Main-Chain Zwitterionic Supramolecular Polymers Derived from N

Apr 6, 2018 - Main-Chain Zwitterionic Supramolecular Polymers Derived from N-Heterocyclic Carbene–Carbodiimide (NHC–CDI) Adducts. Nolan M...
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Main-Chain Zwitterionic Supramolecular Polymers Derived from N‑Heterocyclic Carbene−Carbodiimide (NHC−CDI) Adducts Nolan M. Gallagher, Aleksandr V. Zhukhovitskiy, Hung V.-T. Nguyen, and Jeremiah A. Johnson* Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States S Supporting Information *

ABSTRACT: Polyzwitterions have found extensive applications in biological and materials sciences. Despite this success, most polyzwitterions have nondegradable polyolefin backbones with pendant zwitterionic groups. Transcension of this structural paradigm via the formation of main-chain zwitterionic supramolecular polymers could lead to readily processable, as well as self-healing and/or degradable, polyzwitterions. Herein, we report the synthesis and characterization of poly(azolium amidinate)s (PAzAms), which are a new class of supramolecular main-chain polyzwitterions assembled via the formation of N-heterocyclic carbene−carbodiimide (NHC−CDI) adducts. These polymers exhibit a wide range of tunable dynamic properties due to the highly structure-sensitive equilibrium between the NHC−CDI adduct and its constituent NHCs and CDIs: e.g., PAzAms derived from N-aryl-N′-alkyl CDIs are dynamic at lower temperatures than those derived from N,N′-diaryl CDIs. We develop a versatile synthetic platform that provides access to PAzAms with control over the main-chain charge sequence and molecular weight. In addition, block copolymers incorporating PAzAm and poly(ethylene glycol) (PEG) blocks are water soluble (>30 mg mL−1) and self-assemble in aqueous environments. This work defines structure−property relationships for a new class of degradable mainchain zwitterionic supramolecular polymers, setting the stage for the development of these polymers in a range of applications.

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INTRODUCTION Polymers that incorporate zwitterionic functional groups have attracted interest across a variety of fields due to their antifouling properties,1−3 biocompatibility,4−6 ability to stabilize therapeutic proteins,7−9 and high ionic conductivity.10,11 Despite this breadth of valuable properties, the vast majority of such polymers are polyolefins (e.g., polyacrylates, polyacrylamides) with pendant zwitterionic moietiesusually sulfobetaines or phosphobetaines.12,13 A few notable exceptions to this trend include main-chain zwitterionic polymers of phospholipids14,15 and polysquaraines.16 Nonetheless, a drawback of existing polyzwitterionic materials is their very slow degradation under ambient conditions, which can lead to long-term environmental accumulation.17 In the context of medicinal applications of polyzwitterion-based biomaterials,4 lack of degradability can lead to undesirable long-term tissue accumulation. Supramolecular polyzwitterions could address limitation. In general, supramolecular polymers, which are macromolecules formed via noncovalent interactions (e.g., H-bonding, metal− ligand bonds, etc.) between monomers, possess a variety of unique properties compared to conventional polymers in terms of their processability, self-healing, and degradability.18−22 Yet, reports of supramolecular polyzwitterions are sparse.23 In an effort to design supramolecular polyzwitterions, we envisioned polymers in which the monomers were linked by reversible © XXXX American Chemical Society

dative bonds between organic components (Figure 1) and where each linkage generated a zwitterion embedded within the polymer main chain. The equilibrium constant (Keq) for zwitterion formation and the rate constant for zwitterion dissociation (kd) would govern the (thermo)dynamics of these polymers.24 In addition, their charge sequence could be controlled (Figure 1b), e.g., by employing monomers that are hetero-difunctional (AB polymerization) or homo-difunctional (AA + BB polymerization), where A and B are complementary functional groups. Such a synthetic approach could provide convenient entry to a broad new class of organic-based coordination polymers. To achieve these goals, we were drawn to the versatile reactivity of N-heterocyclic carbenes (NHCs).25−28 Zwitterionic betaine adducts of NHCs with heteroallenes (e.g., CO2, CS2) are well-known;29 the isolation of NHC−carbon disulfide adducts30 (Figure 1c, X = Y = S) even predates Arduengo’s isolation of the first stable NHC.31 Recently, we broadened the scope of this class of compounds with the discovery that classical N,N′-diaryldihydroimidazol-2-ylidenes undergo thermal cycloelimination to produce carbodiimides (CDIs) that are immediately trapped by another equivalent of NHC to produce stable NHC−CDI adducts.27 This discovery led us to Received: March 19, 2018

