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

Multicyclic Polymer Synthesis through Controlled/Living Cyclopolymerization of α,ω-Dinorbornenyl-Functionalized Macromonomers Takuya Isono,*,† Tetsuya Sasamori,‡ Kohei Honda,‡ Yoshinobu Mato,‡ Takuya Yamamoto,† Kenji Tajima,† and Toshifumi Satoh*,† †

Division of Applied Chemistry, Faculty of Engineering, and ‡Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-8628, Japan S Supporting Information *

ABSTRACT: A novel synthesis of multicyclic polymers that feature ultradense arrays of cyclic polymer units has been developed by exploiting the cyclopolymerization of α,ω-norbornenyl end-functionalized macromonomers mediated by the Grubbs thirdgeneration catalyst (G3). Owing to the living polymerization nature, the number of cyclic repeating units in these multicyclic polymers was controlled to be between 1 and approximately 70 by varying the initial macromonomer-to-G3 ratio. The ring size was also tuned by choosing the molecular weight of the macromonomer; in this way we successfully prepared multicyclic polymers that possess cyclic repeating units composed of up to about 500 atoms, which by far exceeds those prepared to date by cyclopolymerization. Specifically, cyclopolymerizations of α,ω-norbornenyl end-functionalized poly(L-lactide)s (PLLAs) proceeded homogeneously under highly dilute conditions (∼0.1 mM in CH2Cl2) to give multicyclic polymers that feature cyclic PLLA repeating units on the polynorbornene backbone. The cyclic product architectures were confirmed not only by structural characterization based on NMR, MALDI-TOF MS, and SEC analyses but also by comparing their glass transition temperatures, viscosities, and hydrodynamic radii with their acyclic counterparts. The cyclopolymerization strategy was applicable to a variety of α,ω-norbornenyl end-functionalized macromonomers, such as poly(ε-caprolactone), poly(ethylene glycol) (PEG), poly(tetrahydrofuran), and PLLA-b-PEG-b-PLLA. The successful statistical and block cyclocopolymerizations of the PLLA and PEG macromonomers gave amphiphilic multicyclic copolymers.

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INTRODUCTION Cyclic polymers have attracted significant attention due to their unique properties that cannot readily be achieved by their linear counterparts. Examples of these properties include increased glass transition temperatures,1 reduced viscosities,2,3 reduced domain spacings in block copolymer microphase separations,4−6 increased stabilities of block copolymer micelles,7,8 enhanced fluorescence,9 and slower degradation rates10,11 when compared to their linear counterparts. Such differences in chemical and physical properties between cyclic and linear polymers have been attributed to the absence of polymer chain ends. Furthermore, the material12−14 and biomedical properties15,16 of cyclic and related polymer architectures have been widely investigated in recent years; these studies highlighted the exciting potential of cyclic polymers, not only for academic interest but also for practical applications. © XXXX American Chemical Society

On the other hand, multicyclic polymers composed of more than two cyclic units, such as figure-eight-, trefoil-, and quatrefoil-shaped polymers, as well as cyclic polymer grafts, have been largely unexplored to date because they are difficult to synthesize, despite the high expectation that such complex chain architectures will give rise to unusual or unexpected properties. Although multicyclic polymers have been synthesized previously,17−19 access to a series of multicyclic polymers with varying numbers of cyclic units (i.e., from a monocyclic polymer to multicyclic polymers composed of more than two cyclic units) is highly challenging and has therefore rarely been achieved. A known strategy for the synthesis of a multicyclic Received: February 14, 2018 Revised: April 28, 2018

A

DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. Strategies for the syntheses of multicyclic polymers. (a) Intramolecular coupling between an azido- and ethynyl-functionalized cyclic polymer precursor. (b) Intramolecular cyclization of a clickable star-shaped polymer precursor. (c) Polyaddition of a cyclic polymer precursor bearing an ethynyl and an azido group. (d) This work: the cyclopolymerization of an α,ω-norbornenyl end-functionalized macromonomer.

