible formation of a symmetric polymer via a carbon-carbon bond and is only well-suited for polystyrene. In contrast, both nitroxide- and nitrone-mediated radical coupling result in an asymmetric and symmetric alkoxyamine, respectively, and functions well with polyacrylates.27

Scheme 1. General reaction scheme for nitrone-mediated radical coupling (NMRC).

Furthermore, nitrones give direct access to nitroxide radicals when the reaction is stopped after the addition of one radical (see Scheme 1), making nitroxide-equipped particles directly accessible. The potential of such nitroxide-containing particles has recently been demonstrated for overcoming multidrug resistance in epidermoid cancers.28 The second addition is generally reversible at higher temperature and leads to the formation of an internal alkoxyamine (refer to Scheme 1). In principle, the formed alkoxyamine allows for block copolymer formation via nitroxide-mediated polymerization if no α-H is present that would facilitate elimination reactions.26, 29 Alkoxyamines further allow for radical crossovers at higher temperatures,30 which has been exploited for the formation of graft polymers,31 crosslinking systems,32 star polymers33, and sidechain modification on surfaces34-35. However, strong excluded volume effects led to low degrees of crossover on surfaces and a scaffolding polymer backbone was always required. Nevertheless, alkoxyamine-based crossovers give direct access to dynamic covalent surface chemistry, which can only be achieved by very few other methodologies such as triazolinedione conjugation,36 reversible disulfide formation,37-38 and β-cyclodextrin host-guest systems39-40 and few others.41-44


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Even though dynamic covalent exchange/reversibility and post-coupling block copolymerization are excellent features of alkoxyamines obtained from NMRC, nitrones received most attention in synthetic organic chemistry for their use in [2+3] cycloadditions45-47 and as radical spin-traps,48-50 yet only little in the context of polymer chemistry.51 Initially nitrones were assessed as control agents in enhanced spin capturing polymerization29,

52-54

and further as coupling reagent in

nitrone-mediated radical coupling (NMRC) that allows for the introduction of a new mid-chain alkoxyamine functionality55-56, e.g. to construct dendrimers,57 star polymers58 and other architectures.59-60 More recently, NMRC has also been used to couple polymers derived from reverse iodine-transfer polymerization, further underpinning that any precursor of non-persistent radicals can be employed.61 We herein exploit both key features of NMRC, i.e. dynamic covalent reversibility and postcoupling NMP, for surface grafting. We have selected two approaches on flat surfaces and further on particles for quantification. First, the precursor of a radical – here an ATRP initiator – was grafted to a planar silicon substrate and subsequently subjected to nitrone-mediated radical coupling with a bromine-capped polyacrylate and the nitrone in solution. The reversibility of the NMRC coupling was demonstrated via both a degrafting experiment and nitroxide-mediated polymerization with styrene. Similarly, our second approach employed nitrones grafted to a surface and their subsequent use in nitrone-mediated radical coupling, degrafting experiments and nitroxide-mediated radical polymerization. The grafting density of the latter approach was assessed on silica nanoparticles. Finally, silica particles with tunable radical concentration were produced and characterized. The methodology was further extended to silicon, BaTiO3 and ZnO nanoparticles, of which the latter two are very interesting compounds for second harmonic imaging microscopy.


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Scheme 2. (Top row) Nitrone-mediated radical coupling with the nitrone species in solution. 1: silicon substrate decorated with an ATRP initiator. 2 represents the of product nitrone-mediated radical coupling of 1 and poly(n-butyl acrylate). Sample 2 subjected to degrafting in the presence of tributyltin hydride to yield 3. (Bottom row): Nitrone-mediated radical coupling with the nitrone species grafted onto the surface, 4. Poly(n-butyl acrylate) grafted by nitrone-mediated radical coupling, resulting in 5. 6 consitutes the degrafting product of 5.

Results and Discussion In nitrone-mediated radical coupling, the nitrone acts as a linker between two radicals of which one is reversibly attached. Therefore, two general options for surface grafting exist: one fully reversible in which radicals are generated on the surface and one partially reversible, where a nitrone is immobilized and all radicals are solution borne. Both approaches are depicted in Scheme 2 and described in detail below.


