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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Polym Sci A Polym Chem. Author manuscript; available in PMC 2012 October 23.
Published in final edited form as:
J Polym Sci A Polym Chem. 2012 June 15; 50(12): 2319–2329.
doi:  10.1002/pola.25989
PMCID: PMC3478948
NIHMSID: NIHMS408303

Clickable Amphiphilic Triblock Copolymers

Abstract

Amphiphilic polymers have recently garnered much attention due to their potential use in drug-delivery and other biomedical applications. A modular synthesis of these polymers is extremely desirable since it offers precise individual block characterization and increased yields. We present here for the first time a modular synthesis of poly(oxazoline)-poly(siloxane)-poly(oxazoline) block copolymers that have been clicked together using the copper-catalyzed azide-alkyne cycloaddition reaction. Various click methodologies for the synthesis of these polymers have been carefully evaluated and optimized. The approach using copper nanoparticles was found to be the most optimal among the methods evaluated. Furthermore, these results were extended to allow for a reactive Si-H group-based siloxane middle block to be successfully clicked. This enables the design of more complex amphiphilic block copolymers that have additional functionality, such as stimuli responsiveness, to be synthesized via a simple hydrosilylation reaction.

Keywords: Triblock copolymers, click chemistry, self-assembly

Introduction

Self-assembly on the nano-scale is a key property that Nature relies on to generate biological membranes. These membranes provide a structural framework via a microenvironment and a functional framework by incorporation of channels, receptors and pumps. By exploiting hydrophobic-hydrophilic interactions these membranes assemble into bilayers and other structures. If we hope to mimic the principles of natural nanoarchitectures the self-assembling membrane is a critical component. Recently, a plethora of polymeric systems have successfully exploited self-assembly for the purposes of drug-delivery,1 biomedical coatings,2 virus assisted gene delivery,3 and nanoreactors.4 These are amphiphilic diblock or triblock copolymers that self-assemble into micelles, worm-like micelles, tubular structures, membranes or vesicles in a suitable solvent.5 Recently, click chemistry has found considerable use in polymer-polymer conjugation via the copper-catalyzed azide-alkyne cycloaddtion (CuAAC) reaction.6 Click-based conjugation allows for the modular synthesis of block copolymer architectures with well-defined block lengths and end-groups. This allows for systematic investigation of the effect of a single parameter variation on the self-assembling properties of the macromolecular system. For example, by using individually well-characterized hydrophobic and hydrophilic blocks, the effect of the hydrophilic block length on the self-assembling properties could be studied. This exquisite level of control allows for sophisticated scientific exploration and will enable the understanding of the underlying structure-function relationships that influence the physics of self-assembly in these macromolecules.

Though there are myriad block copolymer architectures, the ABA triblock copolymer is particularly attractive from a self-assembly standpoint due to its inherent ability to form vesicular structures, albeit with high hydrophobic to hydrophilic ratios.7 From a biomedical perspective, the pseudo-polypeptide architecture offered by poly(oxazoline) is particularly attractive and was chosen as the hydrophilic A-block.8 Poly(siloxane)s, especially those that contain at least one methyl group, exhibit very low glass transition temperatures and are mostly liquids at room temperatures, due to the partial ionic character of the Si-CH3 bond.9 Furthermore poly(siloxane)s have very low surface energy and are extremely hydrophobic, thus they were chosen as the B-block. This ABA block copolymer system has been studied by our group and others using a macroinitiation-based synthesis scheme and has been shown to possess interesting biomedical and self-assembling properties.1014 However, macroinitiation-based schemes suffer from low yield and poor repeatability. To increase yield and enable accurate molecular weight control of the hydrophilic blocks, we envisioned that a modular click-based approach would be superior. In this paper, we report for the first time a facile and versatile click-based methodology for the synthesis of poly(oxazoline)-poly(siloxane)-poly(oxazoline)-based block copolymers (Scheme 1).

Scheme 1
Schematic view of our click-based triblock copolymer synthesis. The A-blocks bear an alkyne terminal group, while the B-blocks are terminated with azides. The two blocks are clicked via a Copper catalyzed azide-alkyne click reaction. The blocks can be ...

Results and Discussion

Though our main objective was to demonstrate the synthesis of amphiphilic ABA triblock copolymers that contain a poly(siloxane) B-block and poly(oxazoline) A-blocks (Scheme 2), we used a cohesive approach that optimized every step. We began with the synthesis of two telechelic bis-azide poly(siloxane) B-blocks; one consists of poly(dimethylsiloxane) (PDMS), the other is a copolymer of dimethylsiloxane and methylhydrosiloxane (P(DMS-co-MHS)), with free Si-H groups available for further derivatization. Synthesis of the poly(methyloxazoline) (PMOXA) A-block with alkyne functionality was accomplished in high yield using a propargyl tosylate initiator. We envisioned the alkyne end-group allowing for facile and modular attachment of a PMOXA block to each end of the bis-azide poly(siloxane)s block via CuAAC. The bis-azide PDMS was used as a model for CuAAC reactions with PMOXA, with that methodology later applied to the more functionally complex P(DMS-co-MHS) copolymer. The polymer-polymer conjugation of these blocks was thoroughly investigated using an array of CuAAC click conditions.

Scheme 2
Synthesis of ABA triblock copolymer from alkyne-functionalized poly(oxazoline) A-block and bis-azide poly(siloxane) B-block homopolymers via copper-catalyzed alkyne-azide cycloaddtion reaction.

Synthesis of Bi-functional Disiloxane End-blockers

The synthesis of bi-functional poly(siloxane)s were achieved via cationic ring-opening polymerization (CROP) of cyclic siloxane monomers, terminated by a short-chain disiloxane (Scheme 3). This short-chain disiloxane is commonly referred to as the end-blocker since it serves as the end-groups of poly(siloxane) and also terminates the polymerization. The reactivity of short-chain disiloxanes is higher than the corresponding cyclic in a CROP, allowing the disiloxane to serve as an initiator.15 Acid-labile Si-O bonds are constantly broken and reformed during the cationic polymerization, thus the acid-stable Si-C bonds of the end-blocker terminate the growing chain and serve as end-groups.15 Bis-tosylate end-blocker (2) was synthesized from commercially available 1,3-bis(4-hydroxybutyl)tetramethyldisiloxane (1). Previously, we reported the synthesis of tosylate end-blockers that suffered from poor yields.14 This was primarily due to acidic cleavage of the highly acid-labile disiloxane bond, probably due to the hydrochloric acid by-product produced during the course of the reaction, and/or acidic cleavage by silica chromatography used for purification. The addition of 10 equivalents of triethylamine (rather than the 4 equivalents of triethylamine used previously) ensured neutralization of the hydrochloric acid by-product during the course of the reaction. Siloxane cleavage during purification was circumvented by passing the crude product through a silica gel plug that had been deactivated by spinning in a triethylamine solution. These additional steps reduced the acidic cleavage of disiloxane, providing the bis-tosylate end-blocker in an improved yield of 70%. Bis-iodide end-blocker (3) was synthesized in 70% yield, by conversion of the hydroxyl groups of 1 using a known iodination procedure.16

Scheme 3
Synthesis of bis-azide poly(siloxane) B-blocks 6 and 7 via cationic ring-opening polymerization of cyclic siloxane monomers using the end-blocker method.

