Utilizing Self-Immolative ATRP Initiators To Prepare Stimuli

Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

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Utilizing Self-Immolative ATRP Initiators To Prepare StimuliResponsive Polymeric Films from Nonresponsive Polymers Leigh Peles-Strahl,†,‡ Revital Sasson,† Gadi Slor,‡,§ Nicole Edelstein-Pardo,‡,§ Adi Dahan,*,† and Roey J. Amir*,‡,§,∥ †

Chemistry Department, Soreq Nuclear Research Center, Yavne 81800, Israel Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, §Tel Aviv University Center for Nanoscience and Nanotechnology, and ∥BLAVATNIK CENTER for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel

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‡

S Supporting Information *

ABSTRACT: Stimuli-responsive polymers were synthesized by atom transfer radical polymerization (ATRP) using a photoresponsive self-immolative bifunctional initiator. The photoactivated self-immolative junctions allow transforming nonresponsive polymers into photocleavable polymers that can be split into two equally sized fragments when exposed to the stimulation. We demonstrate this modular approach by preparing a series of photoresponsive poly(benzyl methacrylate) and polystyrene polymers of various molecular weights. Taking advantage of the well-defined architecture of the polymers, we studied their photoresponse as thin films and examined the effect of irradiation time and solvent addition on the degree of response and splitting. The results show that the polymers can be split in the solid phase, confirming that the self-immolative quinone methide elimination can occur in solid phase. Importantly, we could also obtain insights into the role of the mobility of the polymer chains in the solid phase and in the presence of solvent molecules on the responsiveness of the films and degree of splitting. The potential to introduce such modular self-immolative units into different types of widely used of polymers will allow the utilization of this approach to create wide range of responsive materials that can undergo vast structural changes by relatively minor synthetic modifications.

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responsiveness as solid polymeric films to understand the role of the mobility of the polymeric chains in determining the degree of response.

INTRODUCTION Stimuli-responsive polymers (SRPs) are designed to change their chemical and physical properties at a specific location and time in response to external chemical, physical, or biological stimuli.1−7 The ability of SRPs to transform their structure upon stimulation can offer great advantages for numerous applications such as drug delivery, tissue engineering, sensors, lithography, adhesives, and electronics.4,8−18 SRPs contain responsive moieties that are incorporated into the polymeric structure and allow it to respond to specific stimuli, which trigger a series of chemical transformations. The chemistry of the responsive moieties and their location along the polymer framework can strongly affect the chemical and the physical properties of the obtained polymer. Some moieties undergo reversible changes such as protonation and isomerization,19−21 while other groups can undergo irreversible transformations by cleavage of chemical bonds. Most of the reported irreversible SRPs have been studied in solution or in gel phase22−28 with the exception of few elegant examples of self-immolative polymers, including linear and cyclic polyphthaladehyde that were investigated also as bulk polymeric films.29−33 In this work we aimed for a simple modular approach for the introduction of self-immolative responsive junctions into widely used nonresponsive polymers to design splittable polymers and carry out a detailed comparative study of their © XXXX American Chemical Society

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MOLECULAR DESIGN The stimuli-responsive polymers were designed to contain splittable units at their center (Figure 1), based on a selfimmolative AB2 spacer attached to a cleavable protecting group (PG) and two initiators for atom transfer radical polymerization (ATRP). Both styrene and methacrylate based vinyl polymers were selected to demonstrate and study the responsiveness of these modular splittable polymers. UV light was chosen as a model stimulus since it allows remote activation and does not require the use of chemicals for initiating the splitting process, enabling us to pursue the degradation studies of the polymeric films in the absence of solvent. Because many of the vinyl based polymers absorb light and can degrade when irradiated at 200−250 nm, we chose 4,5-dimethoxy-2-nitrobenzyl (DMNB), a photoresponsive protecting group, which can be removed by irradiation at 365 nm as the photoresponsive group.34−36 The selfimmolative spacer 2,6-bis(hydroxymethyl)-p-cresol (BHMPC, Received: December 5, 2018 Revised: March 30, 2019

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DOI: 10.1021/acs.macromol.8b02566 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Figure 1. Proposed splitting mechanism via the activation of self-immolative junction for the UV-responsive polymer.

Figure 2. Schematic presentation of nonresponsive polymers functionalized with self-immolative unit that lack the photoresponsive headgroup.