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Reversible nitrone-mediated radical coupling on surfaces with the nitrone in solution

Reversible nitrone-mediated radical coupling with the nitrone species in solution requires generation of a transient radical on the surface. The key advantages of this approach are its full reversibility and higher accessibility based on readily available and broadly used brominecarrying silanes, which can be combined with commercially available nitrones. As depicted on the top row of Scheme 2, an ATRP initiator with a long alkyl spacer was selected as precursor for the surface radical and was grafted in a silanization reaction, yielding a deactivated radical on substrate 1. A C11-alkyl spacer was selected to ensure the formation of a self-assembled monolayer.62 Consequently, a poly(n-butyl acrylate) (Mn=1570 g·mol-1, Ɖ = 1.12) with bromine terminus and a 10 fold excess of nitrone were used to conduct the nitrone-mediated radical coupling under SET-LRP conditions. A polymer-coated substrate 2 was obtained, indicating the in-principle the success of the reaction. Next to product 2, it is likely that two surface radicals recombine, via ATRC or NMRC, despite the high concentration of nitrones. Degrafting experiments were conducted to reverse the polymer grafting, exploiting the thermolabile carbonoxygen bond of the alkoxyamine, and to demonstrate absence of competing atom transfer radical coupling for polymer grafting. If the nitrone is built-in efficiently, these bonds will open, allowing for cleavage of the polymer grafts. ATRC coupling, in contrast, would not allow for such reversible grafting. Therefore, 2 was heated to 130 °C in the presence of tributyltin hydride as hydrogen donor. After hydrogen-capturing, the cleaved polymer-grafts remained in solution, leaving only structure 3 on the surface.


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Figure 1. (l.h.s.) C 1s XPS spectra of a silicon substrate, after silanization 1, after nitrone-mediated radical coupling with poly(n-butyl acrylate) 2, and after degrafting with tributyltin hydride 3. (r.h.s.) 500 × 500 µm² ToF-SIMS images of steps 1 to 3. Intensity maps of the characteristic fragments of the grafted poly(n-butyl acrylate), C4H7O- and C4H9O-; C2H4NO- and SiO3- from the substrate.

Figure 1 depicts XPS and ToF-SIMS images of substrates 1 to 3. On the right in Figure 1, the ToF-SIMS spectra of two characteristic poly(n-butyl acrylate) fragments, C4H7O- and C4H9O- as well as C2H4NO- and SiO3- are depicted. The absence of C4H7O- and C4H9O- before the nitronemediated radical coupling on both the blank (not displayed) and 1 shows – as expected – the absence of poly(n-butyl acrylate) prior to NMRC grafting. After NMRC grafting, both fragments appear with significant intensity. Since the control sample – a blank substrate exposed to NMRC conditions – did not show any increase of the respective intensities, physisorption can be ruled out. The substrate fragment SiO3- behaved contrary to the C4 fragments and clearly lost intensity after grafting, indicating a polymer layer thickness above the SIMS probing depth of a few nanometers. The almost complete absence of C2H4NO- is associated with the instability and/or low ionization yield of this fragment in ToF-SIMS. Presence of the alkoxyamine is demonstrated via the above 8 ACS Paragon Plus Environment

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described degrafting experiment that relies on radical crossover at elevated temperatures. The degrafted sample 3 indicates almost complete disappearance of the characteristic polymer signals C4H7O- and C4H9O- and an increase in the substrate signal SiO3- (Figure 1, r.h.s.). In conclusion, there is no poly(n-butyl acrylate) remaining after degrafting, evidencing that all polymer was reversibly removed from the substrate, and hence was grafted in the first place via the desired NMRC mechanism. XPS experiments were performed to add quantitative information to the qualitative ToF-SIMS results (refer to Fig. 1). For the grafted initiator 1, XPS showed the presence of bromine covalently bound to a carbon atom (Br 3d5/2 at 70.1 eV44, refer to SI, Figure S4) and the expected C 1s component ratios as previously reported.63 After nitrone-mediated radical coupling, the presence of poly(n-butyl acrylate) has been evidenced by the clear increase of the O=C-O carbon signal at 288.9 eV.64 The quantitative analysis of all spectra allows for an approximation of the film thickness. The quantitative analysis reveals a contribution of the substrate (silicon and corresponding oxygen) of close to 65 at%, whereas approx. 28 at% total carbon was detected. With respect to the information depth of the method of about 8-10 nm and under the assumption of a homogenous, closed layer, the XPS results suggest a layer thickness of close 3-4 nm at the maximum. This film thickness is fully in line with the SIMS data showing a significant decrease of the SiO3- intensity for 2 as compared to 1. However, the small film thickness is no surprise, given the average DP of 10 of the polymer. This length corresponds – in its stretched state – only to close to 2.5 nm. After degrafting, XPS indicates a strong decrease of the O=C-O species which supports the degrafting of the polymer, yet the surface coverage with carbon remained the same and the total surface coverage even increased. This increase was probably due to the presence of tributyltin on the substrate 3 and the corresponding control sample since a significant amount of tin was found. Despite extensive washing with a sequence of solvents from toluene to MilliQ, 9 ACS Paragon Plus Environment