macromonomer would meet the requirements of such a process. Cyclopolymerization is known to involve the chain polymerization of bifunctional monomers, in which intramolecular cyclization and intermolecular propagation processes occur in an alternating manner, to give soluble polymers bearing cyclic repeating units.23,24 Hence, we envisaged that the cyclopolymerization of a bifunctional macromonomer would afford a multicyclic polymer with the desired number of cyclic units (Figure 1d). This strategy, however, is exceedingly challenging since the cyclization reaction of long linear precursors to form large rings is thermodynamically disfavored. Indeed, typical cyclopolymerizations provide thermodynamically stable five- or six-membered rings,23−27 and a 37membered ring28 is the ring-size record for cyclic repeating units prepared so far by cyclopolymerization. The root cause of this issue involves the interplay between the monomer concentration and the polymerization kinetics. Decreasing the monomer concentration favors intramolecular cyclization but dramatically decreases the polymerization reaction rate. Consequently, an extremely active polymerization process that can be implemented even under highly dilute conditions is essential in order to realize macromonomer cyclopolymerization. The norbornenyl group was chosen as the polymerizable moiety in our macromonomer design because it has been reported that the ring-opening metathesis polymerization (ROMP) of norbornene-containing macromonomers, mediated by the Grubbs third-generation catalyst (G3), proceeds in a living manner with extremely fast polymerization kinetics.29−31 Herein, we report the first example of the controlled/living cyclopolymerization of α,ω-norbornenyl end-functionalized

polymer involves the preparation of a macrocyclic unit bearing a reactive group followed by the coupling reaction of the cyclic unit (Figure 1a).20 The intramolecular coupling reaction of a specially designed precursor polymer, possessing reactive groups at controlled positions, under high-dilution conditions, is an alternative pathway to a multicyclic polymer (Figure 1b).21 However, these strategies require tedious multistep syntheses and sometimes require the preparations of elaborately designed small molecules, such as initiators, terminators, and cross-linkers. Furthermore, such multistep syntheses can result in small defects, such as imperfect chainend fidelity, which eventually results in either the formation of ill-defined multicyclic polymers, or contamination by inseparable acyclic byproducts. On the other hand, Monteiro et al. recently reported an interesting strategy for the synthesis for multicyclic polymers in which cyclic polystyrene bearing an ethynyl and an azido group was polymerized through click chemistry (Figure 1c).22 Although this strategy provides access to multicyclic architectures in one step, considerable effort is required to synthesize the multifunctional cyclic precursor. In addition, due to the step-growth polymerization nature of this process, the resultant multicyclic polymer exhibits broad dispersity. Consequently, the development of a simple but robust pathway for the synthesis of multicyclic polymers that does not involve cyclic polymer precursors is of great interest. The repetitive use of the intramolecular macrocyclization of a linear polymer precursor followed by intermolecular propagation (e.g., cyclopolymerization) is an ideal strategy for realizing the expeditious synthesis of a multicyclic polymer. We proposed that the cyclopolymerization of an α,ω-bifunctional B

DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Cyclopolymerizations of α,ω-Norbornenyl End-Functionalized PLLA Macromonomersa

SEC-RI

SEC-MALS

Mn,SECb (g mol−1)

(Mw/ Mn)RIb

Mw,MALSc (g mol−1)

N.D.f

N.D.f

N.D.f

N.D.f

N.D.f

49.3 85.5 8.8

N.D.f N.D.f 95 87 82 94 93 87

run

macromonomer

[MM]0 (mM)

1

1a (Mn,NMR = 2820 g mol−1; Mw/Mn = 1.10)

10.0

6/1

5.0 1.0 0.10 0.10 −e 0.10 0.10 0.10

6/1 6/1 6/1 1/1 1/6 25/1 50/1 6/1

36 300 17 300 19 100 4 150 3 490 49 800 101 000 22 600

3.05 1.29 1.24 1.23 1.20 1.17 1.27 1.24

N.D.f N.D.f 49 100 N.D.f N.D.f 171 000 222 000 46 400

N.D.f N.D.f 1.14 N.D.f N.D.f 1.04 1.05 1.17

0.10 0.10 0.10

25/1 50/1 6/1

63 500 115 000 38 100

1.23 1.26 1.25

177 000 366 000 83 400

1.11 1.13 1.13

33.7 68.9 9.0

96 93 96

0.10 0.35

25/1 50/1

79 600 102 000

1.22 1.60

229 000 360 000

1.06 1.14

29.2 55.5

91 90

2 3 4 5 6 7 8 9 10 11 12 13 14

1b (Mn,NMR = 5020 g mol−1; Mw/Mn = 1.13)