Scheme 1. Synthetic Strategy of the Self-Immolative Bifunctional Initiators

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1) was chosen as a linker between the photoresponsive DMNB and the two ATRP initiators, which can be used for the polymerization of the two polymer chains. Upon irradiation, the photodegradable PG is expected to be cleaved, causing the self-immolative unit to undergo quinone methide elimination,37,38 leading to the splitting of the polymer chain in the middle into two shorter polymers (Figure 1). A second 1,4 elimination can occur in the presence of a nucleophilic species (such as water) that can perform a nucleophilic attack of the oquinone methide species to yield the hydroquinone form, which can undergo an additional elimination of the second chain.39 It is interesting to note that although only one elimination reaction might occur in the absence of a solvent, we hypothesize that the splitting of the polymer would not require the second elimination step as the polymeric chain will already split into two as a result of the first elimination event. Nonsplittable control polymers, which contain the selfimmolative spacer but lack the photoresponsive group, were also designed by using benzyl (Bn) headgroup as a non-UVresponsive protecting group (Figure 2).

RESULTS AND DISCUSSION

Synthetic Strategy of the Bifunctional Initiators. The synthesis of the stimuli-responsive junction was performed in two simple steps as illustrated in Scheme 1. First, the selfimmolative spacer 1 was reacted with DMNB−Br (2) for the production of UV-responsive unit 3. In parallel, benzyl bromide (Bn−Br) 4 was used to synthesize a nonresponsive analogue 5 that can serve for the polymerization of the control polymer. In the second stage, the benzyl alcohols of 3 and 5 were reacted with α-bromoisobutyryl bromide (6) to obtain a photoresponsive (7) and a nonresponsive (8) bifunctional initiator for ATRP polymerization. Polymerization by ATRP. The UV-responsive selfimmolative unit 7 served as a bifunctional initiator for the polymerization of two different vinyl monomers: benzyl methacrylate (BnMA) and styrene. Pentamethyldiethylenetriamine (PMDETA) was used as a ligand and copper bromide (CuBr) as a metal source for the polymerization that was performed under an inert nitrogen environment. Scheme 2 B


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Macromolecules Scheme 2. ATRP Polymerization of Different Vinyl Monomers Using DMNB Bifunctional Initiator 7 To Produce Photoresponsive Polymers Containing Self-Immolative Junctions

illustrates the ATRP polymerization of the “splittable” DMNB−PBnMA polymers (9−11) and DMNB−PS polymers (12−14) of different chains lengths. A B−PBnMA control polymer 15 was also polymerized using the same conditions for comparison (Figure S1). To achieve diversity in the molecular weight of the PS-based polymers, the reaction times were changed, and for BnMA polymers different monomer quantities were also used due to the fast kinetics of the polymerization (see the Supporting Information). Characterization of the Polymer Size. 1H NMR, gel permeation chromatography (GPC), and UV−vis spectroscopy were used to determine the number-average molecular weight (Mn) of the polymers. The 1H NMR peaks of the bifunctional junction protons were compared to the peaks of the polymer main chain and side groups. Mn determination with GPC was performed using PS-based calibration curve. Because each polymer chain contained a single nitro-aryl group, we could take advantage of the typical absorbance (∼350 nm)31 and determine the Mn of the responsive polymers by measuring the absorbance of a polymer sample of a known weight (Figures S2A and S3A) and comparing it to a calibration graph of the UV-responsive bifunctional initiator 7 absorbance as a function of its concentration (Figure S4). Table 1 presents the measured and calculated Mn values of the polymers, and the obtained results show very good correlation between the three different measurement methods. Degradation in Solution. After we completed the synthesis and characterization of the polymers, we studied the degradation of polymers 9 and 14 in solution as representative examples for the poly(benzyl methacrylate) (PBnMA) and polystyrene (PS) polymers, respectively. In addition, we also studied the control polymer 15, which lacks the photocleavable group. The polymers were dissolved in DCM and exposed to UV light (UV-A centered at 350 nm, average intensity of 7 ± 0.7 mW/cm2) for 180 min. First, we used UV−vis spectroscopy to follow the response of the photocleavable group and noticed a decrease in the peak at 350

Table 1. Mn of Polymers 9−15 Based on 1H NMR, UV−Vis Spectroscopy, and GPC Mn [kDa] polymer DMNB−PBnMA

DMNB−PS

B−PBnMA

9 10 11 12 13 14 15

1

H NMR

UV−vis spec

GPC

34.1 12.5 7.5 12.5 9.8 4.1 37.5

35.9 11.2 7.2 11.8 8.0 4.5 N/A

35.2 13.2 7.3 14.5 10.4 4.2 36.2

nm that correlates with the disappearance of the nitro group, hence indicating the cleavage of the photoresponsive groups (Figure 3). Next, we analyzed the change in the molecular weight of the two photoresponsive polymers 9 and 14 and the control polymer 15 by GPC. The results showed the expected decrease in polymer size by a factor of 2 for the two responsive polymers 9 and 14, indicating the splitting of the polymer junction in response to UV irradiation, whereas no change in size was observed for the control polymer 15 (Figure 4). Degradation in Solid Phase. After we confirmed the ability of the polymers to split in response to irradiation in solution, we continued to study their response as thin films. Irradiation was performed on polymeric films made by spin coating of the polymer solutions (50 mg/mL in ethyl acetate) on a glass slide, followed by drying of the formed films, which were measured by interferometer to have a thickness of ∼0.6 μm (see the Supporting Information). UV−vis spectroscopy was first used to monitor the polymer degradation after 10 and 20 min of irradiation, and we were encouraged to see a redshift and decease in the peak of the nitro-aryl group to 380− 400 nm already after 10 min of irradiation (Figure 5). These changes indicate the response and cleavage of the nitrocontaining group in the first 10 min of UV exposure, as no C