Synthesis of Bi-functional Poly(siloxane)s

Bi-functional poly(siloxane)s were synthesized rapidly and in excellent yields via CROP of cyclic siloxane monomers (Scheme 3). Molecular weight control was achieved using the end-blocker method. When octamethylcyclotetrasiloxane (D4) was used as the siloxane monomer and bis-tosylate disiloxane (2) as the end-blocker, TsO-PDMS-OTs (4) was synthesized in high yield. Using bis-iodide disiloxane end-blocker (3) with a combination of D4 and 1,3,5,7-tetramethylcyclotetrasiloxane (D4H) afforded the copolymer of dimethylsiloxane and methylhydrosiloxane, I-P(DMS-co-MHS)-I (5). Bis-iodide disiloxane (3) was used as the end-blocker for the siloxane copolymer synthesis as opposed to bis-tosylate disiloxane (2), which allows for room-temperature conversion of the poly(siloxane) end-groups to azides. This prevents undesired heat-activated reaction pathways that give rise to side-products as discussed in the next section. Our group previously reported the synthesis of a TsO-P(DMS-co-MHS)-OTs polymer that employed a bis-tosylate end-blocker and used p-toluenesulfonic acid as the catalyst.14 However, this method suffered from moderate yields and long reaction times, with subsequent experiments revealing incomplete monomer consumption and precipitation of the acid catalyst, indicating the need for a different acid catalyst. When bulk polymerizations of siloxanes were conducted using sulfuric acid as the ring-opening catalyst at 80°C, the reactions proceeded overnight in excellent yields with high monomer consumption, probably due to the better solubility of the acid catalyst. 1H NMR was used to monitor reaction progress. After removal of unreacted cyclics in-vacuo, followed by aqueous workup, the poly(siloxane)s were provided. TsO-PDMS-OTs (4) was synthesized in 94% yield with Mn~5300, while I-P(DMS-co-MHS)-I (5) was synthesized in 96% yield with Mn~5300. Molecular weights of the poly(siloxane)s were determined by 1H NMR using end-group analysis.

Synthesis of Bis-azide Poly(siloxane)s

Poly(siloxane)s were converted into clickable partners for the alkyne-functionalized poly(oxazoline) A-blocks by conversion of the iodide or tosylate end groups into azides, using sodium azide (Scheme 3). Although we experienced no safety issues when handling azides, we chose to convert the poly(siloxane)s end-groups to azides post polymerization because azides can be explosive - especially under acidic conditions.17 The tosylate end-groups of TsO-PDMS-OTs (4) were easily converted to azides via nucleophilic substitution using sodium azide at 60°C to give N3-PDMS-N3 (6) in high yield. DMF is the classic solvent used for this reaction,17 though the insolubility of siloxanes in DMF required a binary solvent system of THF:DMF v/v 2:1 to ensure complete solubility of the siloxanes. However, when azide substitution was conducted on I-P(DMS-co-MHS)-I (5) using the same procedure, 1H NMR revealed the Si-H peak at 4.7 ppm was perturbed (Figure 1). Poly(methylhydrosiloxane) is a known reducing agent18 and thus interacted with radicals produced during the reaction. We therefore hypothesized an antioxidant radical scavenger such as Ethylenediaminetetraacetic acid (EDTA) would preserve the Si-H groups. Indeed, when the reaction was repeated with the addition of EDTA, 1H NMR revealed the Si-H peaks were unaffected while the desired substitution at the end-groups occurred quantitatively to give N3-P(DMS-co-MHS)-N3 (7). In addition, we attempted an azide substitution reaction on a TsO-P(DMS-co-MHS)-OTs polymer using the conditions used to synthesize 7, but found that conversion to the azide was incomplete at room temperature. Upon heating to 60°C conversion to the azide proceeded to completion, however the Si-H peaks were perturbed in a similar manner to Figure 1. Hence, as mentioned earlier, we chose to use iodo-functionalized end-blockers when reactive Si-H groups were present. Azide conversion of 6 and 7 was further supported by FTIR spectroscopy with the appearance of an azide peak at 2096 cm−1 (see supporting information).

Figure 1
1H NMR spectra of the Si-H peak of I-P(DMS-co-HMS)-I (5) and N3-P(DMS-EDTA was included. The peak was perturbed when EDTA was not present, but remained unaffected with EDTA in the reaction. co-HMS)-N3 (7) when EDTA was not added to the substitution reaction ...

Synthesis of Alkyne-functionalized Poly(methyloxazoline)

The hydrophilic PMOXA A-block was synthesized via CROP using a propargyl tosylate initiator, which ensured terminal alkyne functionality on one end of the polymer (Scheme 4). Tosylation of propargyl alcohol proceeded rapidly and in good yield at 0°C when a bi-phasic solvent system of NaOH (aq) and THF was used. Tosylation of alcohols are generally carried out with an excess of tosyl chloride, however chromatography is usually required to remove unreacted tosyl chloride. Using a slight excess of propargyl alcohol ensured complete tosyl chloride consumption while allowing for easy removal of excess propargyl alcohol by aqueous workup to provide propargyl tosylate (8) in 85% yield.

Scheme 4
Synthesis of alkyne-functionalized poly(methyloxazoline) (9) was achieved via cationic ring-opening polymerization of 2-methyl-2-oxazoline using propargyl tosylate (8) initiator.