1c (Mn,NMR = 7690 g mol−1; Mw/Mn = 1.12)

[MM]0/ [G3]0

(Mw/ Mn)MALSc

number of cyclic unitd

16.1

yield (%)

a Conditions: N2 atmosphere; solvent, CH2Cl2; temperature, rt; time, 1.5 h. bDetermined by SEC equipped with a refractive index detector (SEC-RI) in THF using polystyrene calibration. cDetermined by triple-detection SEC equipped multiangle light scattering, viscosity, and refractive index detectors (SEC-MALS) in THF. dAverage-number of cyclic repeating unit of the obtained multicyclic polymer was estimated as [(Mw,MALS of multicyclic polymer)/((Mw/Mn)MALS of multicyclic polymer)]/(Mn,NMR of macromonomer). eA solution of 1a in CH2Cl2 (0.30 g L−1) was slowly added to a stirred solution of G3 in CH2Cl2 (0.13 mM). fNot determined.

catalyzed) ring-opening polymerization (ROP)32 of L-lactide, initiated by 2,2-diethyl-1,3-propanediol, followed by the esterification of the hydroxyl end groups with excess exo-5norbornenecarboxylic acid; macromonomer 1a, with an Mn,NMR of 2820 g mol−1 and a polydispersity ((Mw/Mn)RI) of 1.10, was obtained in this manner. The quantitative incorporation of the norbornene end groups was verified by NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (see Supporting Information for further details). Higher molecular weight PLLA macromonomers 1b and 1c were also prepared in a similar manner. Cyclopolymerization of α,ω-Norbornenyl End-Functionalized PLLA Macromonomers. We first attempted to cyclopolymerize 1a in CH2Cl2 at a macromonomer concentration ([MM]0) of 10 mM in the presence of G3, with a 6/1 [MM]0/[G3]0 ratio (run 1 in Table 1). Unfortunately, these reaction conditions afforded an insoluble gel within several seconds of the addition of the catalyst. This suggested the formation of intermolecular cross-links, rather than the desired cyclopolymerization. To optimize the polymerization conditions, cyclopolymerization was then examined with decreasing macromonomer concentrations (5.0 mM in run 2, 1.0 mM in run 3, and 0.10 mM in run 4). Under these conditions, no

macromonomers to yield multicyclic polymers with the desired ring size and number of cyclic units. Owing to the excellent functional-group tolerance of G3, we successfully obtained multicyclic polymers that feature ultradense arrays of cyclic polymer units from a variety of α,ω-norbornenyl endfunctionalized macromonomers, such as poly( L-lactide) (PLLA), poly(ε-caprolactone) (PCL), poly(ethylene oxide) (PEO), poly(tetrahydrofuran) (PTHF), and PLLA-b-PEO-bPLLA. Cyclopolymerizations under the optimized reaction conditions facilitated the formation of multicyclic polymers that possess cyclic repeating units composed of up to about 500 atoms, which by far exceeds those prepared to date by cyclopolymerization.27 Moreover, multicyclic polymers composed of two different cyclic units were easily prepared by either statistical or block copolymerizations of two different macromonomers.

