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Relay Conjugation of Living Metathesis Polymers Liangbing Fu, Tianqi Zhang, Guanyao Fu, and Will R. Gutekunst J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07315 • Publication Date (Web): 30 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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Journal of the American Chemical Society

Relay Conjugation of Living Metathesis Polymers Liangbing Fu, Tianqi Zhang, Guanyao Fu and Will R. Gutekunst* School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive NW, Atlanta, Georgia 30332, United States Supporting Information Placeholder ABSTRACT: The covalent coupling of complex macromolecules is a modern challenge in both chemistry and biology. The development of efficient and chemoselective methods for polymer coupling and functionalization are increasingly important for designing new advanced materials and interfacing with biochemical systems. Herein, we present a new strategy to directly conjugate living polymers prepared using ring-opening metathesis polymerization (ROMP) to both small molecules and synthetic macromolecules. Central to this methodology is a terminal alkyne that serves as a directing group to promote a rapid, intramolecular reaction with an otherwise unreactive olefin. This highly chemoselective relay conjugation is compatible with a range of monomer families and uses a bench-stable enyne motif that can be easily introduced to functional targets. The rapid rate of the conjugation reaction paves the way for greatly streamlined construction of complex macromolecular systems derived from metathesis polymerization techniques without the need for specialized equipment.

Introduction A longstanding challenge in polymer science is the ability to rapidly build functional materials under milder conditions and with more straightforward protocols. “Click chemistry” has furthered this goal by enabling polymer scientists to treat macromolecules as individual building blocks in order to construct complex polymer architectures and block polymers, provided the appropriate functional groups are installed (e.g. azides, alkynes, cyclooctynes, tetrazines, cyclopropenes).1 Unfortunately, these privileged reactive groups frequently needs to be introduced through post-polymerization modification, thereby requiring additional synthesis and purification steps.2 A more straightforward approach would be to use the reactive species or catalyst employed during polymerization to immediately couple the “living” polymer to another macromolecule of interest. Unfortunately, the stringent demands of polymerpolymer coupling resulting from macromolecular entanglement and low chain-end concentration prevents the use of this approach with most polymerization techniques, and application of this strategy with functional-group tolerant methods has not yet been reported.3 One technique which appears to have all the features necessary for this ideal goal is ring-opening metathesis polymerization (ROMP) using Grubbs-type ruthenium initiators.4 In addition to the established chemoselectivity and functional group compatibility of ROMP,5 modern Grubbs systems are capable of rapid and repeated macromolecular couplings during the synthesis of densely-grafted bottle-brush polymers from macromonomers.6 Despite the clear power of the propagating ruthenium alkylidene, methods to rapidly and stoichiometrically terminate this species with functional small molecules are lacking, as are methods to terminate with macromolecules.7 Significant efforts towards this end have been reported, starting with a seminal report by Kiessling in 2000.8 Here, a substituted vinyl ether derivative was shown to undergo regioselective cross-metathesis to install an ester at the polymer terminus, while also deactivating the ruthenium species as a Fisher-carbene complex (Figure 1A). Later developments by Kilbinger introduced creative approaches to install specific functional groups (aldehydes, carboxylic acids, amines, and others) using unsaturated heterocyclic, chain-transfer, and sacrificial synthesis strategies.9 Symmetrical cis-olefins have also been frequently employed to generate