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DOI: 10.1021/acs.macromol.8b00579 Macromolecules XXXX, XXX, XXX−XXX

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As the applications of NHCs expanded28 beyond their classical uses in organometallic catalysis32 and organocatalysis,33 they began to find use as components of polymeric materials. For instance, Bielawski and co-workers developed a series of organometallic polymers formed via NHC−metal coordination.34−36 The formation of triazenes upon reaction of NHCs with azides has also been used to generate poly(triazenes) from appropriate bis-functionalized components.37 Despite progress in this area, the use of NHCs to generate polyzwitterions has received little attention. To our knowledge, the only example consists of a brief investigation of the reaction of a bis-NHC with a bis-isothiocyanate.23 While this report was encouraging, we reasoned that CDIs would possess a variety of advantages as polyzwitterion building blocks relative to isothiocyanates and isocyanates. Namely, CDIs possess two N-substituents that could be utilized to tune the adduct geometry, the kd and Keq of NHC-adduct formation, negative charge delocalization, and air and water stability of the resulting polymers. Furthermore, the CDI-derived amidinate fragments provide a versatile handle for metal ion ligation,24 which would introduce an additional level of supramolecular hierarchy. Herein we report detailed studies of several novel NHC− CDI complexes; these investigations lead us to design a novel class of supramolecular organic polymers: poly(azolium amidinate)s (PAzAms), which contain main-chain zwitterionic NHC−CDI linkages. We initially focus on two types of PAzAms to illustrate the tunable structural dynamics of these materials: those derived from N-aryl-N′-alkyl- versus N,N′diaryl-CDIs (referred to hereafter as mono- and diaryl-PAzAms, respectively). The former display facile depolymerization at 50 °C and the ability to be reconfigured into diaryl-PAzAms. In contrast, the latter require much more intense conditions (100 °C in bulk diaryl CDI) to induce depolymerization. In addition, the monoaryl-PAzAms undergo slow decomposition in THF solution over the course of a day upon exposure to ambient atmosphere while diaryl variants are significantly more robust either in solution or in solid state. To further expand the structural diversity of PAzAms, we develop a robust and modular synthetic strategy to access a wide variety of these polyzwitterions with control over polymer number-average molar mass (Mn), main-chain charge sequence, and water solubility. Finally, we describe the synthesis of block copolymers that contain a PAzAm block and a poly(ethylene glycol) (PEG) block. These block copolymers are shown to self-assemble in aqueous solution to form nanoparticles. This work establishes PAzAms as a versatile new class of main-chain zwitterionic supramolecular polymers with a wide range of potential applications.

Figure 1. Supramolecular zwitterionic polymers accessible through Nheterocylic carbene (NCH) chemistry: (a) Typical polyzwitterions feature side-chain zwitterionic groups. (b) Where “A” and “B” represent species that react to from zwitterions, A−B and A−A/B− B monomers will lead to main-chain zwitterionic polymers with different main-chain charge sequences. (c) NHCs and heteroallenes are known to form zwitterionic adducts and are a suitable choice for “B” and “A”, respectively. (d) In the case of NHC−CDI adducts (X = Y = NR1 or NR2), Keq can be easily modulated by altering the CDI substituents. NHC−CDI Keq values were measured by 1H NMR spectroscopy (for symmetric CDIs where R1 = R2, see ref 27; for CDIs where R1 ≠ R2, Keq values were measured in this work; see the Supporting Information, Figures S2−S4).