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RESULTS AND DISCUSSION Preparation of α,ω-Norbornenyl End-Functionalized Macromonomers. We first prepared the α,ω-norbornenyl end-functionalized PLLA 1a as the macromonomer. The PLLA diol (Mn,NMR = 2420 g mol−1, (Mw/Mn)RI = 1.10) was prepared by the 1,8-diazabicyclo[5.4.0]undec-7-ene-catalyzed (DBUC

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moieties and did not show signals corresponding to unreacted norbornenyl groups. This is convincing evidence for the absence of dangling norbornenyl groups; consequently, we conclude that the mole fraction of the cyclized unit is close to 100%. On the basis of the SEC and NMR results, we conclude that the ROMP of 1a, under highly dilute conditions, follows a cyclopolymerization pathway, with virtually no uncontrolled intermolecular cross-linking, leading to a multicyclic polymer composed of cyclic PLLA units on the polynorbornene backbone (i.e., poly(1a)). The absolute molecular weight (Mw,MALS) of poly(1a) was determined by triple-SEC in THF (consisting of multiangle light scattering (MALS), viscosity (Visc), and refractive index (RI) detectors; SEC-MALS) to be 49 100 g mol−1, from which the average-number of cyclic repeating unit was calculated to be ∼16. Here, it should be emphasized that each cyclic repeating unit is composed of approximately 100 atoms, which is much larger than the ring size of the cyclopolymers prepared to date by cyclopolymerization (37-membered ring).27 To further disclose the microstructure of the resulting polymer and to gain insight into the polymerization mechanism, we prepared a series of low molecular weight poly(1a)s by the cyclopolymerizations of 1a with [MM]0/ [G3]0 ratios of 1/1 and 1/6. The poly(1a) obtained at a [1a]0/ [G3]0 ratio of 1/1 (run 5 in Table 1) exhibited two SEC elution peak maxima at both shorter and longer elution times compared to that of 1a (Figure 3a). Notably, complete consumption of the norbornenyl end groups was confirmed by 1H NMR spectroscopy. Therefore, the higher molecular weight peak was assigned to a multicyclic PLLA with a low degree of polymerization formed by cyclopolymerization, while the lower molecular weight peak is assigned to the monocyclic PLLA formed by intramolecular cyclization without intermolecular propagation. In contrast, the SEC trace of the product obtained at a [1a]0/[G3] ratio of 1/6 (run 6) displayed a monomodal peak in the lower molecular weight region, which is strong evidence in favor of the formation of a pure monocyclic polymer. In order to directly determine the microstructure of this product, we employed MALDI-TOF mass spectrometry. The MALDI-TOF mass spectrum of the product from run 6 exhibited two molecular weight distributions, both of which are assignable to a monocyclic PLLA composed of a ring-opened dimeric norbornene and a benzene ring that originated from the G3 catalyst (Figure 3b,c). For example, the peaks at m/z values of 2301.2 and 2373.2 Da can be assigned to the sodium adduct of monocyclic PLLAs composed of 25 and 26 lactyl units, respectively. Note that the PLLA composed of odd number of lactyl units seems to be formed by the transesterification reaction during the PLLA diol preparation (see Figure S1). To our surprise, there was no peak corresponding to a linear PLLA byproduct (see Chart 1), which indicates that intramolecular cyclization occurred very rapidly rather than coordination of another G3 catalyst. Hence, the initiation step of the present cyclopolymerization process can be described as follows: G3 coordination to one of the norbornenyl group of 1a leads to the ring-opening of the norbornene ring and subsequent Ru carbene formation. The Ru carbene then rapidly attacks another norbornenyl group in the same molecule, leading to the formation of the intramolecularly cyclized polymer that still bears an active Ru−carbene moiety. Because of the highly dilute conditions, the intermolecular propagation reaction is the rate-determining step. Repetitive

gelation was observed during the course of the polymerization reaction. Multimodal elution peaks were observed in the size exclusion chromatograms (SEC traces) of the products obtained at macromonomer concentrations of 5.0 and 1.0 mM (runs 2 and 3), while a unimodal and narrowly dispersed SEC elution peak, with an (Mw/Mn)RI value33 of 1.24, was observed for the product obtained at a macromonomer concentration of 0.10 mM (run 4) (Figure 2a). Hence,

Figure 2. (a) SEC traces (refractive index (RI) detection; eluent, THF; flow rate, 1.0 mL min−1) of the products obtained from the cyclopolymerizations of 1a at various macromonomer concentrations. (b) 1H NMR spectra of 1a and the corresponding multicyclic polymer (run 4) in CDCl3 (400 MHz).

