Aqueous-Phase Ring-Opening Metathesis Polymerization-Induced

Mar 15, 2018 - We report aqueous-phase Ring-Opening Metathesis Polymerization-Induced Self-Assembly (ROMPISA) for forming well-defined micellar polyme...
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Letter Cite This: ACS Macro Lett. 2018, 7, 401−405

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Aqueous-Phase Ring-Opening Metathesis Polymerization-Induced Self-Assembly Daniel B. Wright,†,‡,§ Mollie A. Touve,† Matthew P. Thompson,†,‡,§ and Nathan C. Gianneschi*,†,‡,§ Departments of †Chemistry, ‡Materials Science and Engineering, and §Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States of America S Supporting Information *

ABSTRACT: We report aqueous-phase Ring-Opening Metathesis Polymerization-Induced Self-Assembly (ROMPISA) for forming well-defined micellar polymer nanoparticles at room temperature and high solids concentration (20 w/w%). This is achieved with a new polymerization initiator, in the form of a water-soluble cationic Hoveyda-Grubbs second generation catalyst. This reaction was used in water to produce diblock copolymers from norbornenyl monomers, which then selfassemble into myriad nanostructure morphologies for which a phase diagram was constructed. Additionally, the living nature of the polymerization initiated by the aqueous initiator was confirmed, as shown by kinetic evaluation under mild conditions in water.

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at high solids, 20 w/w%, in an organic solvent mixture. It is understood that the special requirements for the monomer and polymer solubility limit the scope of aqueous-phase PISA.29,30 In this work, we explored ROMPISA in aqueous solution and deploy a water-soluble ruthenium initiator.31 For a successful ROMPISA process, the initiator must be soluble in the polymerization solvent, as insoluble catalysts may affect the kinetics of the reaction and thus alter the morphology control for the formation of nanostructures.28 Therefore, an aqueous quaternary amine Hoveyda-Grubbs second generation initiator (I) was utilized that is fully soluble in pure water (Figure 1). Although water-soluble ruthenium catalysts have been exploited for olefin metathesis only a few examples exist where they were

olymerization-induced self-assembly (PISA) is a promising route to polymeric materials formed reproducibly in high yields on the nanoscale.1−15 Classically, polymer nanoparticles are formed in a two-step process. The first is the synthesis and purification of the polymer chains, the second is the assembly of these chains into the desired solvent via either direct dissolution or solvent switching.15−18 In contrast, PISA is a process whereby a polymeric macroinitiator is prepared fully solubilized and the monomer added to generate the second block is dissolved freely in the same solvent, but the resulting block is insoluble. This leads to a phenomenon in which, as the polymerization proceeds, the insolubility of the second block causes spontaneous self-assembly.7,19 Therefore, both synthesis and assembly of the material occurs in a single step in one pot. The applications of self-assembled block copolymers are extensive and vary greatly from lubricant additives to delivery agents in biological systems, such that scale up and morphological control become of paramount importance, features that characterize the PISA strategy.20−27 Therefore, functional group tolerant polymerization routes, amenable to both aqueous and organic solvents, for the incorporation of diverse chemistries and morphologies via PISA are desirable. PISA has predominantly involved the use of reversible deactivation radical polymerizations (RDRP),4,6−8,10,12−14 with recent extension to photoinitiation (Photo-PISA).1,5 We recently demonstrated an alternative route via Ring-Opening Metathesis Polymerization-Induced Self-Assembly (ROMPISA).28 In the initial demonstration, an oligo ethylene glycol (OEG) brush stabilized block was utilized with a peptide functionalized norbornene dicarboximide monomer as the core forming monomer. Polymeric micellar nanoparticles consisting of spheres, worms, and vesicles were produced in one pot and © XXXX American Chemical Society

Figure 1. (a) Structure of the aqueous Initiator (I). (b) Structure of the quaternary amine phenyl norbornene dicarboximide. (c) Structure of the amphiphilic diblock copolymer formed. Blue highlights hydrophilic; red highlights hydrophobic. Received: February 1, 2018 Accepted: March 12, 2018

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DOI: 10.1021/acsmacrolett.8b00091 ACS Macro Lett. 2018, 7, 401−405