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these tin contaminations could not be removed. The presence of tributyltin on the substrate accounts for the rather constant surface coverage with carbon, while ToF-SIMS shows the complete removal of the poly(n-butyl acrylate). Moreover, grazing angle ATR-FTIR spectroscopy was employed to complement the characterization (refer to Figure 2). As expected, the blank sample indicates the absence of specific functionalities as there was no peak besides the major SiO2 signal which is found in all spectra. The silanized ATRP initiator in 1 was chosen to form a well-defined and consequently very thin monolayer, featuring only a little peak for its C=O stretch vibration at 1730 cm-1. The grafted poly(n-butyl acrylate) of 2 features sufficient carbonyl groups to give a signal at around 1735 cm-1. The reaction in solution above the substrate can give an indication for the coupling efficiency on the surface. For the solution reaction, a coupling efficiency of 65% is calculated from SEC results (refer to SI, Figure S5). After degrafting, no carbonyl peak was observed, further underpinning the XPS and ToF-SIMS results, which indicate that the majority of polymer chains was coupled via reversible NMRC.


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Figure 2. GAATR-FTIR spectra of the blank sample (blank), the grafted ATRP initiator 1, the grafted poly(n-butyl acrylate) after the NMRC reaction 2, the degrafted sample 3 and finally the NMP-modified sample NMP A. Poly(n-butyl acrylate) was evidenced by the presence of a carbonyl peak at 1730 cm-1. The NMP-modified sample NMP A shows three characteristic polystyrene peaks at 1600, 1494 and 1455 cm-1 and a very small carbonyl peak of remaining poly (n-butyl acrylate).

Scheme 3. Nitroxide-mediated polymerization was employed for chain insertion of styrene at 110 °C in the presence of 1.00 equivalent polystyrene obtained from enhanced spin capturing polymerization with PBN and 0.12 equivalents TEMPO, leading to NMP A. Chain extension in solution increased the molecular weight from Mn = 2300 to 37000 g·mol-1. TEMPO end groups are not displayed, yet they represent around 12% of all end groups.


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Finally, the NMRC-grafted substrate 2 was subjected to nitroxide-mediated polymerization (NMP) with styrene (see Scheme 3). In this NMP reaction, styrene monomers are inserted when the thermolabile carbon-oxygen bond is reversibly cleaved into a carbon-centered radical on the surface and a nitroxide radical in solution. However, the nitroxide readily diffuses into the solution and consequently cannot be reused for reversible spin trapping. Thus, some polystyrene obtained from enhanced spin capturing polymerization (ESCP-polymer; 1.00 equivalent) and free stable free nitroxide TEMPO (0.12 equivalent) were added along with the monomer to allow for the swift reversible deactivation of the surface radical. The ESCP-polymer of PBN was used to have the very same nitroxide in solution and on the surface. Furthermore, the addition of TEMPO was necessary to suppress any non-controlled polymerization via autoinitiation of styrene at 110 °C. Instead of TEMPO, an alternative free nitroxide can be used, yet TEMPO was chosen for its ready availability. TEMPO-based alkoxyamines, however, feature higher thermostability than PBN-based ones and are therefore primarily incorporated, leading to around 12% TEMPOcapped polymer chains. As the entire process represents an equilibrium, the high amount of ESCP-polystyrene polymer in solution compared to poly(n-butyl acrylate) on the surface clearly dominates the nitroxide exchange.14 Consequently, poly(n-butyl acrylate) was expected to be completely exchanged for polystyrene from ESCP polymer in NMP A. The successful grafting of polystyrene was evidenced by the appearance of three characteristic aromatic C-H stretching vibrations at 1600 cm-1, 1494 cm-1 and 1455 cm-1 as well as a small peak of the aromatic C-H deformation vibration at 1020 cm-1 (Figure 2). As expected, no poly(n-butyl acrylate) remained on the surface due to the equilibrium with the ESCP polymer in solution. Blank samples exposed to the same reaction conditions showed no polystyrene signals, ruling out physisorption during NMP grafting. Further evidence for a successful NMP process was obtained from a solution experiment. The molecular weight increased from Mn = 2300 to 37000 g·mol-1 12 ACS Paragon Plus Environment