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RESULTS AND DISCUSSION Prior to embarking on PAzAm synthesis, we sought to further explore the impact of the CDI structure on the Keq of NHC− CDI adduct formation. As noted above (Figure 1d), our previous work showed that diaryl-CDIs tend to produce very stable NHC−CDI adducts, while those derived from dialkylCDIs are very unstable. In the context of supramolecular polymerizations to form PAzAms, we anticipated that these differences would lead to stable polymers for monomers derived from diaryl CDIs, but no polymerization for monomers derived from dialkyl-CDIs. These differences are due to the ability of the diaryl-CDI to stabilize the negatively charged amidinate fragment of the NHC−CDI adduct. On the basis of this rationale, we hypothesized that monoaryl-CDIs would

investigate the synthesis of a range of NHC−CDI adducts via the addition of NHCs to diaryl CDIs (Figure 1d).27 Notably, the dative bond in an NHC−CDI complex is reversible and considerably weaker than a typical covalent bond; thus, NHC− CDI adducts can be viewed as organic analogues of supramolecular complexes derived from dative metal−ligand interactions where the equilibrium constant for NHC−CDI formation depends on the electronic structure and steric environment of the CDI. For example, NHC−CDI adducts derived from N,N′-diaryl-CDIs tend to have relatively large Keq values (≫550 M−1) and can be readily isolated, while analogous adducts derived from N,N′-dialkyl-CDIs have much lower Keq values (e.g., 25 25 8 4 ∼16 16 11 8 3 2 4 2

78 89 95 86 90 92 92 85 51 53 76 92

2.26 1.85 1.64 1.47 3.31 2.78 2.38 2.52 1.65 1.47 1.71 1.33

a

GPC traces shown in Figure 4a. b1H NMR Mn measurement used to calibrate GPC/MALLS detector, dn/dc = 0.33. cPolymerizations conducted in anhydrous toluene (entries 1−7) or anhydrous 1,2-dichloroethane (entries 8−13) under inert atmosphere at 75 °C (monomer concentration: 0.5 M for entries 1−7, 0.25 M each monomer for entries 8−13). dMn determined by GPC/MALLS (GPC) or by 1H NMR end-group analysis (NMR). e Determined by NMR, or when no cap is used (entries 1 and 5) by qualitative comparison of GPC Mn with analogous capped polymers. fIsolated polymer yields after precipitation into diethyl ether/filtration or decantation. gDetermined by GPC-MALLS. hWe note that monomers 2 + 5 → poly2 and that higher/controllable Mn’s are more easily obtainable using the bis-pentafluorobenzene adduct route relative to imidazolium route previously described, likely due to solvent effects in the latter (longer polymers generated from this route, e.g., entry 8, are not well soluble in THF).

CDI adduct underwent a similar upfield chemical shift (the γCH2 group shifts from 1.36 to 1.12 ppm, in close agreement to the chemical shift observed for the capped polymer, δ = 1.13 ppm). The upfield shift of the cc-CDI protons upon polymerization confirms that the cc-CDI reacts with polymer chain ends to form an amidinate cap and effectively rules out a physical mixture of polymer and cc-CDI.

Infrared spectra of representative AB and AA + BB PAzAms are shown in Figure 4c. In the case of AB polymerizations (for instance, 3 → poly3), we observed the disappearance of the distinct CDI vibration at 2110−2140 cm−1 present in monomer 3 and a new vibrational band at 1540−1560 cm−1 in poly3. This observation is consistent with amidinate formation. Indeed, this same characteristic amidinate IR absorption band was previously observed in molecular diaryl NHC−CDI G