Preparation of PMOXA with an acetylene end-group using a microwave irradiation approach has been previously published.20 In contrast, our synthesis used conventional methods and is described next. Propargyl tosylate (8) was kept under reduced pressure overnight to remove trace water, freshly distilled 2-methyl-2-oxazoline was then added to a solution of the tosylate initiator in acetonitrile and heated to 80°C. After 16 hours, 1H NMR revealed quantitative initiation along with complete monomer consumption. Choosing the correct termination procedure is of the utmost importance as side reactions with the acetylene end-group occur with certain popular oxazoline terminating methods. For example, termination with methanolic potassium hydroxide19 resulted in a side reaction at the acetylene group – as evidenced by the absence of acetylene peaks in 1H NMR. Termination with water is another popular method,20 however this does not lead to well defined end-groups.21 Secondary amines are an ideal choice for termination due to their good nucleophilicity, thus the living chain ends of PMOXA were terminated with piperidine. The resulting piperidine salt can be deprotonated with potassium carbonate,22 but doing so in situ resulted in a side reaction at the acetylene group. Therefore, excess piperidine must be removed before adding potassium carbonate to ensure no side reactions occur. 1H NMR was used to follow the termination progress as a shift in peaks was seen with each termination step (see supporting information). After workup, PMOXA (9) was obtained in quantitative yield. End-group analysis using 1H NMR revealed Mn~1350, close to the expected Mn of 1500, and GPC indicated a PDI of 1.17 using a poly(styrene) standard.

Synthesis of PMOXA-PDMS-PMOXA Triblock Copolymer via CuBr/PMDETA Method

Polymer-polymer conjugation of amphiphilic blocks is especially challenging due to the inherent incompatibility of the blocks. We explored several popular CuAAC methods including Copper(I) salt with an amine ligand, Copper(II) salt in conjunction with a reducing agent, and a heterogeneous coupling catalyst, namely copper nanoparticles. 1H NMR was used to monitor reaction progress for all click reactions utilizing the appearance of the triazole-CH2-PMOXA peak at 4.58 ppm as a standard for percent conversion to triazole from azide. The results of all methods studied are shown in Table 1.

Table 1
Results for the formation of PMOXA-PDMS-PMOXA (10) and PMOXA-P(DMS-co-HMS)-PMOXA (11) triblock copolymers using various CuAAC methods.

Click reactions with polymer applications frequently employ CuBr/PMDETA as the catalyst,23 thus we attempted to conjugate homopolymers PMOXA (9) and N3-PDMS-N3 (6) using this catalytic method. Although tetrahydrofuran and dimethylformamide are frequently used solvents, we found the toulene:dimethylformamide v/v 1:1 solvent system was most effective since toluene is a theta solvent for siloxanes.24 Many CuAAC reactions are known to proceed at room temperature, however full conjugation did not occur at room temperature-even after 2 days. Thus heat was required to drive the reaction to completion. Quantitative conversion occurred after 1 hour using 1 equivalent of N3-PDMS-N3 (6) and 2 equivalents of PMOXA (9), circumventing the need for an excess of either block. These results were confirmed by 1H NMR with the disappearance of the PDMS-CH2-azide peak at 3.3 ppm and PMOXA-CH2-alkyne peak at ~4.0–4.3 ppm, coupled with the appearance of triazole peaks at ~4.2–4.6 ppm and 7.6 ppm (Figure 2). Further evidence was provided by FTIR spectroscopy with the disappearance of the azide peak at 2096 cm−1 (see supporting information). Although conversion was quantitative and rapid, the reaction yielded a dark-green product due to the presence of copper, which was rather difficult to purify.

Figure 2
1H NMR spectra of N3-PDMS-N3, 6 (a), PMOXA, 9 (b), and CuAAC product PMOXA-PDMS-PMOXA, 10 (c). The disappearance of azide and alkyne peaks along with the appearance of triazole peaks indicated quantitative conversion to the triazole click product (see ...

Removal of copper contaminate from PMOXA-PDMS-PMOXA (10) was challenging for two reasons. Firstly, the polyamide functionality of PMOXA can chelate copper, making its disassociation from the polyamide difficult. Secondly, any attempt to remove copper in a solvent that does not solubilize both blocks can cause polymer aggregation, allowing the copper to be “hidden” in the polymer aggregate. Efficient copper removal from CuBr/PMDETA click reactions proved unsuccessful-even after purification steps such as EDTA (aq) wash, solvent precipitation, soxhlet extraction, silica chromatography, alumina chromatography, or the use of Dowex M4195 chelating resin.25 Sodium sulfide has been used for removal of copper from amine groups,26 owing to the insoluble copper sulfide salt that is formed. When 1 equivalent (to copper) of 1M Na2S (aq) was added to a solution of copper-contaminated triblock in dichloromethane, a brown solution immediately formed along with the insoluble copper sulfide, which was removed by filtration. Although copper was successfully removed using this method, the product was pale orange, indicating the presence of trace amounts of sulfur.

Synthesis of PMOXA-PDMS-PMOXA Triblock Copolymer via CuSO4/Sodium L-ascorbate Method

Both PDMS27 and PMOXA20 have been used successfully in CuAAC reactions using the CuSO4/sodium L-ascorbate (Cu/Asc) method, leading us to consider it for PMOXA-PDMS-PMOXA triblock synthesis. Most conditions involve a binary solvent system that includes water, which serves to solubilize Cu/Asc. All attempts to synthesize triblock 10 using an aqueous-based binary solvent system were met with moderate conversion <60%. We reasoned that the extreme hydrophobicity of poly(siloxane) causes self-aggregation in the presence of water, thus hiding the azide end-groups and preventing the reaction from proceeding to completion. We therefore attempted the CuAAC reaction in ethanol, which has the ability to solubilize both blocks, minimizing self-aggregation. Despite the heterogeneous nature of Cu/Asc in ethanol, the CuAAC reaction occurred quantitatively in 2 hours at 60°C. Furthermore, the product can be isolated by simple filtration, albeit the triblock polymer was yellow/green - indicating the presence of trace amounts of copper. When CuSO4 was used as the catalyst, in the absence of sodium L-ascorbate reducing agent, the reaction proceeded to 50% completion after 2 hours, and quantitative completion in 15 hours at 60°C. This reaction was also successful when acetone, 2-propanol, or chloroform was used as the solvent system.

The heterogeneous nature of Cu/Asc in ethanol led us to attempt our conjugation reactions using copper nanoparticles (CuNPs), owing to their use in the synthesis of block copolymers.28 When the CuAAC reaction was conducted using CuNPs in ethanol with 1 equivalent of N3-PDMS-N3 (6) and 2 equivalents of PMOXA (9) at 60°C, 1H NMR revealed quantitative conjugation after 2 hours (Scheme 5). Furthermore, after removal of the CuNPs via filtration, triblock copolymer 10 was obtained as a beige solid, unlike the yellow, green or blue products of previous methods, indicating negligible copper contamination.