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with a moderate rise of dispersity to 1.41 from 1.19 which is associated with constant initiation from the autopolymerization of styrene (refer to the SI, Figure S8). In a first conclusion, the NMRC of surface radicals with nitrones in solution allowed for successful grafting of the surface with a polyacrylates chains. Degrafting or exchange with another type of polymer may in future proof to be very useful when the technique is combined, for example, with methods of spatiotemporal control such as photoNMRC. Nitrone-mediated radical coupling on the surface

Our second approach reverses the above procedure in that the nitrone-species is immobilized on the surface and both radical reactants are located in the solution (refer to the bottom row of Scheme 2). The second approach requires more synthetic effort, yet has its charm in a potential combination with widely used [3+2] cycloadditions.65 However, nitrones are rather sensitive molecules, which readily undergo hydrolysis in the presence of acids,66 and further exhibit some sensitivity towards light that leads to intramolecular cyclization and eventually to the formation of amides.67 Given the low overall nitrone concentration present in a surface monolayer, precautions are required when working with nitrones on surfaces. A specifically designed reactor is thus employed to avoid any exposure to light or acids (refer to the SI, Figure S6). To attach the nitrone onto the surface, a nitrone-carrying triethoxysilane was grafted in the dark under nitrogen atmosphere. In order to reduce photo degradation reactions, the functionalized substrates 4 were kept in a custom-made reactor flushed with copious amounts of dry solvents of different polarities (refer to the Supporting Information, Chapter 4.1.3) before the NMRC reaction. Due to its sensitivity towards light and hydrolysis, the nitrone-functionalized substrate 4 could not be isolated as degradation occurs before analysis is possible. In contrast to the welldefined monolayers in 1, triethoxysilanes generally lead to less well-defined yet thicker layers.18 13 ACS Paragon Plus Environment

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Subsequently, a poly(n-butyl acrylate) with bromine terminus was introduced in the presence of copper and PMDTA. Nitrone-mediated radical coupling subsequently proceeded via spintrapping of radicals from solution. Here, in principle an alkoxyamine with two poly(n-butyl acrylate) arms to either side should be formed (refer to structure 5), in contrast to the first approach with the nitrone in solution, where only one arm is attached per nitrone moiety (see Scheme 2). The recombination of two radicals for the attachment of the second arm requires no activation energy, while during the first attachment an activation energy of approximately 24 kJ·mol-1 has to be overcome.52 Even though the two-arm product is kinetically favored, it is, however, likely that there are one-arm products present because of the expectedly high grafting density of the nitrone silane. Degrafting experiments were performed in the presence of tributyltin hydride at 130 °C, leading to sample 6.

Figure 3. (l.h.s.) C 1s XPS spectra of a blank, the PnBA-coated, 5, and the degrafted, 6, silicon substrates. (r.h.s.) 500 x 500 µm² ToF-SIMS images of the respective steps from blank to degrafted


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sample are displayed. Intensity maps of the characteristic fragments of the grafted poly(n-butyl acrylate), C4H7O- and C4H9O-, as well as of C2H4NO- and SiO3-.