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Figure 3. UV−vis absorbance spectra overlay of (A) DMNB−PBnMA 9, (B) B−PBnMA 15, (C) DMNB−PS 14 in solution, before (solid line, blue) and after (dashed line, red) exposure to UV light for 180 min.

Figure 4. GPC measurements of (A) DMNB−PBnMA 9, (B) B−PBnMA 15, and (C) DMNB−PS 14 before (blue) and after (red) exposure to UV in solution for 180 min.

additional major changes were observed for the films after irradiating them for 20 min. After confirming the removal of the photocleavable group, we monitored the thin film degradation by GPC by dissolving the samples after irradiation and analyzing the Mn of the polymers using PS-based calibration (Table 2). The results showed full degradation of all DMNB−PBnMA films after 10 min of UV exposure (Figure 6). However, DMNB−PS films underwent only partial degradation after 180 min of irradiation. The partial splitting, which can be clearly observed in Figure 6, indicates that when increasing the chain length for the PS-based polymers 12−14, the degree of splitting decreased. We deconvoluted the two overlapping peaks of the starting and split polymers, and the ratio was calculated for each polymer (Table 2). The results showed a 3:1 ratio for the shortest polymer (12), a 2:1 ratio for polymer 13, and a 1:1 ratio for the longest polymer (14) for the split and starting polymers, respectively. Noticeably, when comparing between DMNB−PBnMA 11 and DMNB−PS 12, which had similar molecular weights, we observed significant differences between the two types of polymers in terms of their degree of response. Changes in the IR spectra of the polymeric films, measured by FTIR-ATR, further supported cleavage of the polymers in solid phase (Figure S5). According to the suggested degradation mechanism (Figure 1), the DMNB group undergoes rearrangement when exposed to UV light to receive the nitroso aldehyde34,40 and the deprotected phenol. The

release of the latter induces the degradation of the selfimmolative spacer by 1,4-elimimation to release one-half of the polymer chain.41,42 For example, the IR spectra of PS polymer 14 after irradiation (Figure S5F) showed that peaks corresponding to vibrations of benzyl ether (1221 cm−1), esters (1070 cm−1), and nitro (1521, 1328 cm−1) groups decreased in comparison with the peaks of aliphatic vibrations (1493, 1452 cm−1), which remained the same. In addition, new peaks emerged, a sharp peak at 1694 cm−1 and a broad peak around 3264 cm−1, indicating the formation of the aldehyde moiety and carboxylic acid and the hydroxyl groups that were released upon cleavage, respectively. Similar results were observed for all the photoresponsive polymers (Figure S5A− F). It can be observed that as the polymers get longer, the changes in the IR spectra become smaller due to the lower ratio between the self-immolative unit and the nonresponsive monomers. Solvent Effect after Film Irradiation. After establishing that the polymers can be split in the middle in response to the stimulus, we were curious to examine the effect of solvent exposure after the irradiation. We wanted to understand whether the fragmentation of the polymers occurred at the solid state or whether the presence of the solvent is required to increase the mobility of the polymer chains and push the selfimmolative-based splitting mechanism to completion. To study this question, we referred to differential scanning calorimetry (DSC), which unlike GPC, allows measurements of solid D


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Figure 5. UV−vis absorbance spectra overlays of DMNB polymeric films before (blue) and after irradiation of 10 min (red) and 20 min (green). DMNB−PBnMA (A) 9, (B) 10, (C) 11, DMNB−PS (D) 12, (E) 13, and (F) 14.

Table 2. Mn of the Polymer Films before and after Solid Film Irradiation (and Peak Area Calculation for Polymers 12−14) Mna [kDa] polymer before DMNB− PBnMA