lowering the macromonomer concentration effectively facilitated controlled cyclopolymerization rather than uncontrolled intermolecular reactions, resulting in the formation of a soluble polymer with very narrow dispersity. We were surprised that the macromonomer conversion exceeded 99% within 1.5 h, even at the very low macromonomer concentration of 0.10 mM, which we attribute to the extraordinarily high reactivity of the G3 catalyst. The polymer obtained from run 4 was subjected to 1H NMR spectroscopy in order to examine its microstructure and to determine the mole fraction of the cyclized unit (Figure 2b). The precursor polymer 1a exhibited proton signals due to the norbornenyl group (e.g., olefinic proton i at 6.12 ppm in Figure 2b), while the product following cyclopolymerization exhibited signals due to the polynorbornene backbone and PLLA D

DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX

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Figure 3. Structural analyses of low molecular weight multicyclic PLLAs prepared by the cyclopolymerization of 1a. (a) SEC traces of the multicyclic and monocyclic PLLAs obtained at [1a]0/[G3]0 ratios of 1/1 (run 5) and 1/6 (run 6). (b) MALDI-TOF mass spectrum of the monocyclic PLLA obtained from run 6. An enlarged spectrum of the 2280−2400 Da range is also shown. (c) Expected chemical structure of the monocyclic PLLA.

Chart 1. Mechanism for the Formation of a Multicyclic Polymer through Cyclopolymerization

intramolecular cyclization and intermolecular propagation then occur to form the multicyclic polymer (Chart 1). The chain-growth mechanism of the present cyclopolymerization process can be confirmed by monitoring the reaction by SEC. As shown in Figure 4a, the polymerization system always contained a mixture of multicyclic polymers and the macromonomer, with the apparent molecular weight of the products increasing with increasing polymerization time, accompanied by the continuous consumption of the macromonomer. This behavior is in clear agreement with the chaingrowth polymerization mechanism, which further verifies that the present polymerization proceeds in a cyclopolymerization manner. Given that G3-catalyzed ROMP is known to proceed in a living fashion,29−31 the present cyclopolymerization should also exhibit living behavior. To confirm the living nature of this cyclopolymerization system, we examined its kinetics based on the macromonomer conversion values calculated from the SEC profiles. The correlation between ln([MM]0/[MM]) and time is displayed in Figure 4b and clearly demonstrates that the present cyclopolymerization process follows first-order kinetics with respect to the macromonomer, which is consistent with the intermolecular propagation reaction being the ratedetermining step. This is compelling evidence that the cyclopolymerization process proceeds in a living fashion even

under highly dilute conditions; this living nature is highly beneficial for controlling the numbers of cyclic repeating units on the resulting multicyclic polymers as well as the synthesis of multicyclic block copolymers. With these promising results in hand, we next investigated the scope of this cyclopolymerization strategy for the synthesis of multicyclic polymers with varying ring sizes and cyclic units. The syntheses of cyclopolymers possessing larger ring sizes have been challenging tasks in cyclopolymerization chemistry because of the difficulties associated in forming the thermodynamically unfavorable large ring; consequently, several strategies to overcome this issue have been developed, including the incorporation of a rigid spacer in the monomer34 and the use of a template.35 With this in mind, we attempted to cyclopolymerize PLLA macromonomers with higher molecular weights, i.e., Mn,NMR values of 5020 and 7690 g mol−1 (1b and 1c, respectively), with a [MM]0/[G3]0 ratio of 6/1 at a macromonomer concentration of 0.10 mM in CH2Cl2. Despite the increase in the macromonomer molecular weight, the cyclopolymerizations proceeded quantitatively, without gelation, to give the corresponding multicyclic polymers, i.e., poly(1b) and poly(1c), with narrow dispersities of 1.24−1.25 (runs 9 and 12); however, a small shoulder in the higher molecular weight region was visible in each SEC trace (Figure E

DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX

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incorporate the norbornenyl groups, and cyclopolymerization. This is in sharp contrast to conventional synthetic approaches reported to date for the synthesis of multicyclic polymers, such as trefoil- and quatrefoil-shaped polymers. Physical Properties Associated with Multicyclic Architectures. It is well-known that polymer properties, such as glass-transition temperature (Tg), viscosity, and hydrodynamic radius,1,36−39 are affected by polymer architecture. For example, a cyclic polymer exhibits a higher Tg and a lower viscosity and hydrodynamic radius compared to its linear counterpart. Hence, a comparison of these properties for the obtained poly(1)s with those of the corresponding acyclic counterparts, i.e., PLLA brush polymers, provides supporting evidence of their multicyclic architectures. Here, we compared the Tg values, intrinsic viscosities ([η]), and hydrodynamic radii (Rh) of the poly(1b)s with those of PLLA brush polymers of comparable side-chain and main-chain lengths, i.e., the poly(1′)s. In accordance with our previous report,40 poly(1′)s with a variety of main-chain lengths were prepared by the G3initiated ROMP of NB-PLLA (1′; Mn,NMR = 2890 g mol−1, (Mw/Mn)RI = 1.09) (Figure 5a). The only structural difference between poly(1b) and poly(1′) is the presence/absence of cyclic structures on the PLLA moiety. Importantly, the molecular weight of 1′ is nearly half that of 1b, so that the fully extended lengths of the PLLA chains in poly(1b) and poly(1′), as measured from the polynorbornene backbone, are comparable (Figure 5b). Differential scanning calorimetry (DSC) was employed to study the Tg of the poly(1b)s and poly(1′)s (Figure 5c). Tg values in the 54.4−56.4 °C range were observed for the poly(1b)s, which are approximately 5 °C higher than those of the poly(1′)s (51.0−51.7 °C). The higher Tgs of the poly(1b)s is attributable to the cyclic architecture of the PLLA moiety; the PLLA brushes in the poly(1′)s possess free chain ends on their arms, while the poly(1b)s do not have chain ends on their PLLA moieties. The cyclic architecture of poly(1b) restricts its molecular motion in the solid state, which contributes to an increase in the Tg of the PLLA moiety. The [η] and Rh of a high molecular weight poly(1b) in THF were investigated using an online SEC system equipped with viscosity and MALS detectors. As compared to a poly(1′), with Mw,MALS of 353 000 g mol−1, a poly(1b) with Mw,MALS of 366 000 g mol−1 exhibited smaller [η] and Rh in the same absolute molecular weight region (Figure 5d,e). These results are consistent with the observation that cyclic polymers are dimensionally smaller in solution than their acyclic counterparts. On the basis of thermal and solution−property analyses, we conclude that the polymers produced by the cyclopolymerization reactions in this study possess multicyclic architectures. Synthetic Applications of the Cyclopolymerization Approach. To further extend the potential of the present cyclopolymerization strategy, we examined the cyclopolymerizations of a variety of macromonomers that possess a norbornenyl group at each chain end. Here, we employed the α,ω-norbornenyl end-functionalized poly(ε-caprolactone) (PCL, 2), poly(ethylene glycol) (PEG, 3), poly(tetrahydrofuran) (PTHF, 4), and a triblock copolymer of PLLA and PEG (PLLA-b-PEG-b-PLLA, 5) as macromonomers (Scheme 1). Note that these macromonomers were prepared in one or two steps from commercially available starting materials (see Supporting Information for more details). The previously established polymerization conditions (vide supra) were very effective for the cyclopolymerizations of the PCL (2), PEG (3),

Figure 4. Determining the kinetics of the cyclopolymerization of 1a ([1a]0/[G3]0 = 50/1; [1a]0 = 0.18 mM). (a) Time-dependent SEC profiles during cyclopolymerization. (b) Time−conversion and firstorder kinetic plots for the cyclopolymerization process.