As noted above, with the nitrone on the surface, the substrate has to be handled in the dark under nitrogen atmosphere and was hence used directly to obtain substrate 5. The successful grafting of the nitrone-species (4) has been indirectly evidenced by the grafting of poly(n-butyl acrylate) proved via XPS (refer to Figure 3 l.h.s.). The C 1s spectrum of 5 shows a clear peak at 288.9 eV (O-C=O), associated with the polymer since the nitrone silane does only entail one urethane carbon. Moreover, a carbon ratio O-C=O : C-O,C-N : C-C,C-H. of 1 : 1.5 : 6.5 was found. While poly(n-butyl acrylate) alone shows a peak ratio of 1:1:5, the differences can be explained by the short chain length (DP = 10) of the employed poly(n-butyl acrylate) and the long spacer used for the nitrone in 4. Further, a significant increase of the nitrogen concentration could be observed, which is associated with the successful grafting of the nitrone silane (4). Compared to the first approach with the nitrone in solution, qualitatively a higher surface coverage is obtained with around 36 at% total carbon in the XPS spectrum and a slightly higher contribution of the specific O-C=O component stemming from the polymer which shows here 3.8 at% compared to 2.5 at% in the case of the coupling in solution. However, the higher grafting density might also be associated with the less well-defined monolayer of the nitrone silane in 4 rather than with a better grafting of polymer in 5. ToF-SIMS measurements further underpin the XPS results as depicted in Figure 3 (right hand side). While both blank and control sample (not displayed) do not show any poly(n-butyl acrylate) fragments, the NMRC-functionalized substrate 5 shows both the characteristic poly(n-butyl acrylate) signals C4H7O- and C4H9O- and the nitroxide-derivative C2H4NO-. Degrafting experiments (6) reduced the surface coverage with carbon in XPS from 36 at% to 20 at%, yet again left some tin compounds behind which are known to add to nitroxide radicals.68 15 ACS Paragon Plus Environment

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Surprisingly, XPS showed again the removal of most of the O=C-O species, hence of the poly(nbutyl acrylate). This has been rather unexpected since the NMRC grafting with the nitrone on the surface involves the addition of two (polymeric) radicals of which only one is linked via a thermolabile carbon-oxygen bond. ToF-SIMS indicated almost no signal for C4H9O- and no signal for C2H4NO-, suggesting removal of almost all poly(n-butyl acrylate) and nitroxides. C4H7O- fragments, however, were found and even less of the substrate fragment SiO3- was observed. It is possible that these C4H7O- fragments arise from the nitrone silane grafted in the previous step or from the attachment of tributyltin derivatives. The grazing angle ATR-FTIR spectra show a carbonyl peak at 1730 cm-1, the C–O–C asymmetric stretching vibration at 1263 cm-1 and the C–O–C symmetric stretching vibration at 1105 cm-1, evidencing the presence of poly(n-butyl acrylate). The absence of the respective peaks on the blank and the control samples demonstrates successful NMRC grafting (refer to Figure 4). In addition, GAATR-FTIR shows the complete removal of the carbonyl species at 1730 cm-1 and most of the C–O–C asymmetric stretching vibration at 1263 cm-1, thus successful degrafting.


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Figure 4. Grazing Angle ATR-FTIR of the substrate after nitrone-mediated radical coupling (5), the degrafted NMRC-functionalized substrate (6), the NMP block formation with styrene in NMP B, and the degrafted NMP-sample NMP Q.

Similar to the approach described above, sample 5 was subjected to chain insertion via nitroxidemediated polymerization of styrene with ESCP-polystyrene and 12 mol% TEMPO as mediators, Scheme 4. In contrast to the NMP reaction described above in Scheme 3, the controlling nitroxide remained on the surface, potentially covered by some poly(n-butyl acrylate). Hence, steric hindrance can be of significant influence. For successful grafting, the growing polystyrene radicals need to able to access the surface, which becomes less likely with increasing chain length and grafting density. Steric hindrance may also be seen as the reason why there is almost no literature for this type of NMP-grafting.14 Finally, degrafting was performed at 130 °C in the presence of tributyltin hydride, giving NMP Q. 17 ACS Paragon Plus Environment

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Scheme 4. Nitroxide-mediated polymerization on 5 for chain exchange-insertion of styrene (pink) should give structure NMP B. Subsequent degrafting should lead to NMP Q.