DOI: 10.1021/acs.macromol.8b00579 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules adducts.27 The absence of any significant CDI vibrational band in the case of poly3 indicates that CDI side reactions or cyclization may be implicated in chain termination events. In the case of an AA + BB polymerization (poly2), although similar bands attributable to the aforementioned amidinate vibrations (∼1540−1565 cm−1) are dominant, we also observe less intense CDI vibrational bands. The intensity (relative to the most intense amidinate vibration) of the CDI bands increases with the stoichiometric excess of bis-CDI (2) used in the polymerization, consistent with the formation of progressively smaller CDI-capped PAzAms as the stoichiometric excess of 2 increases. PAzAms are observed to universally exhibit a characteristic, brilliant yellow/orange color (Figure 4b). UV−vis spectroscopy (Figure S19) of representative PAzAms shows a trailing absorbance into the visible region with absorbance at λ > 400 nm. The same UV−vis absorbance is observed for molecular diaryl NHC−CDI adducts. This absorbance at visible wavelengths was previously rationalized in terms of π-conjugation in the amidinate as well as the imidazolium segments leading to a decreased HOMO/LUMO gap, as supported with DFT calculations.27 Noteworthy for future studies, it is likely that a wide variety of colors and photophysical properties could be obtained by further extending the π-conjugation in CDIs, use of “donor−acceptor” CDIs, or employing different types of NHCs. Further support of the structure of PAzAms was obtained from molecular model reactions. Under the same conditions used for typical polymerizations, a pentafluorobenzene adduct of SIMes in the presence of a diaryl-CDI (DPTCDI) undergoes quantitative conversion (assessed by 1H NMR spectroscopy) to the ditolyl adduct over the course of 12 h

(SIMes)2 readily formed crystals of suitable quality for X-ray crystallography (Figure 5). The single crystal geometry of 8·

Figure 5. Single crystal X-ray structure of 8·(SIMes)2.

(SIMes)2 displays many structural similarities to our previously studied simpler diaryl NHC−CDI adducts, such as NHC−CDI C−N bond lengths of 1.51−1.52 Å, NHC/amidinate C−N bond lengths of 1.30−1.33 Å, and amidinate CNC bond angles of 138°−139°. Interestingly, the four aryl rings of the bisamidinate core segment adopt a helical conformation where the central diphenylene spacer possesses a torsion of 52° and the bulkier amidinate mesitylene groups orient themselves in opposite directions to minimize steric repulsion. For detailed structural information as well as packing views along different crystallographic axes, see Table S1 and Figure S1. In agreement with results obtained for poly2 discussed above, all of the diaryl CDI-derived PAzAms possessed excellent stability under ambient conditions. They were stable in 1,2-dichloroethane-d4 solution under air upon heating to 70 °C (assessed by VT-NMR, Figure S26) and can be annealed as a solid at 100 °C for 24 h under N2 with no significant change in Mn observable by GPC (Figure S25). Despite this stability, these PAzAms do undergo depolymerization (assessed by GPC, Figure S25) when heated to 100 °C in the presence of external DPTCDI, confirming their supramolecular nature. Thermogravimetric analysis (TGA, Figure S20) indicates that in the absence of external CDI they are likely stable even at higher temperatures, as a mass loss is not incurred until ∼175−200 °C. Given their robust stability and modular synthesis, we wondered if the aqueous solubility of PAzAms could be tuned and if such polymers would possess stability in aqueous environments. Most PAzAms (excluding entries 2−4 in Table 1) are either not at all or only very sparingly water-soluble (at neutral pH). To improve water solubility, we utilized a macromolecular capping agent cc-NHC-PEG to access block copolymers with a hydrophilic PEG block and a relatively hydrophobic PAzAm block. The ratio of the hydrophilic/ hydrophobic blocks can be varied by simply altering the amount of cc-NHC-PEG included in the polymerization; samples with average block sizes PEG2k-b-(AzAm)4, PEG2k-b(AzAm)8, and PEG2k-b-(AzAm)25 (block sizes were measured by 1H NMR, Figure 6 and Figure S13) were readily prepared (Table 1, entries 2−4). All of these block copolymers exhibited water solubility ≥5 mg mL−1; notably, the block copolymer with the highest PEG content (entry 4) exhibited water solubility exceeding 30 mg mL−1. While the 1H NMR of block copolymers in CDCl3 clearly showed signals attributable to the PAzAm and PEG blocks (Figure 6), only a broadened PEG peak was observable in the

Scheme 4. Molecular Model Reactions for PAzAms

accompanied by evolution of pentafluorobenzene (Scheme 4, 1 H NMR spectra for this transformation shown in Figure S32). The absence of any significant side reactions under these conditions implies that NHC−CDI adduct formation is the dominant reaction in analogous polymerizations. In the case of AA + BB polymerizations, the polymerizations can be modeled through the formation of bis-adducts. While stable bis-adduct 2· (SIMes)2 exists as an orange low-melting-point solid that could not be easily crystallized (presumably due to the two butyl side chains), bis-adducts could also be formed with more conformationally rigid bis-diaryl CDIs, such as 8. Indeed, bis-adduct 8· H