DMNB−PS

B−PBnMA

after

9

37.0

22.3

10 11 12 13 14 15

13.2 7.3 15.1 10.4 4.2 36.2

7.0 4.3 10.5 6.2 2.6 36.5

(Figure 7A). DSC measurements of the DMNB−PS polymers 12−14 before UV exposure presented elevated Tg values than those measured for the DMNB−PBnMA polymers due to the higher rigidity of polystyrene in comparison with poly(benzyl methacrylate) backbones.46 Interestingly, in contrast to the benzyl methacrylate-based polymers, the PS-based polymers demonstrated very different results for the two types of treatments of the samples. The dissolved PS samples presented more significant decrease in Tg (∼20 °C) than the DMNB− PBnMA polymers, even though the cleavage was not full. However, the PS-based samples that were not dissolved showed only minor change in their Tg values (Figure 7B). As expected, the control polymer B−PBnMA 15 showed no change in its Tg before and after it was irradiated (Figure S6). The differences in the degree of response between the two types of polymeric films, as observed both in GPC and in DSC measurements, show that the nature of the polymers has a major effect on the responsiveness of the polymers and their degree of splitting. While all PBnMA samples underwent full splitting when irradiated as films and analyzed by GPC, the PS polymers did not get fully cleaved even after significantly longer irradiation times. Furthermore, the PBnMA polymers showed the same degree of change in their Tg values, regardless of the presence or lack of solvent in the sample preparation. In contrast, although the partially split PS polymers showed greater changes in their Tg values in comparison with the PBnMA polymers after the polymeric films were dissolved (∼20 °C for PS and ∼5 °C for PBnMA polymers), only negligible changes in the Tg values of the PS polymers were observed when the samples were not dissolved. These results demonstrate that the more flexible PBnMA polymers, as indicated by their lower Tg values,46 enable these polymers to undergo the 1,4-elimination mechanism with greater ease than the more stiff PS-based polymers. The higher rigidity of PSbased polymers as indicated by their higher Tg values is

peak areab [%] starting material

degraded polymer

51 32 24

49 68 76

a

Mn was measured by GPC. bPeak area calculated by deconvolution.

samples without dissolving them. It is well established that the chain length of polymer has an effect on the Tg of amorphous materials, and as the chains get shorter, the Tg decreases (Figures S2B and S3B).43−45 DSC analysis was performed on all of the polymeric film, before and after irradiation in solid phase. To examine the role of post-exposure to the solvent, the thin films were exposed to UV, and the irradiated samples were measured either by scrapping the films without exposing them to any solvent or by dissolving the film in DCM and drying the irradiated polymeric samples again before performing DSC measurement. Table 3 summarizes the changes in Tg values before and after stimulus exposure for all polymers. When analyzing polymers DMNB−PBnMA 9−11, they all showed similar trend: an average decrease of about 5 °C in Tg after irradiation. In addition, no significant differences were detected between the nondissolved and the dissolved samples after irradiation, giving strong indication that the splitting occurred in the solid phase with no requirement of a solvent E


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Figure 6. GPC measurements of DMNB polymeric films before (solid line, blue) and after (solid line, red) exposure to UV. DMNB−PBnMA (A) 9, (B) 10, and (C) 11 were irradiated for 10 min; DMNB−PS (D) 12, (E) 13, and (F) 14 were irradiated for 180 min and deconvolution of DMNB−PS after irradiation appear in dashed lines, representing the starting materials (dashed line, purple) and the degraded polymer (dashed line, orange).

PBnMA films showed changes of the same order of magnitude in Tg, for the irradiated films of different polymer lengths and different treatments (exposed to a solvent after irradiation or not) PS films showed a variety of responses, indicating a more complex phenomenon is taking place under the tested conditions. One noticeable trend is the higher degree of splitting of the PS polymers as they get shorter, as indicated by the GPC results for the polymeric films. This can be attributed to the greater mobility of the shorter chains, which based on the presented results seems to be a major factor in the ability of the polymers to be split. The correlation between mobility and responsiveness of the polymers can be assumed to relate to the degradation mechanism. Because the 1,4-elimnation reaction can be reversed if the quinone methide specie is attacked back by the leaving group, one can assume that the mobility of the chains and the ability of the leaving group to move away from the formed quinone methide should significantly affect the reversibility of the process and the splitting of the polymer chain into two fragments. We assume that the more rigid nature of the PS-based polymers in comparison with the PBnMA ones may prevent the separation of the leaving carboxylate end group of the PS polymers and quinone methide groups that are formed. This can possibly cause a reversible splitting/addition cycle for the highly rigid PS polymers that may prevent their full degradation. Upon introduction of the solvent as part of sample preparation, the mobility of the chains should increase and the elimination and splitting of the polymers become irreversible. In addition, residual water molecules present in the solvent may serve as competing nucleophiles that can capture the quinone methide

Table 3. Tg of the Polymer Films before and after Solid Film Irradiation and Their Degree of Degradation Tga [°C] after

sample before DMNB− PBnMA

DMNB− PS

B− PBnMA

no solvent addition

dissolved after irradiation

degree of degradationb [%]

9

67

63

63

100

10 11 12

61 60 100

56 55 100

56 55 78

100 100 49

13 14 15

97 84 61

96 81 N/A

74 58 61

68 76 0

a

Tg midpoint was measured by DSC. bDetected by GPC.