Letter

ACS Macro Letters

final concertation of 20 w/w% (see SI for experimental details). After 3 h, the solutions were opened to air and quenched with ethyl vinyl ether. After the reaction, the polymerization solution was analyzed further by SEC-MALS, 1H NMR, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The corroboration of SEC-MALS and 1H NMR highlighted that the ROMP polymerization was unaffected by the second monomer addition in water and the low dispersity was maintained (Table 1 and SI). Additionally, the combination of DLS and TEM confirmed the presence of spherical micelles in solution with a diameter of approximately 30 nm (Figure 2). Additional kinetic

used for polymerizations.31−34 Therefore, to our knowledge, this presents the first example of a single cationic quaternary amine Hoveyda-Grubbs second generation initiator utilized for living polymerizations in pure water. The macroinitiator was an OEG brush homopolymer synthesized via aqueous-phase ROMP with the initiator, I (Table 1). An initial screening of Table 1. Molecular Characterization of the Block Copolymers polymera

MnTheob (kDa)

MnSECb (kDa)

Đc

NOEGc (m)

Naminec (n)

20-0 20-20 20-25 20-50 20-75 20-100 10-20 10-25 10-50 10-55 10-60 10-65 10-75 10-100 5-20 5-25 5-50 5-65 5-75 5-80 5-85 5-100

7.0 15.2 17.2 27.3 37.4 47.6 11.6 13.7 23.8 25.8 27.8 29.9 33.9 44.0 9.9 11.9 22.0 28.1 32.2 34.2 36.2 42.3

8.1 17.1 19.5 31.5 40.3 55.9 13.1 15.4 28.3 30.3 32.0 36.7 37.8 51.3 11.1 13.5 25.8 34.6 36.9 38.5 39.7 49.4

1.08 1.18 1.06 1.20 1.15 1.07 1.12 1.10 1.08 1.06 1.19 1.05 1.15 1.17 1.21 1.12 1.09 1.11 1.07 1.11 1.08 1.10

20 20 20 20 20 20 10 10 10 10 10 10 10 10 5 5 5 5 5 5 5 5

20 25 50 75 100 20 25 50 55 60 65 75 100 20 25 50 65 75 80 85 100

Figure 2. (a) Distribution of hydrodynamic radius from DLS for the 20-20. (b) TEM image of the nanostructures formed by polymer 20-20 in pure water.

evaluation was obtained by taking aliquots at different time points throughout the polymerization. It was observed that aqueous ROMPISA was unaffected by the aqueous environment and that a first order rate was still observed with low dispersity polymers and >99% monomer conversion. Furthermore, the linear relationship between monomer conversion and molecular weight concludes that the living nature is maintained (Figure 3).37 From these results it was evident that ROMPISA could be extended to the aqueous phase with the aqueous initiator, I. Next, to extend this approach to other morphologies, the core-

a The block length of the blocks for OEG-b-quaternary amine phenyl norbornene dicarboximide. bDetermined by monomer conversion from 1H NMR spectroscopy. cTargeted block lengths calculated from SEC-MALS based on poly(styrene) standards in DMF.

the aqueous ROMPISA protocol was undertaken with a macroinitiator block length of 20. This block length was selected as to provide adequate stabilization of the propagating core block during polymerization in solution. It is well understood that norbornene polymers are highly hydrophobic, a consequence of the hydrophobic nature of the backbone. Thus, to successfully perform PISA in water, monomer selection must be carefully made.35 That is, the monomer must be soluble in the solvent of choice, yet the polymer is insoluble. To achieve this, a quaternary amine-based phenyl norbornene dicarboximide was utilized as the core-forming monomer (Figure 1).36 For the initial aqueous ROMPISA, OEG monomer, I, and water were placed under a nitrogen atmosphere and left to stir at room temperature. After 45 min, an aliquot of the solution was removed and analyzed by size exclusion chromatography multi-angle light scattering (SEC-MALS) and 1H NMR. SEC analysis highlighted low dispersity and 1H NMR concluded full monomer conversion (see SI). The combination of these techniques confirm that ROMP with the selected initiator could be carried out successfully in water without diversion from its living nature.37 The OEG polymerization solution was then charged with the quaternary amine phenyl norbornene dicarboximide for a targeted block length of 20 and to give a

Figure 3. Kinetic plot of (a) Mn SEC-MALS vs conversion. (b) ln([M0]/[M]) vs reaction time for polymer 20-20. (c) Molecular weight distributions by SEC-MALS for 20-20, DMF eluent. (d) Conversion vs dispersity (Đ) for 20-20. 402