The NMP reaction and subsequent degrafting were investigated via GAATR-FTIR (refer to Figure 4). The aromatic C-H stretching vibrations at 1600 cm-1, 1494 cm-1 and 1455 cm-1 plus a small peak of the aromatic C-H deformation vibration at 1020 cm-1 demonstrate the presence of grafted polystyrene. As expected, some poly(n-butyl acrylate) remained on the surface, as reflected by the C=O stretch vibration at 1735 cm-1. After degrafting, no C=O stretch vibration was observed, yet the three characteristic peaks of polystyrene at 1600 cm-1, 1494 cm-1 and 1455 cm-1. Control experiments ruled out physisorption due to insufficient washing. Thus, only the removal of poly(n-butyl acrylate) was successful, yet not of grafted polystyrene, indicating that grafting was rather uncontrolled despite the high concentration of added TEMPO radicals. From theory, one would expect a reversed outcome with the styrene degrafted and the poly(n-butyl acrylate) remaining on the substrate. Unfortunately, we have no explanation for this unexpected, yet interesting behavior. In conclusion, NMRC via surface-grafted nitrones allowed for grafting of poly(n-butyl acrylate) onto flat silicon substrates. Even though unexpected, the reaction seems to be fully reversible as shown via degrafting experiments. Subsequent NMP grafting provided a simple way to introduce a second functionality, yet NMP-grafting was not reversible. 18 ACS Paragon Plus Environment

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Nitrone-mediated radical coupling on particles

While grafting-to reactions usually allows for the grafting of very well-defined polymers, they often suffer from lower grafting densities due to steric hindrance. Based on the inherently very low overall concentrations in thin layers, it is very challenging to assess the grafting density on planar substrates. Higher amounts of grafted materials are obtained when particles instead of flat surfaces are employed due to the much higher total surface area. In addition, the higher amount of grafted nitrone reduces the problems of undesired degradation due to light or acids.

Scheme 5. NMRC grafting of poly(n-butyl acrylate) onto silica nanoparticles with surface-bound nitrone. a: silanization of a nitrone silane onto silica nanoparticles, b: NMRC grafting of poly(n-butyl acrylate) (blue).

Therefore, NMRC with surface-grafted nitrones was carried out on monodisperse silica particles with 60 nm in diameter (refer to the SI, Figure S10 and Figure S11 for DLS) and a surface area of close to 50 m²·g-1 (refer to Scheme 5). Monodisperse nanoparticles were produced from tetraethoxysilane and functionalized with nitrone silane prior to washing. Subsequently, poly(n-butyl acrylate) was grafted under NMRC conditions. The high surface area of the nanoparticles allowed for the use of thermogravimetric analysis (TGA) and 1H-NMR analysis (see SI, Figure S9). While XPS was used to confirm the presence of the grafted nitrone and poly(n-butyl acrylate) (refer to SI, Table S1), respectively, the combination of DLS and TGA gives a good indication of the grafting density. In order to prevent centrifuge- and ultrasoundinduced aggregation prior to DLS measurements, the particles were dialyzed to remove excess 19 ACS Paragon Plus Environment

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reagents after grafting. The pore-size of the used semipermeable membrane was chosen to allow for the complete removal of both small silane aggregates and polymer species. In addition, all particles were centrifuged three times prior to TGA. Figure 5 shows the TGA results for the nitrone-coated (l.h.s.) and the polymer-coated silica nanoparticles (r.h.s.), respectively. Both relative weight loss (solid black line) and its derivative (dashed blue line) are depicted. Note that not all weight loss could be associated with loss of thermolysis of organic material. The blank silica nanoparticles indicated a constant weight loss until around 600 °C, which is associated with condensation reactions and leads to a relative mass loss of approx. 10% at 600 °C (refer to the SI, Figure S12).

Figure 5. (l.h.s.) Thermogravimetric analysis of silica nanoparticles functionalized with a nitrone silane. Relative weight loss in black, differential weight loss in blue. The weight loss above 400 °C is due to an artefact and not present in the pure silane. (r.h.s.) Thermogravimetric analysis of silica nanoparticles functionalized via NMRC with poly(n-butyl acrylate) . Relative weight loss in black, differential weight loss in blue. Strong weight loss around 375 °C has been assigned to poly(n-butyl acrylate).