end-functionalized polymers, as shown initially by Li and later explored in detail by Grubbs, though this reaction leaves behind an active ruthenium species.10 While each of these methods have proven useful,11 they all require a large excess of the terminating reagent (3-20 equivalents) and extended reaction times (3-15 hours) to generate the desired functional polymers. Very recently, a report by Elling and Xia demonstrated rapid single monomer addition with near stoichiometric quantities of cyclopropene derivatives (1.1 eq) that provide chain-end functionalized polymers after further termination.12 While a significant development, this and prior strategies have not demonstrated the ability to perform direct and efficient polymer-polymer coupling. In this study, the first mild and stoichiometric method to couple living polymers with other macromolecules is reported that simultaneously removes and deactivates the ruthenium catalyst. In order to overcome issues of reactivity and selectivity in small molecule organic synthesis, directing groups are commonly employed, as can be seen in the flourishing area of C–H activation (Figure 1B).13 A directing group guides a moderately reactive catalyst species into close proximity with the desired reaction site. By lowering the entropic barrier, an otherwise unfavorable process is facilitated. Surprisingly, this powerful bond forming strategy is not frequently applied to macromolecular systems. To translate this concept to metathesis polymerization, we envisioned that a directing group could be strategically applied to promote the reaction of the ruthenium alkylidene with a hindered olefin. The design of the developed termination system takes inspiration from both Hoye’s relay-ring closing metathesis14 (Figure 1B) and Choi’s enyne metathesis polymerization,15 and uses a terminal alkyne as the directing element. Terminal alkynes display remarkable reactivity with NHC-ligated Grubbs systems16 and have also seen increased utility to promote metallotropic polymerizations,17 as well as to serve as a promoter for in situ initiator modification.18 The overall design of the termination system has three key elements (Figure 1C). First is the terminal alkyne, which rapidly reacts with the living polymer chain and directs the ruthenium alkylidene towards the neighboring olefin. Second is the nitrogen linker, which becomes covalently linked to the end of the polymer and can be attached to an array of functional groups or polymers. The final design component is the

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Figure 1: Overview of methods for ROMP termination. A. Direct cross-metathesis and sacrificial synthesis strategies. B. Strategic applications of directing groups to overcome reactivity issues in small molecule synthesis. C. Design of new alkyne-directed relay metathesis for polymer chain-end conjugation. low-brown reaction solution transitioned to a light green. Analysis cinnamyl sulfide, which, after enyne metathesis, traps the metal of the oligomer by size exclusion chromatography (SEC) showed a center as a thioether chelate that is inert to further metathesis.19 These components combine to create an extremely robust and single, unimodal peak demonstrating that chain-chain coupling did bench stable motif for polymer conjugation. The reactions are highnot occur. ly efficient and remarkably fast, such that the stoichiometric couAfter precipitation into methanol, the purified polymer P1-Ts pling of two synthetic polymers can be achieved in a matter of chain ends were analyzed by 1H NMR (Figure 2C). Diagnostic hours and without the need for installation of traditional “click” protons were observed that confirmed the presence of a vinyl dihyfunctional groups. dropyrrole unit with a tosyl group attached to the polymer (see Figure S4 for full characterization). Importantly, diagnostic protons Results and discussion at each end of the polymer chain can be independently integrated to compare the efficiency of the conjugation reaction. On the initiatTo demonstrate this concept, a short and scalable synthesis of the ing end, the styryl protons present from the G-3 initiator were visiversatile enyne amine 4 was developed starting from 2ble at 6.59 ppm (blue squares), and the peak at 7.75 ppm could be fluorobenzaldehyde 1 (Figure 2A). First, nucleophilic aromatic assigned to the two equivalent protons of the tosyl ring (red triansubstitution of the fluoride with odorless dodecanethiol was pergle) at the polymer terminus. The relative integration of these two formed to give aldehyde 2 in 88% yield. Wittig reaction with a peaks was 1:1.95, which implies the desired enyne metathesis reacphosphorus ylide acetal, followed by hydrolysis upon workup, tion took place with very high efficiency (>95%). While this reacafforded the substituted cinnamaldehyde 3. Lastly, reductive amition and others appear to be quantitative, limitations in the NMR nation of 3 with propargyl amine gave the targeted terminator technique prevents confidence in assigning chain-end fidelity amine 4 in 88% yield. Given the numerous methods available to above 95% and the results in this manuscript are reported accordfunctionalize secondary amines, this molecule serves as a key diingly. vergent intermediate to generate a range of functional terminators for ruthenium metathesis polymerization. Additional support for the designed termination reaction was observed in the ruthenium alkylidene C–H region (15 - 20 ppm) of In order to verify the enyne termination concept and permit the crude 1H-NMR spectrum. During polymerization, the propagatstraightforward characterization, a p-toluene sulfonyl (tosyl, Ts) ing alkylidene can be observed as a broad peak at 18.6 ppm. After group was installed on the terminator amine through reaction with addition of the enyne terminator, this broad peak shifts to a new, tosyl chloride. To simplify the chain-end characterization by nuclesharp signal at 17.28 ppm along with a smaller peak at 17.18 ppm ar magnetic resonance (NMR), short oligomers were prepared from (Figure 2D). These two peaks were verified to be isomers of the the ring-opening metathesis polymerization of exo-methyl norsame sulfur chelated complex in which the initially formed transbornene imide monomer M1 with a target degree of polymerization isomer slowly converts into the more stable cis-isomer. This isom(DP) of eight monomer units (M/I = 8). After rapid initiation and erism has also been observed by Lemcoff in the study of sulfur polymerization using the third generation Grubbs catalyst (G3), a chelated latent olefin metathesis catalysts.19 Independent studies slight excess of the tosyl terminating agent 4-Ts (1.3 eq) was dialso rectly added to the polymerization solution (Figure 2B). A color change was observed over the course of minutes in which the yel2