hypothesized to limit their mobility and ability to be split even in the presence of solvent. The DSC results for the PS polymers that were not dissolved indicate that this effect is further enhanced, and only negligible change in the Tg values for these sample implies that the chains remained intact. It is important to note that for both types of polymers and their corresponding films similar changes were observed in the UV− vis spectra of the irradiated films. These results demonstrate that the degree of cleavage of the photoresponsive headgroup was similar in both cases and that the observed degree of responsiveness emerges from the ability of the polymers to be split by the 1,4-elimination mechanism. Interestingly, while F


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Figure 7. DSC analysis overlay of (A) DMNB−PBnMA and (B) DMNB−PS films before (solid blue line) and after films exposure to UV treatment, differed by sample preparation. Film was dissolved in DCM (dashed red line) or was not dissolved (dotted green line) in sample preparation.

Figure 8. Effect of irradiation time on the degree of degradation of 2 μm thick DMNB−PBnMA 9 films measured by GPC. (A) GPC chromatograms of DMNB−PBnMA films before (blue) and after irradiation for 10 min (purple), 20 min (green), 30 min (yellow), and 60 min (red). (B) Degree of degradation as a function of irradiation time.

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species and transform it into a benzyl alcohol, making once again the elimination an irreversible process. Effect of Irradiation Time on the Degree of Degradation. To evaluate the effect of irradiation time on the degree of degradation, we prepared 2 μm thick films of polymer DMNB−PBnMA 9 by spin coating a more concentrated polymer solution (150 mg/mL). The films were irradiated for 10−60 min and then dissolved and injected to the GPC. As can be seen in Figure 8, after the first 10 min of irradiation, 66% splitting was observed, as indicated by the shift of the peak to a higher retention volume and its broadening due to the presence of shorter split polymer chains and residual longer polymer chains of the starting material. For longer irradiation times of 20 and 30 min, the degradation reached 79% and 82%, respectively. Longer irradiation times did not show significantly higher degree of degradation as 84% degradation was observed after 1 h, indicating that the thicker films cannot be fully degraded, probably due to limited penetration of the UV light into these thicker films.

CONCLUSIONS

In this work, we presented a simple and modular approach to design and synthesize splittable polymers with well-defined architecture and cleavage pattern. Our molecular design is based on utilization of trifunctional self-immolative units that can allow the potential introduction of different responsive groups into variety of polymeric structures by adjusting the stimuli-responsive headgroup and the two polymerization initiators with high modularity. Taking advantage of the widely used 2-nitrobenzyl-based photocleavable group and the ability of ATRP initiators to polymerize various vinyl monomers, we successfully prepared two series of photoresponsive poly(benzyl methacrylate) and polystyrene polymers that can be split in the middle by UV irradiation. Using GPC, we clearly demonstrated the ability to utilize the wellestablished 1,4-elimination mechanism to translate the removal of the photocleavable group into the splitting of the polymers at their center. A detailed study of the degree of response of G


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Macromolecules polymeric films of the two types of polymeric series by GPC, UV spectroscopy, and DSC revealed interesting insights into the role of mobility and rigidity on the responsiveness of the films and their ability to be cleaved. In general, we observed that polymers with lower Tg values and higher flexibility, due to either the nature of the polymer or shorter lengths of the polymer chains, showed reasonable degree of splitting. On the other hand, polymers with high Tg values required the introduction of a solvents to facilitate their splitting. For thicker films, we observed that longer irradiation times were needed to push the cleavage of the polymer chains to nearly 90%; however, we did not achieve full degradation, most likely due to the limited penetration of the irradiated light into the lower layers of the thicker film. The highly modular molecular design and insights into the cleavage mechanism can further extend the ability to apply this approach to different nonresponsive polymeric structures for various applications.