DOI: 10.1021/acs.macromol.8b00579 Macromolecules XXXX, XXX, XXX−XXX

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similar or smaller sizes compared to those measured by DLS, although minor populations of elongated worm-like morphologies were observed for PEG2k-b-(AzAm)8 (Figure 6 and Figure S30). The apparent independence of the aggregate characteristics (morphology type, particle size) and average hydrophobic block size could result from the high molecular weight dispersity (1.47−1.85) of the constituent block copolymers.48

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CONCLUSIONS Poly(azolium amidinate)s (PAzAms), a new class of zwitterionic supramolecular polymers, have been synthesized and thoroughly characterized. The (thermo)dynamics of these polymers can be tuned in a predictable manner by choosing NHC/CDI pairs with different adduct dissociation rate constants (kd) and equilibrium constants (Keq) as monomers. Such polymers derived from monoaryl-CDIs undergo depolymerization at 50 °C over the course of a few hours and are dynamically reconfigurable. Those derived from diaryl-CDIs, on the other hand, require harsher conditions for depolymerization. As the Keq value that governs PAzAm properties (it is likely that the different kd values for these adduct types is a direct consequence of their different Keq values) is related to anionic charge stabilization when one or both substitutents are aryl, it is foreseeable that supramolecular parameters of these (and future) PAzAms can be related to easily measurable/ known parameters, such as the pKa of the analogous amidine (conjugate acid of the amidinate) or Hammett parameters. As an additional advance, we demonstrated that a variety of diaryl-CDI-derived PAzAms of different structure, molecular weight, and backbone charge sequence can be synthesized from easily accessible, thermally labile NHC precursors, and that such polymers can be isolated as bench stable main-chain polyzwitterions. They can also be engineered to possess reasonably high water solubility (>30 mg mL−1) by using a macromolecular water-solubilizing cap. Because of the hydrophobic nature of PAzAms studied in this work, such block copolymers aggregate to form nanoscale spherical particles in water. Future work is aimed at the development of less hydrophobic NHC and CDI precursors for PAzAms. Such polymers are predicted to be water-soluble in their own right without the need for external solubilizing agents (PEG). The antifouling and biological properties of such supramolecular zwitterionic polymers will be examined. Also, given the plethora of substrates that can be functionalized with NHCs,25 it should be possible to polymerize PAzAms from these surfaces, altering the properties of various materials of interest.

Figure 6. Top to bottom: 1H NMR of poly3 and PEG2k-b-AzAm4 (CDCl)3, 1H NMR of PEG2k-b-AzAm4 (D2O), and TEM images (unstained) of PEG2k-b-AzAm4 after slow dialysis into H2O. 1

H NMR spectra obtained for the materials dissolved in D2O. This observation suggested aggregation-induced peak broadening, which is to be expected for amphiphilic block copolymers.47 Importantly, after a few hours in D2O, the block copolymers could be extracted back into organic solvent. No significant differences in the 1H NMR spectra of the native sample and D2O-extracted sample were observed (Figure S31), which indicates that PAzAms are stable in water at room temperature on the time scale of at least several hours. The aggregation of these block copolymers in an aqueous environment was further probed with dynamic light scattering (DLS) and transmission electron microscopy (TEM) after slow dialysis from acetone into H2O. All block copolymers in water exhibited Gaussian size histograms by DLS with average diameters in the range of 66−100 nm. No discernible correlation was observed between hydrophobic block size and particle diameter (Figure S30). TEM indicated that all of the block copolymers aggregated to form spherical morphologies of

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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/acs.macromol.8b00579. Additional characterization of polymers, synthetic procedures, characterization of 1−8 and synthetic intermediates (PDF) X-ray crystal structure of 8·(SIMes)2 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (J.A.J.). I

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Aleksandr V. Zhukhovitskiy: 0000-0002-3873-4179 Hung V.-T. Nguyen: 0000-0002-6945-4057 Jeremiah A. Johnson: 0000-0001-9157-6491 Present Address

A.V.Z.: Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported as part of The Dow Chemical Company University Partner Initiative under Dow agreement number 250498. We also thank the NSF (CHE-1351646) for support of this work. We thank Dr. Peter Mueller for X-ray crystallography studies.