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Figure 2: Synthesis and characterization of enyne termination. A. Synthesis of enyne amine 4. B. Polymerization and termination to prepare a tosyl-terminated ROMP polymer. C–E. Characterization of the chain-end functionalized polymer with NMR and mass spectrometry. also synthesized and evaluated. These included a trifluoromethyl verified that the chelated benzylidene is no longer reactive in benzamide (P1-CF3) to facilitate characterization, a cyclic carROMP (see Figure S35). bonate (P1-carbonate) and a TMS-alkyne (P1-alkyne). Each of While the NMR data was encouraging and no other chain-ends these examples gave results as impressive as the initial P1-Ts were observed, Matrix-Assisted Laser Desorption/Ionization – study, which is perhaps unsurprising given the established funcTime of Flight (MALDI-TOF) mass spectrometry was also used to tional group tolerance of the Grubbs catalyst. High chain-end confurther confirm the structure and high chain-end fidelity. The versions (>95%) were seen in all cases by 1H NMR, and no other MALDI-TOF spectrum of P1-Ts is shown in Figure 2E and disside reactions were observed. MALDI-TOF analysis of the polyplays a single series of narrowly distributed molecular ions with the mers further reinforced this assertion, though some displayed some highest intensity at 2026.811 m/z. Each of the peaks in the series intensity dependent peaks attributed to ion fragmentation. A particare separated by 177 atomic mass units, corresponding to the moularly notable substrate in this series is the TMS-alkyne terminator. lecular weight of the exo-norbonene imide monomer, M1. ImWhile a free terminal alkyne enables the relay conjugation reaction portantly, each of the observed molecular ions in the spectrum to occur, the sterically hindered TMS-alkyne is unreactive and directly corresponds to the calculated molecular weight of a silver leads to an alkyne terminated polymer for possible further funccharged oligomer with a phenyl group at one end and a tosyl sultionalization with copper catalyzed azide-alkyne click chemistry.20 fonamide at the other. To further verify that the sulfonamide chainFurthermore, while 1.3 equivalents were employed for these experend did not bias the observed spectrum through preferential ionizaiments to ensure full conversion, use of 1.05 equivalents gave idention, MALDI was performed on a mixture of P1-Ts and an ethyl tical results after extending the reaction time to one hour (See Figvinyl ether terminated P1 analog. Two distinct series of molecular ure S34). ions were clearly observed in the spectrum at similar intensities, In addition to different terminating groups, various monomer suggesting selective ionization is not occurring (See Figure S6). types (M2−M6) were evaluated for compatibility with this method Having established confidence in the chemistry, exploration of the and were characterized using SEC, 1H NMR spectroscopy and scope of the method was undertaken. A series of terminators were MALDI-TOF analysis (Table 1B). Both endo- and exo-benzyl norprepared in a straightforward manner from terminator amine 4 (see bornene imides cleanly reacted to deliver the chain-end terminated Supporting Information for syntheses) and were reacted with a polymers exo-P2-Ts and endo-P2-Ts, respectively. The oxanorpolymer derived from M1 to give a series of functional P1 polybornene derivative (M4) terminated uneventfully, and the faster mers (Table 1A). For each entry, a P1-[Ru] living polymer was polymerizing norbornene butyl ester monomer (M3) successfully synthesized with DP of 30 and was terminated using 1.3 equivaunderwent the termination reaction in a rapid and high yielding lents of each enyne. To maintain homology to the tosyl unit, sulmanner to give P4-Ts and P3-Ts, respectively. Completely differfonamide derivatives were initially evaluated with useful functionent monomer classes such as cyclic enyne (M5) and yne-yne (M6) ality. These include a bromo-isobutryate that could serve as an monomers were also explored to provide chain-end functionalized ATRP initiator (P1-Br), a benzyl alcohol derivative (P1-OH), an products. The final monomer tested in this series was a 1,6-diyne N-hydroxy succinimide (NHS) ester (P1-NHS), and a thiolactone monomer M6, in which slightly lower reaction efficiency was seen (P1-thiolactone). Amide derivatives of terminator amine 4 were 3