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Materials. Most chemicals were purchased from Sigma-Aldrich, and solvents were purchased from Bio-Lab. Benzyl methacrylate (BnMA, 98%) and α-bromoisobutyryl bromide (97%) were purchased from Alfa Aesar. Deuterated CDCl3 was purchased from Cambridge Isotope Laboratories Inc. All chemicals were used as received but the styrene and BnMA monomers, which were purified in advanced by an aluminum oxide column for destabilization. All reactions requiring anhydrous conditions were performed under a nitrogen atmosphere. Synthesis of UV-Responsive Self-Immolative Initiator. (2((4,5-Dimethoxy-2-nitrobenzyl)oxy)-5-methyl-1,3-phenylene)dimethanol (3). BHMPC 1 (1.2 g, 7.2 mmol, 1 equiv) was dissolved in 20 mL of DMF. K2CO3 (2.0 g, 22 mmol, 3 equiv) and DMNB−Br 2 (2.0 g, 7.2 mmol, 1 equiv) were added, and the reaction mixture was stirred in the dark at room temperature (RT) for 5 h. A crude mixture was added dropwise into water leading to precipitation of the product as yellow solid, which was filtered, washed with water, and dried under high vacuum (2.3 g, 87% yield). 1H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H, arom H), 7.61 (s, 1H, arom H), 7.21 (s, 2H, arom H), 5.38 (s, 2H, arom−CH2−O−), 4.70 (d, J = 5.9 Hz, 4H, arom−CH2−OH), 4.04 (s, 3H, CH3−O−arom), 3.99 (s, 3H, CH3−O−arom), 2.36 (s, 3H, CH3−arom), 1.80 (t, J = 6.0 Hz, 2H, arom−CH2−OH). 13C NMR (DMSO-d6, 100 MHz): δ 153.6, 151.2, 147.5, 138.6, 134.7, 132.9, 129.2, 128.1, 109.8, 107.9, 72.2, 58.2, 56.3, 56.1, 20.7. HRMS (ESI, positive mode): calculated mass of C18H21NO7 (+Na): 386.1216, found: 386.1218. (2-((4,5-Dimethoxy-2-nitrobenzyl)oxy)-5-methyl-1,3-phenylene)bis(methylene)bis(α-bromo-2-methylpropanoate) (DMNB Bifunctional Initiator (7)). 3 (1.0 g, 2.7 mmol, 1 equiv), Et3N (1.2 mL, 8.2 mmol, 3 equiv), and DMAP (67 mg, 0.27 mmol, 0.2 equiv) were dissolved in anhydrous DMF (20 mL). After being purged with nitrogen, α-bromoisobutyryl bromide (1 mL, 8.2 mmol, 3 equiv) was added dropwise at 0 °C. After the addition, reaction mixture was allowed to heat to RT and stirred in the dark overnight. The crude mixture was filtered through Celite, which was further washed with EtOAc. Filtrate was washed with water and brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to afford the product as light yellow solid (1.4 g, 80% yield). 1H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H, arom H), 7.62 (s, 1H, arom H), 7.30 (s, 2H, arom H), 5.39 (s, 2H, arom−CH2−O−), 5.24 (s, 4H, arom− CH2−O−), 4.06 (s, 3H, CH3−O−arom), 3.98 (s, 3H, CH3−O− arom), 2.37 (s, 3H, CH3−arom), 1.89 (s, 12H, CH3−C). 13C NMR (CDCl3, 100 MHz): δ 171.6, 154.4, 153.8, 148.0, 138.7, 135.0, 132.3, 129.6, 128.8, 109.2, 108.2, 74.2, 63.1, 56.8, 56.6, 55.6, 30.8, 21.0. HRMS (ESI, positive mode): calculated mass of C26H31Br2NO9 (+Na): 682.0264, found: 682.0263. Synthesis of Nonphotoresponsive Control Initiator. (2(Benzyloxy)-5-methyl-1,3-phenylene)dimethanol (5). BHMPC 1 (3.0 g, 18 mmol, 1 equiv) was dissolved in 10 mL of DMF. K2CO3 (3.7 g, 27 mmol, 1.5 equiv) and benzyl bromide 4 (2.4 mL, 20 mmol, 1 equiv) were added, and reaction was stirred overnight at RT. The reaction mixture was diluted with 50 mL of DCM and filtered. Solvents were removed under reduced pressure, and product was purified by flash silica column with hexanes/EtOAc (1:1) as the eluting solvent. Product was obtained as a white solid (3.9 g, 85% yield). 1H NMR (CDCl3, 400 MHz): δ 7.46−7.37 (m, 5H, arom H), 7.16 (s, 2H, arom H), 4.95 (s, 2H, arom−CH2−O−), 4.68 (d, J = 5.4 Hz, 4H, arom−CH2−OH), 2.33 (s, 3H, CH3−arom), 2.00 (t, J = 5.8 Hz, 3H, arom−CH2−OH). 13C NMR (CDCl3, 100 MHz): δ 152.8, 137.0, 134.6, 134.1, 129.8, 128.9, 128.6, 128.3,77.1, 61.3, 21.0. HRMS (ESI, positive mode): calculated mass of C16H18O3 (+Na): 281.1154; found: 281.1161. (2-(Benzyloxy)-5-methyl-1,3-phenylene)bis(methylene)bis(αbromo-2-methylpropanoate) (8). 5 (1 g, 3.9 mmol, 1 equiv), Et3N (1.2 mL, 12 mmol, 3 equiv), and DMAP (95 mg, 0.8 mmol, 0.2 equiv) were dissolved in 25 mL of DCM. After being purged with nitrogen, α-bromoisobutyryl bromide (1.5 mL, 12 mmol, 3 equiv) was added dropwise at 0 °C. After the addition, reaction mixture was allowed to heat to RT and stirred for 4 h. The crude mixture was filtered through Celite, which was further washed with EtOAc. The