S4). Hence, we succeeded in synthesizing multicyclic PLLAs possessing large cyclic units composed of up to 300 atoms (300-membered rings), which is almost 8 times larger than the ring size achieved by conventional cyclopolymerization methods. In addition, multicyclic PLLAs with higher mainchain degrees of polymerization were also easily obtained from macromonomers 1a−c by varying the [MM]0/[G3]0 ratio from 6/1 to 50/1 (runs 10, 11, 13, and 14). Because of the living nature of the present cyclopolymerization system, the molecular weight of the resulting multicyclic PLLA increased with increasing [MM]0/[G3]0 ratio, almost without affecting the (Mw/Mn)RI value. However, prominent increases in the (Mw/Mn)RI values were observed during the cyclopolymerizations of 1b and 1c at the higher [MM]0/[G3]0 ratio (runs 11 and 14), which we ascribe to the formation of appreciable intermolecular cross-links. Notably, in many cases, the averagenumber of cyclic repeating unit of the resultant multicyclic PLLAs roughly agreed with the expected value (= [MM]0/ [G3]0). The highest molecular weight (Mw,MALS) achieved in this system was 366 000 g mol−1, which corresponds to an approximate 29-unit array of rings that are approximately 200membered. These results clearly demonstrate the robustness of the present cyclopolymerization approach for the synthesis of multicyclic polymers. We emphasize here that such complex multicyclic architectures are prepared in only three steps; i.e., preparation of the telechelic polymer, end-functionalization to F

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Figure 5. Comparing the physical properties of multicyclic (poly(1b)) and the corresponding brush PLLA (poly(1′)). (a) Synthesis of poly(1′). (b) Illustrating the structural similarities between poly(1′) and poly(1b). (c) Tg values of poly(1b) (runs 9−11; blue circles) and poly(1′) (runs S16− S18 in Table S4; red squares) as functions of their absolute molecular weights. (d) Mark−Hauwink−Sakurada plots and (e) conformation plots for high molecular weight poly(1b) (run 11; Mw,MALS = 366 000 g mol−1; blue circles) and poly(1′) (run S18 in Table S4; Mw,MALS = 353 000 g mol−1; red squares).

Scheme 1. Cyclopolymerizations of α,ω-Norbornenyl End-Functionalized (a) PCL, (b) PEG, (c) PTHF, and (d) PLLA-b-PEGb-PLLA Macromonomers

the corresponding multicyclic PCL with an Mw,MALS of 556 000 g mol−1 ((Mw/Mn)RI = 1.30). This polymer has ∼69 cyclic repeating units, each of which is composed of around 500 atoms (500-membered rings). The optimized conditions were also applied to the cyclopolymerization of the block copolymer-type macromonomer 5 ([5]0/[G3]0 = 6/1) to successfully give a

and PTHF (4) macromonomers at [MM]0/[G3]0 ratios of 6, 25, and 50, affording the corresponding multicyclic polymers with narrow dispersities (see Tables S1−S2 for the cyclopolymerizations of 2−4, respectively). It is noteworthy that the cyclopolymerization of the PCL macromonomer 2c, which has a relatively high molecular weight (Mn,NMR = 7720 g mol−1), successfully proceeded at a [MM]0/[G3]0 ratio of 50/1 to give G

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Figure 6. Statistical and block cyclocopolymerizations of 1b and 3. (a) Syntheses of amphiphilic multicyclic statistical and block copolymers. (b) SEC traces of the statistical and block copolymers as well as the corresponding macromonomers.

the norbornenyl group was not observed in the 1H NMR spectrum of this copolymer, which also confirms that the mole fraction of the cyclic unit is very high (almost 100%). We are currently exploring the specific properties of these amphiphilic multicyclic copolymers in micellization and microphase separation.