Scheme 5
Synthesis of PMOXA-PDMS-PMOXA (10) and PMOXA-P(DMS-co-PHS)-PMOXA (11) was achieved via CuAAC using CuNPs as the catalyst.

Synthesis of PMOXA-P(DMS-co-PHS)-PMOXA Triblock Copolymer

The click methodology used for the synthesis of triblock 10 containing a PDMS B-block was employed for the conjugation of N3-P(DMS-co-MHS)-N3 (7) and PMOXA (9). Silanes are often used as reducing agents in organometallic chemistry,18 therefore complications during the CuAAC reactions due to the presence of copper were anticipated. Furthermore, Copper(I) can also act as a hydrosilylation catalyst.29 Indeed, when the aqueous Cu/Asc procedure was applied to the synthesis of PMOXA-P(DMS-co-MHS)-PMOXA (11), an insoluble product was produced indicating significant cross-linking of the Si-H groups of the poly(siloxane) block. When the click reaction was conducted using CuNPs in ethanol at 60°C conjugation was quantitative after 2 hours (Scheme 5). However, 1H NMR showed the Si-H peak was perturbed in a similar manner that occurred during azide substitution seen previously (Figure 1). As with the synthesis of N3-P(DMS-co-MHS)-N3 (7), the addition of EDTA to the CuAAC reaction using CuNPs preserved the integrity of the Si-H groups due to EDTA’s radical scavenging ability. Using CuNPs as the catalyst with EDTA in ethanol at 60°C, PMOXA-P(DMS-co-MHS)-PMOXA (11) was obtained after 2 hours as a beige solid in quantitative yield, as confirmed by 1H NMR (Figure 3).

Figure 3
1H NMR spectrum of PMOXA-P(DMS-co-HMS)-PMOXA (11) triblock copolymer.

In all of our triblock preparations, the proof of triblock rather than a diblock formation was gleaned by carefully comparing the integration of the Si-CH3 protons of the poly(siloxane)s block to the N-CH2-CH2 and O=C-CH3 protons of the poly(oxazoline) block using 1H NMR. The integration of the Si-CH3 protons in the triblock were set to the value obtained for the poly(siloxane) homopolymer and the resulting value of the poly(oxazoline) protons in the triblock integrated to twice the value (within experimental error) of that obtained from the poly(oxazoline) homopolymer. The procedure for the NMR based triblock validation is as follows: The integration of the proton peak closest to the azide end-group (Si-CH2-CH2-CH2-CH2-N3) was set to 4, since there are two end-groups, this resulted in an integration of 438 for the Si-CH3 protons of N3-P(DMS-co-HMS)-N3 (7). Similarly, using the proton peak next to the alkyne initiator (OTs-CH2-alkyne), the integration of the N-CH2-CH2 protons of poly(oxazoline) (9) was determined to be 64. When the integration of the Si-CH3 protons in the triblock were set to 438, the integration of the N-CH2-CH2 protons of the triblock resulted in a value of 128, double the integration for the poly(oxazoline) homopolymer, thereby confirming triblock formation. The proton integration values yield a Mn of ~ 8000g/mol for the triblock.

This clearly indicates triblock formation and further lends credence to power of the modular approach. Such characterization is not trivial, since in a macrointiation method it could always be argued that the hydrophilic block is just longer than anticipated. Furthermore, the amphiphilic nature of these polymers does not allow for corroboration using classical characterization techniques such as GPC due to aggregation in the column. This coupled with the excellent PDI of the poly(oxazoline), obtained due to the modular synthesis, makes the click-based approach very attractive for synthesizing this family of triblock polymers.

Self-assembly of Triblock Copolymer

The ability of amphiphilic ABA triblock copolymers to self-assemble into higher architectures is well known,5 thus vesicles of PMOXA-PDMS-PMOXA (10) were prepared by an ethanol injection method.7 Briefly, an ethanolic solution of the triblock was dropped into water under vigorous stirring and then filtered through a 200 nm filter. Vesicle size in solution was determined using dynamic light scattering (DLS), which revealed the hydrodynamic diameter of these vesicles to be 80 nm (see supporting information). Vesicles were also imaged using transmission electron microscopy (TEM) and shown to posses an average diameter of 150 nm (Figure 4). The flattening of the vesicles under drying accounts for the larger vesicle size observed with TEM.

Figure 4
Transmission electron micrograph of PMOXA-PDMS-PMOXA (10) triblock copolymer vesicles showing the self-assembling nature of these amphiphilic copolymers.

Experimental

Materials

Propargyl alcohol (Aldrich, 99%), p-toluenesulfonyl chloride (TsCl) (Alfa Aesar, 98%), 4-(dimethylamino)pyridine (DMAP) (Fluka, 99%), benzyltrimethylammonium chloride (Alfa Aesar, 97%), sodium hydroxide (NaOH) (Fisher Chemical), sodium sulfate anhydrous (Na2SO4) (Fisher Chemical, 99%), potassium carbonate anhydrous (K2CO3) (Fisher Chemical), 1,3-bis(4-hydroxybutyl)tetramethyldisiloxane (Gelest, 95%), sodium azide (NaN3) (Sigma-Aldrich, 99.8%), sulfuric acid (H2SO4) (Fisher Chemical, 98%), Ethanol (EtOH) (Gold Shield, 200 proof), copper(II) sulfate (CuSO4) (Sigma-Aldrich, 99%), (+)-sodium L-ascorbate (Aldrich, 99%), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA) (Aldrich, 99%), triethylamine (TEA) (Fisher Chemical), sodium sulfide nonahydrate (Na2S•9H2O) (Sigma-Aldrich, 98%), iodine (I2) (Sigma-Aldrich, 99%), triphenylphosphine (PPh3) (Sigma-Aldrich, 99%), imidazole (Sigma-Aldrich, 99%), ethylenediaminetetraacetic acid (EDTA) (Sigma-Aldrich, 99–100%), Copper nanopowder (CuNPs) (Aldrich, <50 nm particle size (TEM), 99.5%) were used as received. Copper(I) bromide (CuBr) (Sigma-Aldrich, 98%) was purified by stirring in glacial acetic acid overnight and washing with ethanol then diethyl ether. Silica gel (Silicycle, 230–400 mesh) was deactivated by spinning in an appropriate amount of TEA:Hexanes v/v 5:95 solution for 10 minutes followed by filtration and several washes with hexanes. 2-Methyl-2-oxazoline (Aldrich, 98%) was purified by stirring in calcium hydride (CaH2) overnight then fractionally distilling through a 10 cm vigreux column under argon. Piperidine (Sigma-Aldrich, 99%) was distilled under argon from CaH2. Octamethylcyclotetrasiloxane (D4) (Gelest, 95%) and 1,3,5,7-tetramethylcyclotetrasiloxane (D4H) (Gelest) were distilled from CaH2 under reduced pressure. Tetrahydrofuran (THF), dichloromethane (DCM), toluene (PhMe), acetonitrile (MeCN) and N-N-dimethylformamide (DMF) were obtained from a PureSolv solvent purification system.