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Table 1: Terminator and polymer scope of the enyne-mediated conjugation reaction.

Termination efficiency determined by 1H NMR chain-end analysis and molecular weights determined by SEC (CHCl3) with polystyrene standards. a The reaction was performed in THF (0.4 M) at 0 ºC and N-trisyl enyne terminator S2 was used to enable chain-end analysis by 1 b H NMR. The reaction was performed in THF (0.5 M) at –10 ºC. 1 by H-NMR (85%). It is believed that this is not the result of the method, as the polymerization reaction has been shown to have some chain-end decomposition over time.21 Furthermore, 1H NMR suggested high fidelity (>95%) in all the above examples except the yne-yne, and MALDI data reinforced the assertion in all cases that the polymers were able to ionize. A few limitations were observed during the investigation of the small molecule termination scope. While amides and sulfonamides performed well, basic amine containing terminators, such as 4, were less effective and gave multiple products, even when protonated as a trifluoroacetate salt (See Supporting Information Figures S40). This is perhaps due to the ability of these amines to coordinate to the ruthenium species in solution or interact with the NHC ligand.22 Additionally, this method may be specific for NHCligated metathesis systems, as the reaction of 4-Ts with the first generation Grubbs catalyst was ineffective, even when employing ten equivalents of the terminator (See Supporting Information Figure S39). This could be due to the lower reactivity of Grubbs 1 with terminal alkynes,16 and similar observations have been made in area of yne-yne metathesis polymerization.22 To further evaluate the chain-end fidelity of the new enyne conjugation, chain-extension experiments were performed using bromide-terminated polymer P1-Br as a macroinitiator (Figure 3). A poly(styrene) block was grown from P1-Br using classical atom transfer radical polymerization (ATRP) conditions.10d, 23 As can be seen from the SEC chromatogram, the low dispersity macroinitiator dramatically increases in molecular weight after polymerization of the polystyrene block giving P1-b-PS (Mn = 30.5k, Đ = 1.29). Notably, the complete shift observed in the elution peak of the diblock polymer after polymerization further suggests the very high effiFigure 3: Synthesis of P1-b-PS diblock polymer though chain ciency of the enyne chemistry and also demonstrates the ease in extension with styrene and SEC (CHCl3) characterization. 4