multicyclic polymer bearing amphiphilic cyclic repeating units (poly(5); Mw,MALS = 40 600 g mol−1, (Mw/Mn)RI = 1.07). This type of multicyclic polymer can self-assemble into micelles in water, which is of interest from the perspective of drug delivery. Indeed, poly(5) self-assembled in an aqueous environment to afford a micellar aggregate with a hydrodynamic radius of ∼10 nm (Figure S17). Interestingly, the micellar aggregate from poly(5) was more thermally stable in aqueous solution than that formed from macromonomer 5 (Figure S18). The absence of PLLA free chain ends in poly(5) due to the multicyclic architecture may be responsible for the increased micellar thermal stability.8 The utility of the present methodology was further demonstrated through the synthesis of amphiphilic multicyclic copolymers by either statistical or block cyclocopolymerizations of the PLLA (1b) and PEG (3) macromonomers (Figure 6a). The statistical cyclocopolymerization of 1b and 3 was carried out at a [1b]0/[3]0/[G3] ratio of 3/3/1 to afford a soluble product without gelation (Mw,MALS = 49 800 g mol−1, (Mw/ Mn)RI = 1.43). SEC analysis of the product revealed that both macromonomers had been quantitatively consumed (Figure 6b), and the 1H NMR spectrum clearly exhibited signals due to both PLLA and PEG blocks. Hence, the product obtained from this reaction is undoubtedly assignable to the amphiphilic multicyclic copolymer composed of PLLA and PEG cyclic repeating units (i.e., poly(1b-st-3)). Note that the SEC trace of poly(1b-st-3) exhibited a tailing toward the lower molecular weight region, indicating appreciable formation of byproducts. A possible side reaction involves the backbiting reaction due to the prolonged reaction time.41 The block copolymerization of 1b and 3 was also successful and afforded a multicyclic block copolymer (i.e., poly(1b-b-3)). In the first step, the cyclopolymerization of 1b was performed at a [1b]0/[G3]0 ratio of 6/1 to give a multicyclic PLLA with a quantitative macromonomer conversion. Following the addition of 3 (6 equiv with respect to G3) to the polymerization mixture, an increase in the apparent molecular weight was observed by SEC analysis of the final product (Mw,MALS = 124 000 g mol−1, (Mw/Mn)RI = 1.43). This is excellent evidence for successful block copolymerization. The 1H NMR spectrum also supported the incorporation of both macromonomers (Figure S15); the 1H NMR signal of

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CONCLUSION

In summary, we developed a novel synthetic approach to multicyclic polymers based on the controlled cyclopolymerizations of α,ω-norbornenyl end-functionalized macromonomers using the Grubbs third-generation catalyst (G3). The present methodology enables the easy preparation of multicyclic homopolymers (PLLA, PCL, PTHF, and PEG), as well as multicyclic copolymers (composed of PLLA and PEG segments), in which the number of cyclic repeating unit can be controlled to ∼70 by simply tuning the [macromonomer]0/ [G3]0 ratio, a result of the living polymerization characteristics. More importantly, we successfully synthesized multicyclic polymers possessing cyclic repeating units composed of up to around 500 atoms (500-membered rings); such rings are far larger than ones prepared previously using cyclopolymerization methods. A key to the successful cyclopolymerizations of these macromonomers is the combination of norbornenyl groups as the polymerizable moieties and the highly active G3 catalyst; this facilitates ROMP even under extraordinarily high dilution conditions, which is essential for eliminating undesired intermolecular cross-linking. The present strategy offers significant opportunities for the creation of a wide variety of monocyclic and multicyclic polymers with unique properties and functions. Further studies on the synthetic applications of this methodology are currently ongoing in our group, and the physicochemical properties of a series of multicyclic polymers will be investigated in order to uncover the specific characteristics that originate from the unprecedented and unique architectures that feature ultradense arrays of macrocyclic units. H

DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX

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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.8b00355. Experimental details and additional data (1H NMR, MALDI-TOF MS, SEC, DSC, and DLS) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (T.I.). *E-mail: [email protected] (T.S.). ORCID

Takuya Isono: 0000-0003-3746-2084 Takuya Yamamoto: 0000-0001-9716-8237 Kenji Tajima: 0000-0002-3238-813X Toshifumi Satoh: 0000-0001-5449-9642 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by a MEXT Grant-in-Aid for Challenging Exploratory Research (16K140000). REFERENCES

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DOI: 10.1021/acs.macromol.8b00355 Macromolecules XXXX, XXX, XXX−XXX