Instrumentation

1H NMR spectra were recorded on a Bruker Avance DMX500MHz SB NMR Spectrometer or Varian VNMRS 600MHz SB NMR Spectrometer using solutions of samples in deuterated chloroform. Fourier transform infrared spectra (FTIR) were recorded using a Nicolet Magna 850 FTIR Spectrometer. Gel permeation chromatography (GPC) studies were preformed using a Waters 2695 Separation Module equipped with a 2414 Refractive Index Detector and 2996 Photodiode Array Detector. Dynamic light scattering (DLS) experiments were obtained on a DynaPro NanoStar from Wyatt Technology. HRMS data was obtained using A Waters GCT Premier high resolution Time-of-flight mass spectrometer. Transmission electron microscopy (TEM) images were obtained using a FEI Tecnai G2 Sphera Microscope.

Synthesis of Bis-tosylate Disiloxane End-blocker (2)

1,3-Bis(4-hydroxybutyl)tetramethyldisiloxane (1) (8.36 g, 30 mmol, 1 equiv) was dissolved in DCM (150 mL) and cooled to 0°C. TsCl (14.30 g, 75 mmol, 2.5 equiv) and DMAP (0.73 g, 6.0 mmol, 0.2 equiv) were added followed by TEA (42 mL, 300 mmol, 10 equiv) dropwise at which time a pale yellow precipitate developed. The reaction was kept at 0°C, and after 2 hours thin layer chromatography (TLC) showed complete disappearance of the starting material in addition to the appearance of bis-tosylate. The slurry was filtered and the DCM layer washed with H2O, brine, dried over Na2SO4 and concentrated to yield a crude yellow oil. This oil was purified by passing through a short plug of deactivated silica gel to give a pale yellow oil. Yield: 11.77 g (70%).

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, 4H; arom. H), 7.33 (d, 4H; arom. H), 4.03 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 2.45 (s, 6H; -Ph-CH3), 1.65 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 1.31 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 0.42 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), −0.01 (s, 12H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs). 13C NMR (600 MHz, CDCl3): δ = 144.8 (arom. C), 133.5 (arom. C), 130.0 (arom. C), 128.0 (arom. C), 70.5 (-Ph-CH3), 32.4 (-Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 21.8 (-Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 19.4 (-Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 17.8 (-Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 0.41 (-Si(CH3)2-CH2-CH2-CH2-CH2-OTs). HRMS (m/z): cacd for C26H42O7S2Si2, 586.19; found, 609.18 [M+Na]+.

Synthesis of Bis-iodide Disiloxane End-blocker (3)

PPh3 (31.5 g, 120 mmol, 4 equiv) and imidazole (10.8 g, 159 mmol, 5.3 equiv) were dissolved in Et2O:MeCN v/v 3:1 (151 mL). The solution was cooled to 0°C, iodine (30.5 g, 120 mmol, 4 equiv) was added, and the solution was allowed to stir for 20 minutes. 1,3-Bis(4-hydroxybutyl)tetramethyldisiloxane (1) (8.37 g, 30 mmol, 1 equiv) was added dropwise at 0°C, after which the solution was allowed to warm to room temperature. After 1 hour TLC showed complete consumption of the starting material. The precipitate was filtered off and the filtrate concentrated. The resulting solid was recrystallized in hexanes then filtered and the solvent concentrated to give a clear oil. This oil was dissolved in hexanes and washed with Na2S2O3 (aq), H2O, brine, dried over Na2SO4 and concentrated to yield a clear oil. Yield: 10.4 g (70%).

1H NMR (500 MHz, CDCl3): δ = 3.21 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 1.84 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 1.44 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 0.52 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 0.07 (s, 12H; -Si(CH3)2-CH2-CH2-CH2-CH2-I). 13C NMR (600 MHz, CDCl3): δ = 36.9 (-Si(CH3)2-CH2-CH2-CH2-CH2-I), 24.4 (-Si(CH3)2-CH2-CH2-CH2-CH2-I), 17.3 (-Si(CH3)2-CH2-CH2-CH2-CH2-I), 7.17 (-Si(CH3)2-CH2-CH2-CH2-CH2-I), 0.53 (-Si(CH3)2-CH2-CH2-CH2-CH2-I). HRMS (m/z): cacd for C12H28I2OSi2, 497.98; found, 482.96 [M-CH3]+.

Synthesis of TsO-PDMS-OTs (4)

Bis-tosylate end-blocker (2) (1.96 g, 3.34 mmol, 1 equiv) was added to an oven-dried round bottom flask with a stir bar and stirred at 60°C under reduced pressure for 2.5 hours to remove trace water. The flask was cooled to room temperature, freshly distilled D4 (19.65 mL, 63.3 mmol, 19 equiv) was added, and the mixture was stirred at room temperature for 15 minutes. H2SO4 (0.15 mL, 2.8 mmol, 0.84 equiv) was then added dropwise, at which time the solution became viscous. The reaction was subsequently heated to 80°C. After 17 hours an aliquot was taken for 1H NMR, which indicated complete monomer consumption. Unreacted D4 was removed in vacuo and the polymer was isolated by dissolving in hexanes and washing with H2O, MeOH, brine, dried over Na2SO4 and concentrated to give a clear viscous oil. Yield: 18.86 g (94%), Mn,1H NMR~5300.

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, 4H; arom. H), 7.33 (d, 4H; arom. H), 4.03 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 2.45 (s, 6H, -Ph-CH3), 1.66 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 1.34 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 0.46 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-OTs), 0.071 (br. s, 432H; -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2963 (aliphatic C-H), 1446 (aromatic C=C), 1413 (CH2), 1372 (sulfonyl), 1261 (Si(CH3)2-O), 1098 (Si(CH3)2-O in poly(siloxane)s, 809 (Si(CH3)2).