EXPERIMENTAL SECTION

Instrumentation and Methods. 1H and 13C NMR spectra were recorded on a Bruker Avance III 400 MHz spectrometer. Chemical shifts are reported in ppm and referenced to the solvents used: CDCl3 (1H, 7.26 ppm; 13C, 77.16 ppm) or DMSO-d6 (1H, 2.50 ppm; 13C, 39.52 ppm) and internal standard TMS (1H, 0.00 ppm). The molecular weight of the polymers that was polymerized by ATRP was determined by comparison of the peaks areas corresponding with polymer chain to the initiator’s peaks. High-resolution mass spectrometry (HRMS) analysis was conducted on an Autospec HRMS (EI) Micromass (UK) or a Synapt High Definition MS (ESI), Waters Inc. (USA). For Thin films perpetration the polymers were fully dissolved in ethyl acetate (50 mg/mL). 0.1 mL of the solution was spin-coated on glass slide (75 × 50 mm2) using a POLOS’s spin 150i POLOSPRO V3.16 spin coater at a spinning speed of 500 rpm (PS) or 300 rpm (PBnMA) for 30 s. To form 2.30 ± 0.30 μm thick films, a solution of 150 mg/mL was used. The film thickness determinations were performed by a Vecco WykoNT9100 interferometer. The irradiations as films and in solution were performed using a Luzchem LZC-4 V photoreactor equipped with eight LZCUVA lamps centered at 350 nm with a turntable. An average intensity of 7 ± 0.7 mW/cm2 was measured using an UVA power meter. Irradiation in solution was performed on 0.25 mg/mL for PS and 1 mg/mL for PBnMA in DCM in 1 cm2 quartz cuvettes with a screw cap. GPC measurements were recorded on a Viscotek GPCmax by Malvern using a Viscotek VE3580 refractive index detector equipped with two PSS GRAM 1000 Å and one PSS GRAM 30 Å column (operating temperature of 50 °C; running program: 90 min with mobile phase DMF + 50 mM ammonium acetate and flow rate of 0.5 mL/min). PS standards (purchased from Sigma-Aldrich) were used for calibration. Typically, the sample was dissolved in the mobile phase to afford a final concentration of 10 mg/mL for all polymers. The solution was filtered through 0.45 μm PTFE syringe filter, and then 25 μL was injected into the column. UV−vis spectra measurements were collected using a JASCO V-570 UV−vis−NIR spectrophotometer with a standard cuvette holder using quartz cuvettes or a JASCO PLH-356 film holder using quartz slide (20 × 20 mm2). Infrared spectra measurements were recorded on a NICOLET iS10 FT-IR equipped with an ATR iD5 diamond. All peak sizes were compared to the unchanged aliphatic hydrocarbons (1452 cm−1 for BnMA and 1455 cm−1 for PS). DSC measurements were performed using a METTLER TOLEDO’s DSC1 containing a HUBER TC100 chiller purged with 50 mL/min nitrogen gas. Tg was evaluated on the second heating cycle of a heating and cooling program of 20 °C/min in the −10 to 200 °C temperature range. General sample preparation: samples that were not exposed to a solvent were removed mechanically from the glass slide after irradiation. The other samples dissolved in DCM, and the solution was added dropwise to a 100 μL DSC aluminum pan heated to 50 °C. Typical sample weight: 5−10 mg. H