DOI: 10.1021/acsmacrolett.8b00091 ACS Macro Lett. 2018, 7, 401−405

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ACS Macro Letters forming block length was altered. For this set of studies, the targeted core-forming block lengths were extended above the previous length of 20 to 25, 50, 75, and 100. Specifically moving from a critical packing parameter of >1/3, which gives spheres to p = 1/3 to 1/2 for cylindrical micelles and then 1/2 to 1 for vesicular structures.38 For these new targeted block lengths, the polymerizations were carried under identical conditions to the previous polymerization, 20 wt % and at room temperature under nitrogen. After 3 h, the reactions were quenched and analyzed by SEC-MALS, 1H NMR, DLS, and TEM. Both SECMALS and 1H NMR highlight good control with aqueous ROMPISA (Table 1). However, DLS and TEM highlight that, despite the change in targeted block length, the only observed morphology was spheres, where the size of the spheres increased with block length. This lack of change in morphology is a result of the high surface curvature induced by the OEG brush, which was observed with the previous ROMPISA and PISA systems.8,28 To overcome this, the OEG block length was reduced from 20 to 10 and 5, and these two block lengths were utilized further when the core amine block length was varied. The aqueous ROMPISA studies were undertaken at a 20 w% under a nitrogen atmosphere at room temperature and quenched with ethyl vinyl ether after 3 h. See Table 1 for molecular weight data. In contrast to when the degree of polymerization of the OEG block was 20, block lengths of 5 and 10 both form a diverse range of nanostructures, ranging from spheres to worms to vesicles (Figure 4). Specifically, the longer core forming

Figure 5. Phase diagram for OEG-b-quaternary amine phenyl norbornene dicarboximide block copolymer particles prepared by aqueous ROMPISA at room temperature.

specific morphology can be targeted, yet for some phases, such as pure worms, this can often be difficult due to the small pure phase for worms that exist. Furthermore, it is also interesting to note that if the polymer morphology progresses past vesicles (5−100), the vesicles transform into large compound micelles in solution as the lumen vesicle space fills.11 Therefore, this phase diagram offered a wide range of structures. In conclusion, the ROMPISA protocol has been extended to the aqueous phase. Utilizing a new aqueous initiator for ROMP, it was observed that neither the ROMPISA formulation or the pure water solvent altered the living nature of the polymerization. Moreover, a range of well-defined nanostructures were formed in situ and a phase diagram could be produced for this block copolymer system. Extension of this approach for the direct generation of functionalized micellar nanoparticles for biomedical applications is currently underway in our laboratories.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00091. Synthesis of the polymers and additional characterization of polymers and particles via TEM and DLS (PDF).

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Figure 4. Dry-state TEM images of OEG-b-quaternary amine phenyl norbornene block copolymer particles form by ROMPISA in water; (a) 10-25; (b) 10-65; (c) 10-100; (d) 5-25; (e) 15-75; (f) 5-80. Inset scale bar 50 nm.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Nathan C. Gianneschi: 0000-0001-9945-5475

blocks cause a decrease in surface curvature and increase in hydrophobic volume fraction.39 Consequently, this leads the morphologies to move through different phases that match with classic surfactant packing.38 It should be noted that in cases where a worm phase was observed, a marked increase in solution viscosity was observed, which is a consequence of worm entanglements at the high concentrations observed during PISA formulations.3 With a broad range of block lengths and morphologies, the phase space for these amphiphilic norbornene dicarboximide block copolymers can be explored, and simple phase diagram can be constructed (Figure 5). Here it can be observed that

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was conducted with Government support under and awarded by DoD through a MURI from the Air Force Office of Scientific Research (FA-9550-16-1-0150) and a National Defense Science and Engineering Graduate (NDSEG) Fellowship, 32 CFR 168a. This work made use of the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the Soft and Hybrid 403

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ACS Macro Letters

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Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); and the State of Illinois, through the IIN. Dr Swagat Sahu is kindly thanked for the quaternary amine phenyl norbornene dicarboximide. Apeiron catalysts are thanked for the aqueous initiator (Aquamet).

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DOI: 10.1021/acsmacrolett.8b00091 ACS Macro Lett. 2018, 7, 401−405