Synthesis of I-P(DMS-co-MHS)-I (5)

Bis-iodide end-blocker (3) (2.49 g, 5.00 mmol, 1 equiv) was added to an oven-dried round bottom flask with a stir bar and stirred at 60°C under reduced pressure for 2.5 hours to remove trace water. The flask was cooled to room temperature, freshly distilled D4 (20.17 mL, 65.0 mmol, 13 equiv) was added, followed by freshly distilled D4H (9.76 mL, 40.0 mmol, 8 equiv), and the mixture was stirred at room temperature for 15 minutes. H2SO4 (0.15 mL, 2.8 mmol, 0.84 equiv) was added dropwise at which time the solution became viscous. The reaction was heated to 80°C and after 16 hours an aliquot was taken for 1H NMR that indicated complete monomer consumption. Unreacted D4 and D4H were removed in vacuo and the polymer was isolated by dissolving in hexanes and washing with H2O, MeOH, brine, dried over Na2SO4 and concentrated to give a clear viscous oil. Yield: 28.84 g (96%), Mn,1H NMR~5300.

1H NMR (600 MHz, CDCl3): δ = 4.70 (t, 24H; -Si-H), 3.19 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 1.84 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 1.45 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 0.55 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-I), 0.076 (m, 392H; -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2964 (aliphatic C-H), 2160 (silane), 1348 (CH2), 1261 (Si(CH3)2-O), 1096 (Si(CH3)2-O in poly(siloxane), 800 (Si(CH3)2).

Synthesis of N3-PDMS-N3 (6)

TsO-PDMS-OTs (4) was dissolved in THF (20 mL) then DMF (10 mL) was added, followed by NaN3 (0.18 g, 2.83 mmol, 3 equiv) at room temperature. The mixture was heated to 60°C and after 22 hours 1H NMR showed complete conversion to the bis-azide. The white precipitate that developed during the reaction was filtered off and THF was removed under reduced pressure. The mixture was diluted with hexanes then placed in a separatory funnel and the DMF was removed. The hexanes layer was washed with H2O × 3, brine, dried over Na2SO4 and concentrated to give a clear oil. Yield: 4.56 g (91%).

1H NMR (500 MHz, CDCl3): δ = 3.26 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 1.63 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 1.42 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 0.56 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 0.071 (br. s, 432H -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2963 (aliphatic C-H), 2097 (azide N3), 1413 (CH2), 1261 (Si(CH3)2-O), 1019 (Si(CH3)2-O in poly(siloxane)s, 800 (Si(CH3)2).

Synthesis of N3-P(DMS-co-MHS)-N3 (7)

I-P(DMS-co-MHS)-I (5) was dissolved in THF (20 mL) then DMF (10 mL) was added, followed by EDTA (83 mg, 0.28 mmol, 0.3 equiv). The mixture was degassed by bubbling argon through it for 15 minutes. NaN3 (0.18 g, 2.83 mmol, 3 equiv) was added and the mixture was spun at room temperature. After 14 hours 1H NMR showed complete conversion to the bis-azide. The white precipitate that developed during the reaction was filtered off and THF was removed under reduced pressure. The mixture was diluted with hexanes then placed in a separatory funnel and the DMF was removed. The hexanes layer was washed with H2O × 3, brine, dried over Na2SO4 and concentrated to give a clear oil. Yield: 4.50 g (90%).

1H NMR (500 MHz, CDCl3): δ = 4.70 (t, 24H, Si-H), 3.26 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 1.63 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 1.42 (m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 0.56 (t, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-N3), 0.070 (m, 392H -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2964 (aliphatic C-H), 2160 (silane), 2097 (azide N3), 1412 (CH2), 1261 (Si(CH3)2-O), 1094 (Si(CH3)2-O in poly(siloxane)s, 800 (Si(CH3)2).

Synthesis of Propargyl Tosylate (8)

To a 2.5M NaOH (aq) solution (50 mL) cooled to 0°C, was added THF (50 mL), followed by propargyl alcohol (5.19 mL, 89.2 mmol, 1.1 equiv), and benzyltrimethylammonium chloride (1.66 g, 8.92 mmol, 0.11 equiv). A solution of TsCl (15.30 g, 80.3 mmol, 1 equiv) in THF (50 mL) was added dropwise over 30 minutes and the reaction was kept at 0°C. After 30 minutes TLC showed complete consumption of TsCl. The reaction was then placed in a separatory funnel and the NaOH (aq) layer was removed. The organic layer was diluted with EtOAc and washed with H2O × 3, brine, dried over Na2SO4 and concentrated to give a clear oil. Yield: 15.95 g (85%).

1H NMR (500 MHz, CDCl3): δ = 7.81 (d, 2H; arom. H), 7.35 (d, 2H; arom. H), 4.70 (d, 2H; alkyne-CH2-OTs), 2.47 (t, 1H, alkyne-H), 2.46 (s, 3H; -Ph-CH3). 13 C NMR (600 MHz, CDCl3): δ = 145.4 (arom. C), 133.1 (arom. C), 130.0 (arom. C), 128.3 (arom. C), 77.5 (CH3), 75.5 (C), 57.5 (CH), 21.8 (CH2).

Synthesis of PMOXA (9)

Propargyl tosylate (8) (1.65 g, 7.83 mmol, 1 equiv) was added to an oven-dried round bottom flask with a stir bar and stirred at room temperature under reduced pressure overnight to remove trace water. MeCN (10 mL) was added followed by freshly distilled 2-methyl-2-oxazoline (10 mL, 118 mmol, 15 equiv) and the solution was heated to 80°C. After 17 hours 1H NMR showed complete monomer consumption. After cooling to room temperature, freshly distilled piperidine (2.32 mL, 23.5 mmol, 3 equiv) was added dropwise and the solution was allowed to stir for 3 hours. The solution was then concentrated and the solid was washed with Et2O to remove excess piperidine. The solid was dissolved in MeCN, K2CO3 (10.8 g, 78.3 mmol, 10 equiv) was added, and the mixture was stirred at room temperature overnight. The solution was then concentrated, dissolved in DCM, filtered, and the filtrate was concentrated to yield PMOXA as a white solid in quantitative yield. Mn,1H NMR~1350, PDI 1.17 (PS standards, Eluent: CHCl3 + 0.25% triethylamine).