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DOI: 10.1021/acs.macromol.8b00579 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules (38) Chen, S.-W.; Kim, J. H.; Song, C. H.; Lee, S. Self-supported oligomeric Grubbs/Hoveyda-type Ru−carbene complexes for ringclosing metathesis. Org. Lett. 2007, 9, 3845−3848. (39) Early attempts at poly1/poly2 generation were performed by filtration of the bis-NHC solution under inert atmosphere to remove KBF4 prior to addition to the bis-CDI (see Supporting Information, “procedure A”). This procedure resulted only in the formation of smaller oligomers (DPNMR = 2−4) for both poly1 and poly2, likely due to considerable bis-NHC loss during filtration which altered the stoichiometry. We thus adopted a modified procedure (Supporting Information, ‘procedure B’) where poly1/poly2 polymerization was conducted without prior filtration and instead filtered after the completion of polymerization. This resulted in a higher DPNMR = 11 for poly1 with PDI = 1.67 and typical GPC trace, as shown in Figure 2. However, in the case of poly2 using “procedure B”, although a DPNMR = 9 was observed, the GPC trace of this sample was irregular with a much higher PDI (2.87) relative to poly1 of comparable chain length. This is likely due to solvent/aggregative effects during polymerization in THF-d8: the same poly2 can be generated with DPNMR up to ∼8 using bis-NHC pentafluorobenzene adducts in 1,2-dichloroethane with a more typical GPC trace (see for instance Figure 4 and Table 1, entry 8), and such polymers are not well soluble in THF after isolation. Nevertheless, smaller oligomers of poly2 (generated from “procedure A”, DP ∼ 4) suffice for an initial fundamental investigation of structural dynamics. (40) Kuhn, N.; Steimann, M.; Weyers, G.; Henkelh, G. Z. Naturforsch. B 1999, 54b, 434−440. (41) Badi, N.; Lutz, J.-F. Sequence control in polymer synthesis. Chem. Soc. Rev. 2009, 38, 3383. (42) Barnes, J. C.; Ehrlich, D. J. C.; Gao, A. X.; Leibfarth, F. A.; Jiang, Y.; Zhou, E.; Jamison, T. F.; Johnson, J. A. Iterative exponential growth of stereo- and sequence-controlled polymers. Nat. Chem. 2015, 7, 810−815. (43) Jiang, Y.; Golder, M. R.; Nguyen, H. V. T.; Wang, Y.; Zhong, M.; Barnes, J. C.; Ehrlich, D. J. C.; Johnson, J. A. Iterative exponential growth synthesis and assembly of uniform diblock copolymers. J. Am. Chem. Soc. 2016, 138, 9369−9372. (44) Morozova, S.; Hu, G.; Emrick, T.; Muthukumar, M. Influence of dipole orientation on solution properties of polyzwitterions. ACS Macro Lett. 2016, 5, 118−122. (45) Huo, S.; Jiang, Y.; Gupta, A.; Jiang, Z.; Landis, R. F.; Hou, S.; Liang, X. J.; Rotello, V. M. Fully zwitterionic nanoparticle antimicrobial agents through tuning of core size and ligand structure. ACS Nano 2016, 10, 8732−8737. (46) Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. A general and versatile approach to thermally generated N-heterocyclic carbenes. Chem. - Eur. J. 2004, 10, 4073−4079. (47) Mai, Y.; Eisenberg, A. Self-assembly of block copolymers. Chem. Soc. Rev. 2012, 41, 5969. (48) Jiang, Y.; Chen, T.; Ye, F.; Liang, H.; Shi, A. C. Effect of polydispersity on the formation of vesicles from amphiphilic diblock copolymers. Macromolecules 2005, 38, 6710−6717.

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DOI: 10.1021/acs.macromol.8b00579 Macromolecules XXXX, XXX, XXX−XXX