Nitrone-coated particles showed four mass loss events: the first at around 100 °C, the second at around 200 °C, the third (small) one at 300 °C and finally the fourth one (broad) at around 500 °C. The first peak is associated with the loss of solvent. The nitrone-functionalized particles are prone to undergo degradation at higher temperature and were therefore dried for 2 days in high vacuum only at room temperature prior to TGA. Traces of remaining solvent and potential 20 ACS Paragon Plus Environment

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water absorption due to their high hygroscopicity were consequently associated with the first peak. The second and third mass loss are also associated with the grafted nitrone species as TGA of the pure nitrone silane shows them very prominently (refer to the SI, Figure S2). The fourth peak at around 500 °C, however, does not match the TGA result of the pure nitrone silane. It is ascribed to the loss of silanol groups that were rapidly formed from ethoxy groups in basic (aqueous) solutions during the sol-gel synthesis.69-70 The polymer-coated nanoparticles showed four different mass losses: narrow peak at 50 °C and two broad ones at 200 and 400 °C, respectively. The first one at around 50 °C was again assigned to the loss of solvent. In contrast to the nitrone-coated nanoparticles, the polymer-coated ones were dried at 70 °C in high vacuum and therefore only showed little loss of solvent, probably water absorbed from air. The second peak at 200 °C is much broader than for the nitrone-coated particles. It actually entails two contributions, first of the nitrone around 190 °C, and a second closer towards 230 °C from the poly(n-butyl acrylate) (refer to the SI, Figure S3). The third peak at 400 °C entails a very high portion of poly(n-butyl acrylate) degradation. In contrast to the previous step, no mass loss at 500 °C was observed. Potential explanations could be a more advanced condensation reaction in non-aqueous solutions and the complexation of silanol by copper(II) ions,71 which also explains the light blue color of the particles. To calculate an approximate grafting density, we consider the weight loss between 225 °C and 450 °C which minimizes the contribution of the artefact and covers the entire decomposition range of pure poly(n-butyl acrylate). The difference in mass loss between nitrone@SiO2 and PnBA@SiO2 is 2.77 %. Based on a diameter of around dDLS = 60 nm and silica density

ρ = 2.0 g·cm-3, a grafting density σ = 0.21 nm-2 is estimated.


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Very efficient grafting-to reaction afford grafting densities in the range of 0.1 – 0.6 for Mn = 81.3 – 10.3 kg·mol-1 (thiol-ene)72, 0.3 – 1.2 for Mw = 20 – 5 kg·mol-1 (Huisgen Cycloaddition)73 and 0.1 chains/nm² for Mn = 3.6 – 7.2 kg·mol-1 (hetero-Diels-Alder)74-75. In addition, most graftingfrom reactions do not yield higher grafting densities. Pre-synthesized RAFT agents for surfacemodification often lead to grafting densities below 0.8 initiators/nm² and typical ATRP initiators yield between 1 and 5 initiators/nm².10, 76 However, after subsequent grafting-from reactions, the grafting density of the polymer brushes is often only 0.1 – 0.5 chains/nm² as just small fraction of the initiator sites is actually used for surface-initiated ATRP.10, 76 Thus, our grafting density of

σ = 0.21 nm-2 is in the range of other efficient grafting-to procedures and of many reported grafting-from protocols.10 However, it should be noted that ‘grafting-from’ reactions typically yield thick polymer brushes up to several hundreds of nanometer film thickness and hence have different target applications.10 Particles with tunable radical concentration on their surface

Particles featuring a tunable amount of nitroxide radicals are hence accessible via a variation of the nitrone-mediated radical coupling approach described above. If nitrones are attached as spin traps to the surface without providing a secondary radical for coupling, immobilized nitroxides can be created. When the only provided radical source, e.g. an ATRP initiator, is covalently anchored to the surface of a particle, the NMRC reaction stops at the nitroxide stage if the radicals are trapped by a nitrone before they undergo radical annihilation reactions. We have chosen silica microparticles of 63 - 200 µm in diameter as very readily processable model substrate for our investigations. Later on, the same methodology was also applied to ZnO-, BaTiO3-, and silicon nanoparticles of which the first two are very interesting second harmonic imaging microscopy.77-79


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Scheme 6. NMRC on silica microparticles. a: Silanization with a suitable ATRP initiator trichlorosilane. b: Formation of nitroxide radicals on the surface via NMRC without counterpart.