1H NMR (500 MHz, CDCl3): δ = 4.27-4.08 (br. m, 2H; alkyne-CH2-N(=O)), 3.47 (br. m, 64H; -N(=O)-CH2-CH2-N(=O)), 2.79 (br. m, 2H; -N(=O)-CH2-CH2-pip), 2.41 (br. m, 4H; pip-CH2-CH2-CH2-), 2.15 (br. m, 48H; N(CH3=O), 1.56 (br. m, 4H; pip-CH2-CH2- CH2-), 13.43 (br. m, 2H; pip-CH2-CH2-CH2-); FT-IR (KBr, cm−1): 2963 (aliphatic C-H), 2117 (alkyne), 1635 (amide C=O), 1421 (CH3-N).

General CuBr/PMDETA Click Procedure

N3-PDMS-N3 (6) (1.0 g, 0.19 mmol, 1 equiv) and PMOXA (9) (0.51 g, 0.38 mmol, 2 equiv) were added to an oven-dried round bottom flask with a stirbar then DMF (5.0 mL) was added followed by PhMe (5.0 mL). PMDETA (40 μL, 0.19 mmol, 1 equiv) was added dropwise and the solution was degassed by bubbling argon through it for 15 minutes. CuBr (28 mg, 0.19 mmol, 1 equiv) was added, and the flask was flushed with argon, and allowed to stir at 60°C for 1 hour, at which time 1H NMR showed complete conversion of the azide and alkyne to triazole. The solvent was removed in vacuo to give a green solid. This solid was dissolved in a minimal amount of DCM and to this solution was added 1M Na2S (aq) (0.19 mL, 0.19 mmol, 1 equiv). Upon 1M Na2S (aq) addition the solution turned brown, and was filtered then concentrated to yield a brown solid. The solid was dissolved in i-PrOH and 3 g of MgSO4 was added and the mixture was stirred overnight at room temperature, filtered, and the filtrate concentrated to yield a pale orange solid in quantitative yield.

1H NMR (600 MHz, CDCl3): δ = 7.56 (br. m, 2H; triazole-H), 4.58 (br. m, 4H; triazole-CH2-N(=O)), 4.38-4.29 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 3.48 (br. m, 128H; -N(=O)-CH2-CH2-N(=O)), 2.79 (br. m, 4H; -N(=O)-CH2-CH2-pip), 2.41 (br. m, 8H; pip-CH2-CH2-CH2-), 2.15 (br. m, 96H; N(CH3=O), 1.94 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 1.56 (br. m, 8H; pip-CH2-CH2-CH2-), 1.43 (br. m, 4H; pip-CH2-CH2-CH2-), 1.38 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.59 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.071 (br. s, 432H -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2962 (aliphatic C-H), 1636 (amide C=O), 1420 (CH3-N), 1261 (Si(CH3)2-O), 1019 (Si(CH3)2-O in poly(siloxane)s, 801 (Si(CH3)2).

General CuSO4/Sodium Ascorbate Click Procedure

N3-PDMS-N3 (6) (0.33 g, 0.062 mmol, 1 equiv) and PMOXA (9) (0.17 g, 0.12 mmol, 2 equiv) were added to an oven-dried round bottom flask with a stirbar and dissolved in EtOH (3.3 mL). Sodium L-ascorbate (5 mg, 0.025 mmol, 0.4 equiv) was added and the mixture was degassed by bubbling argon through it for 15 min. CuSO4 (1 mg, 0.0062 mmol, 0.1 equiv) was added and the flask was flushed with argon then allowed to stir at 60°C for 2 hours at which time 1H NMR showed complete conversion of the azide and alkyne to triazole. The mixture was cooled, concentrated, dissolved in DCM, filtered to remove sodium L-ascorbate and CuSO4, and then the filtrate was concentrated to yield a yellow/green solid. Yield: (0.47 g, 94 %).

1H NMR (600 MHz, CDCl3): δ = 7.56 (br. m, 2H; triazole-H), 4.58 (br. m, 4H; triazole-CH2-N(=O)), 4.38-4.29 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 3.48 (br. m, 128H; -N(=O)-CH2-CH2-N(=O)), 2.79 (br. m, 4H; -N(=O)-CH2-CH2-pip), 2.41 (br. m, 8H; pip-CH2-CH2-CH2-), 2.15 (br. m, 96H; N(CH3=O), 1.94 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 1.56 (br. m, 8H; pip-CH2-CH2-CH2-), 1.43 (br. m, 4H; pip-CH2-CH2-CH2-), 1.38 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.59 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.071 (br. s, 432H -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2962 (aliphatic C-H), 1636 (amide C=O), 1420 (CH3-N), 1261 (Si(CH3)2-O), 1019 (Si(CH3)2-O in poly(siloxane)s, 801 (Si(CH3)2).

General Copper Nanoparticles Click Procedure

N3-P(DMS-co-MHS)-N3 (7) (2.50 g, 0.47 mmol, 1 equiv) and PMOXA (9) (1.27 g, 0.12 mmol, 2 equiv) were added to an oven-dried round bottom flask with a stirbar and dissolved in EtOH (25 mL). EDTA (0.10 g, 0.34 mmol, 0.7 equiv) was added and the mixture was degassed by bubbling argon through it for 15 min. CuNPs (50 mg) were added, the flask was flushed with argon then allowed to stir at 60°C for 2 hours at which time 1H NMR showed complete conversion of the azide and alkyne to triazole. The mixture was cooled, filtered through celite, and concentrated to yield a beige solid. Yield: (3.13 g, 83 %).

1H NMR (600 MHz, CDCl3): δ = 7.56 (br. m, 2H; triazole-H), 4.70 (t, 24H, Si-H), 4.58 (br. m, 4H; triazole-CH2-N(=O)), 4.38-4.29 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 3.48 (br. m, 128H; -N(=O)-CH2-CH2-N(=O)), 2.79 (br. m, 4H; -N(=O)-CH2-CH2-pip), 2.41 (br. m, 8H; pip-CH2-CH2-CH2-), 2.15 (br. m, 96H; N(CH3=O), 1.94 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 1.56 (br. m, 8H; pip-CH2-CH2-CH2-), 1.43 (br. m, 4H; pip-CH2-CH2-CH2-), 1.38 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.59 (br. m, 4H; -Si(CH3)2-CH2-CH2-CH2-CH2-triazole), 0.071 (br. s, 392H; -Si(CH3)2-O-); FT-IR (KBr, cm−1): 2962 (aliphatic C-H), 2160 (silane), 1636 (amide C=O), 1420 (CH3-N), 1261 (Si(CH3)2-O), 1019 (Si(CH3)2-O in poly(siloxane)s, 801 (Si(CH3)2).