Macromolecules

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residue was washed with water and brine and dried over anhydrous Na2SO4, and solvents were removed under reduced pressure. Product was purified by flash silica column with hexanes/EtOAc (2:1) as the eluting solvent. Product was obtained as a white solid (1.4 g, 65% yield). 1H NMR (CDCl3, 400 MHz): δ 7.48−7.35 (m, 5H, arom H), 7.26 (s, 2H, arom H), 5.25 (s, 4H, arom−CH2−O−), 4.99 (s, 2H, CH2−O−arom), 2.35 (s, 3H, CH3−arom), 1.93 (s, 12H, CH3−C). 13 C NMR (CDCl3, 100 MHz): δ 171.6, 153.9, 137.0, 134.5, 131.7, 128.8, 128.5, 128.1,77.2, 63.1, 55.8, 31.0, 21.0. HRMS (EI, positive mode): calculated mass of C24H28Br2O5: 554.0335; found: 554.0303. General Procedure for Polymerization Using ATRP. CuBr (50 mg, 0.35 mmol, 1 equiv) was added to a dry Schlenk flask sealed with a rubber septum and deoxygenated using vacuum and nitrogen (three cycles). A deoxygenated mixture of PMDETA (73 μL, 0.35 mmol, 1 equiv) and monomers (preliminarily purified by aluminum oxide column), which were earlier purged with nitrogen, were added to the Schlenk flask using a degassed syringe and stirred for 15 min. A deoxygenated solution of bifunctional initiator (0.35 mmol, 1 equiv) was dissolved in the monomer solution, purged with nitrogen, and added to the Schleck flask, using a degassed syringe. The Schlenk flask was immersed in an oil bath preheated to 80 °C. Upon reaching the desired conversion, the reaction was stopped by cooling the reaction flask to 0 °C and addition of nonstabilized HPLC grade THF for PS or DCM for PBnMA. The crude mixture was filtered through a Celite and neutral aluminum oxide column. After evaporation of the filtrate solvents, residue was dissolved in DCM. The polymeric product was isolated using precipitation by dropwise addition into cold methanol. The filtered polymer was dried under high vacuum. Examples for Polymerization. PBnMA with DMNB-Based SelfImmolative Junction (DMNB−PBnMA) (Polymer 9). A total of 12 mL of BnMA was reacted according to the general polymerization procedure. PMDETA was added to 10 mL of BnMA, and 7 (230 mg) was dissolved in 2 mL of BnMA, which were added to the reaction vessel. The reaction mixture was stirred for 4 h. The polymer was obtained as white solid after purification and precipitation (11.9 g, quantitative yield). Mn = 34.1 kDa, Mw/Mn = 1.11. 1H NMR (CDCl3, 400 MHz): δ 7.73 (s, 1H, arom H), 7.61 (s, 1H, arom H), 7.27 (s, 980H, arom H), 7.14 (s, 2H, arom H), 5.54 (s, 2H, arom−CH2− O−), 5.30 (s, 4H, arom−CH2−O−), 4.88 (d, 392H, J = 10.1 Hz, −O−CH2−arom), 3.98 (s, 3H, CH3−O−arom), 3.90 (s, 3H, CH3− O−arom), 2.29 (s, 3H, CH3−arom), 1.86−1.77 (m, 392H, CH2−C), 1.34 (s, 12H, (CH3)2C), 1.01−0.91 (m, 588H, CH3−C). 13C NMR (CDCl3, 100 MHz): δ 177.8, 177.5, 177.4, 177.3, 177.2, 177.1, 176.7, 176.5, 175.8, 154.4, 148.0, 135.9, 135.6, 135.3, 128.7, 128.5, 128.4, 128.3, 108.2, 98.6, 73.8, 70.8, 68.1, 67.8, 67.6, 66.9, 56.7, 56.5, 54.6, 54.3, 5.2, 53.0, 52.6, 50.8, 45.9, 45.3, 45.2, 45.0, 44.9, 41.7, 33.4, 23.0, 29.3, 25.8, 23.5, 22.4, 21.6, 21.2, 18.7, 18.6, 16.7. Polystyrene with DMNB-Based Self-Immolative Junction (DMNB−PS) (Polymer 14). A total of 8 mL of styrene was reacted according to the general polymerization procedure. PMDETA was added to 5 mL of styrene, and 7 (230 mg) was dissolved in 3 mL of styrene. The reaction mixture was stirred for 7 h, and the polymer was obtained as white solid after purification and precipitation (850 mg, 61% yield). Mn = 4.1 kDa, Mw/Mn = 1.19. 1H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H, arom H), 7.49 (s, 1H, arom H), 7.26−7.12 (m, 93H, arom H), 6.60 (m, 62H, arom H), 5.10 (s, 2H, arom−CH2− O−), 4.56−4.28 (m, 4H, arom−CH2−O−), 3.98 (s, 3H, CH3−O− arom), 3.93 (s, 3H, CH3−O−arom), 2.29 (s, 3H, CH3−arom), 1.88 (m, 31H, CH2−CH−C), 1.47 (m, 62H, C−CH2−CH), 0.86 (t, 12H, J = 17.4 Hz, CH3−C). 13C NMR (CDCl3, 100 MHz): δ 177.0, 154.4, 147.9, 145.5, 138.4, 134.3, 131.0, 130.1, 129.4, 128.1, 126.4, 125.8, 108.9, 108.0, 73.4, 60.8, 56.7, 56.5, 52.6, 46.6, 46.1, 44.4, 41.7, 40.5, 21.1. The characterization and exact polymerization conditions for the other polymers appear in the Supporting Information.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b02566. Additional experimental procedures, NMR characterization, UV−vis, IR spectra, and DSC analysis (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected]. *E-mail [email protected]. ORCID

Roey J. Amir: 0000-0002-8502-3302 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Soreq NRC for funding this research. R.J.A. thanks the Israel Science Foundation for supporting this research (grant No. 1553/18). G.S. thanks the Marian Gertner Institute for Medical Nanosystems in Tel Aviv University for their financial support. N.E.P. thanks the support of The Shulamit Aloni Scholarship for Advancing Women in Exact Science and Engineering, provided by The Ministry of Science & Technology, Israel.

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REFERENCES

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Utilizing Self-Immolative ATRP Initiators To Prepare Stimuli

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