The microparticles were washed, activated with piranha solution and subsequently dried in high vacuum. The dry particles were immersed in a concentrated solution of an ATRP silane (refer to Scheme 6). After the reaction, the particles were extensively washed and used for the same NMRC grafting as described on the top row of Scheme 2, yet without a polymer counterpart in solution. Consequently, the reaction stops at the nitroxide stage, yielding surface-bound radicals. In Figure 6, the EPR spectra of silica microparticles carrying a nitroxide exposed to different amounts of nitrones in otherwise the same reaction mixture are shown on the left hand side. As expected, if the experiment is carried out in absence of nitrone no detectable EPR signal is observed. With increasing nitrone concentration in the reaction mixture, the EPR signal increased, too. Double integration of the recorded EPR signals yields in principle the radical concentration when referenced against a TEMPO calibration curve. TEMPO calibrations are often used in EPR, yet in our case we have to stress that the comparison of surface-bound nitroxides with nitroxides in solution is a good tool for comparison of different measurements, yet might not be a perfect fit for the determination of absolute concentrations. The right hand side of Figure 6 shows the radical concentration is linearly dependent on the employed nitrone concentration, giving access to particles with a tunable radical concentration. The thermal stability of these nitroxide-carrying microparticles was assessed under nitrogen atmosphere at ambient temperature, 7 °C and – 15 °C, respectively, over the course of 82 days (refer to the SI, Figure S14). In the freezer, the nitroxide concentration remained almost constant 23 ACS Paragon Plus Environment

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over the entire observation period, whereas already in the fridge, 25 % was lost within the first 40 days and even 65 % at room temperature. When used for ZnO-, BaTiO3-, and silicon nanoparticles, silicon showed the strongest, BaTiO3 the weakest nitroxide concentration, suggesting that silanization worked more effectively on silicon than on BaTiO3 (see SI, Figure S13).77, 80

Figure 6. l.h.s. EPR spectra of silica microparticles treated with different amounts of PBN. r.h.s double integrated EPR spectra referenced against a TEMPO calibration curve. The evolution radical concentration in mmol as function of the used mass ratio of PBN to silica microparticles is shown. Conclusions

Nitrone-mediated radical coupling is exploited to reversibly graft poly(n-butyl acrylate) via an alkoxyamine that allows for subsequent NMP. Two routes were explored, once with the nitrone species in solution and once on the surface. Both approaches resulted in grafted poly(n-butyl acrylate) on planar silicon substrates. Degrafting experiments indicate that nitrone coupling can be used for reversible grafting of surfaces and concomitantly ruled out a potentially concurrent atom transfer radical coupling for both approaches. Subsequent modification via nitroxidemediated radical polymerization, however, functioned better for the route with the nitrone initially in solution. In addition, the grafting density of the grafted-nitrone approach was assessed 24 ACS Paragon Plus Environment

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on silica particles to be close to 0.21 chains per nm², placing NMRC in the range of other efficient grafting-to and many grafting-from techniques.10 Critically, particles with tunable radical concentration were generated and characterized via EPR. In summary, we demonstrate that reversible nitrone-mediated radical coupling is a powerful alternative for surface modification and for the introduction of surface-bound radicals, which recently have been shown to possess potential for overcoming drug resistance in epidermoid cancers.28

Acknowledgements T.J. and J.L. are grateful for funding from the Fonds Wetenschappelijk Onderzoek (FWO) in the form of a project grant and a PhD scholarship. Additional support by the Karlsruhe Nano Micro Facility (KNMF), a Helmholtz Research Infrastructure at the Karlsruhe Institute of Technology (KIT), is acknowledged. The K-Alpha+ instrument was financially supported by the Federal Ministry of Economics and Technology on the basis of a decision by the German Bundestag. C.B.-K. acknowledges continued support via the STN program of the Helmholtz association, the KIT as well as the Queensland University of Technology (QUT) and the Australian Research Council (ARC) in the form of a Laureate Fellowship.

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Table of Content Figure


Reversible Surface Engineering via Nitrone-Mediated Radical Coupling

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