Vesicle Preparation Procedure

PMOXA-PDMS-PMOXA (10) triblock copolymer (10 mg) was dissolved in ethanol (1mL, 10-wt% polymer). The polymer solution was then added dropwise to water (1 mL, 5-wt% polymer) under vigorous stirring to yield an opaque solution, which cleared after approximately 1 hour of stirring. The vesicles were then filtered twice through 0.2 μL filters (PTFE).

Conclusion

We have successfully demonstrated a versatile yet facile method for synthesizing amphiphilic triblock copolymers using click chemistry. We have presented a matrix of conditions under which such polymers can be synthesized, the optimal method being that which uses copper nanoparticles. We believe that the modular synthesis of these polymers will allow for systematic investigation of the their structure-function relationships. The poly(oxazoline)-poly(siloxane)-poly(oxazoline) ABA blocks can self-assemble into vesicles under appropriate conditions. These polymers are ideal systems for biomedical applications such as drug-delivery and synthetic lipid bilayers for ion-channel studies. Furthermore, we have shown that polymers with the Si-H functionality in the middle block that allows for further functionality via a hydrosilylation reaction. We are currently exploring the functionalization of these polymers and their use in bioengineering and medicine.

Supplementary Material

Supplementary

Acknowledgments

The authors wish to thank Damien Montarnal for useful discussions regarding copper nanoparticles, Sukru Yemenicioglu for help with the TEM images, and Peter Allen for the illustrations. The authors gratefully acknowledge support from the National Institutes of Health, through the NIH Director’s New Innovator Award Program (1-DP2-OD007472-01), the National Science Foundation under Award No. DMR-1121053, the Apprentice Researchers program, the California NanoSystems Institute, the Center for Science and Engineering Partnerships, as well as the National Science Foundation LEAPS project under Award No. DGE 0440576.

References

1. Jain JP, Ayen WY, Kumar N. Curr Pharm Des. 2011;17:65–79. [PubMed]
2. Park JY, Acar MH, Akthakul A, Kuhlman W, Mayes AM. Biomaterials. 2006;27:856–865. [PubMed]
3. Graff A, Sauer M, Van Gelder P, Meier W. Proc Natl Acad Sci U S A. 2002;99:5064–5068. [PubMed]
4. Nardin C, Thoeni S, Widmer J, Winterhalter M, Meier W. Chem Commun. 2000:1433–1434.
5. Förster S, Plantenberg T. Angew Chem Int Ed. 2002;41:689–714. [PubMed]
6. Binder WH, Sachsenhofer R. Macromol Rapid Commun. 2007;28:15–54.(b) Fournier D, Hoogenboom R, Schubert US. Chem Soc Rev. 2007;36:1369. [PubMed](c) Barner-Kowollik C, Du Prez FE, Espeel P, Hawker CJ, Junker T, Schlaad H, Van Camp W. Angew Chem Int Ed. 2011;50:60. [PubMed]
7. Nardin C, Hirt T, Leukel J, Meier W. Langmuir. 2000;16:1035–1041.
8. Schlaad H, Diehl C, Gress A, Meyer M, Demirel AL, Nur Y, Bertin A. Macromol Rapid Commun. 2010;31:511–525. [PubMed](b) Hoogenboom R. Angew Chem Int Ed. 2009;48:7978. [PubMed]
9. Yilgor I, McGrath JE. Adv Polym Sci. 1988;86:1–87.
10. Theogarajan L, Li H, Busse K, Desai S, Kressler J, Scholz C. Polymer Int. 2010;59:1191–1198.
11. Kumar M, Grzelakowski M, Zilles J, Clark M, Meier W. Proc Natl Acad Sci U S A. 2007;104:20719–20724. [PubMed]
12. Onaca O, Enea R, Hughes DW, Meier W. Macromol Biosci. 2009;9:129–139. [PubMed]
13. Broz P, Ben-Haim N, Grzelakowski M, Marsch S, Meier W, Hunziker P. J Cardiovasc Pharmacol. 2008;51:246–252. [PubMed]
14. Theogarajan L, Desai S, Baldo M, Scholz C. Polymer Int. 2008;57:660–667.
15. Yilgor I, Steckle WP, Yilgorj E, Freelin RG, Riffle JS. J Polym Sci Part A: Polym Chem. 1989;27:3673–3690.
16. Wang Y, Dong X, Larock RC. J Org Chem. 2003;68:3090–3098. [PubMed]
17. Bräse S, Gil C, Knepper K, Zimmermann V. Angew Chem Int Ed. 2005;44:5188–5240. [PubMed]
18. Chatgilialoglu C, Griller D, Lesage M. J Org Chem. 1988:3642–3644.
19. Volet G, Chanthavong V, Wintgens V, Amiel C. Macromolecules. 2005;38:5190–5197.
20. Fijten MWM, Haensch C, van Lankvelt BM, Hoogenboom R, Schubert US. Macromol Chem Phys. 2008;209:1887–1895.
21. Hoogenboom R, Fijten MWM, Thijs HML, van Lankvelt BM, Schubert US. Des Monomers Polm. 2005;8:659–671.
22. Schönfelder D, Fischer K, Schmidt M, Nuyken O, Weberskirch R. Macromolecules. 2005;38:254–262.
23. Meldal M, Tornøe CW. Chem Rev. 2008;108:2952–3015. [PubMed]
24. Guiselin O, Lee LT, Farnoux B, Lapp A. J Chem Phys. 1991;95:4632–4640.
25. Matyjaszewski K, Pintauer T, Gaynor S. Macromolecules. 2000;33:1476–1478.
26. Nowshuddin S, Reddy AR. Tetrahedron Lett. 2006;47:5159–5161.
27. Halila S, Manguian M, Fort S, Cottaz S, Hamaide T, Fleury E, Driguez H. Macromol Chem Phys. 2008;209:1282–1290.
28. Pressly ED, Amir RJ, Hawker CJ. J Polym Sci Part A: Polym Chem. 2011;49:814–819. [PMC free article] [PubMed]
29. Marciniec B, Maciejewski H, Pietraszuk C, Pawluć P. Hydrosilylation a Comprehensive Review on Recent Advances. In: Marciniec B, editor. Advances in Silicon Science. Vol. 1. Springer; New York: 2009. p. 39.