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Figure 4: Direct polymer-polymer coupling of living P1-[Ru] with PEO enynes to rapidly and efficiently prepare diblock structures. SEC samples were run in chloroform and the number average molecular weights were determined by multi-angle light scattering. tion of 1.0 mM was also successful under the same reaction condiwhich block polymers can be synthesized using this protocol. tions (See Supporting Information Figures S25-26). The 4- and 8Given the scope, speed, and efficiency of the termination reacarm star PEG macroterminators performed similarly, though resulttions with small molecules, the power of this method was further ed in significantly higher molecular weights (Mn = 44.7 kDa, Đ = examined in polymer–polymer coupling, which would dramatically 1.10 and Mn = 78.6 kDa, Đ = 1.10, respectively), as many more expand the utility of ROMP-based methods.24 In addition to the coupling events occurred. As expected with branched and star polsteric blocking of the reactive site through macromolecular entanymers, the apparent molecular weight measured by SEC relative to glement, the chain-ends that need to encounter each other are usupolystyrene standards was underestimated due to decreased hydroally at much lower concentration than is typically found in standard dynamic volume of these architectures, but accurate molecular small molecule reactions. To test the potential of polymer-polymer weight data was obtained through multi-angle light scattering excoupling with enyne-mediated conjugation, a series of periments. poly(ethylene oxide) (PEO) macroterminators were prepared with a Importantly, the SEC chromatograms shown in Figure 4 are crude terminator enyne motif installed at each chain-end. In addition to a reaction mixtures without any attempt to purify the product dilinear PEO sample (5 kDa), 4-arm and 8-arm star PEO macroterblocks. This highlights the near-stoichiometric ratios of these reacminators were also examined (10 kDa). The PEO macroterminators tants, as only trace quantities of the ROMP homopolymer is detectwere easily prepared in a single step from a commercially available able after relay conjugation. To further demonstrate the high conamine-terminated PEO and NHS-ester derived enyne S6. versions of these coupling reactions, 1H NMR chain-end analysis The polymer–polymer coupling experiments were carried out was per formed. As can be seen in Figure 5, a clear doublet of trianalogously to the previous studies, in this case employing stoichiplets is visible for the styrenic proton of the enyne moiety in the 4ometric quantities of the two reactants (Figure 4). For each PEG arm PEO enyne macroterminator. After reaction with 1.0 equivaarchitecture, a DP 40 P1-[Ru] polymer was synthesized (Mn = 9.3 lent of P1-[Ru], these peaks completely disappear in the 4-arm P1kDa, Đ = 1.04) and directly reacted with each PEO enyne macrob-PEO product spectrum in the same range. Control experiments terminator at concentrations of 3-4 mM. Consistent with the small with substoichiometric amounts of P1-[Ru] clearly show these molecule experiments, a color change of the solution was observed peaks remaining with incomplete coupling (See Figure S29). over the course of minutes and indicated the formation of the sulTo further illustrate the full conversion of the 4-arm macrotermifur-chelated ruthenium complex. Given the stoichiometric and nator, experiments were also performed with an excess of ROMP macromolecular nature of these reactions, the reaction times were polymer. In this case, the peak shape and molecular weight of the extended to three hours. As is shown by the SEC trace in Figure 4, star diblock product does not change or shift by SEC analysis, ima significant increase in molecular weight was observed for the plying complete coupling was achieved (Figure 6). These controlinear terminator, resulting in the symmetrical, unimodal diblock lexperiments were also performed for the linear and 8-arm diblock polymer P1-b-PEG (Mn = 11.9 kDa, Đ = 1.11). Use of a higher series (see Figures S24 and S32) with analogous results. molecular weight P1-[Ru] (DP 150, Mn = 36.0 kDa) at a concentra5



Figure 5: 1H NMR (d-chloroform) of the olefinic region for the 4arm PEO terminator and star diblock product showing full conversion of enyne.

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Figure 7: Kinetic study of the polymer-polymer coupling reaction between P1-[Ru] and 4-arm PEO enyne monitored by sizeexclusion chromatography in chloroform. the course of the reaction (see Figure S37). After enyne metathesis, it is proposed that the thioether chelate displaces a pyridine ligand that was bound to the ruthenium center. This increases the amount of free pyridine in solution, which reduces the rate of reaction, as there is an inverse first-order dependence in pyridine.25 The initial rates for the enyne metathesis appear to be >2 M-1s-1, thereby holding great promise for future terminator designs. This slight product inhibition could also be beneficial, as additional pyridine ligand has been shown to aid in improving catalyst lifetimes.21 Overall, this relay conjugation methodology compares very favorably with existing polymer–polymer coupling methods, such as the coppercatalyzed azide-alkyne cycloaddition, and is of high practical value for the rapid construction of complex macromolecules with ruthenium metathesis.26

Conclusion

Figure 6: Size-exclusion chromatography of a polymer coupling reaction with an excess of P1-[Ru] and one equivalent gives the same molecular weight 4-arm P1-b-PEO. Lastly, DOSY analysis shows a single diffusing species for each diblock product that is well resolved from each of the polymer reactants (See Supporting Information). The speed of the relay conjugation is noteworthy. The absolute kinetics of this process were difficult to measure by 1H NMR due to the fast reaction times and the small signals for the chain-ends, but high reaction rate was clearly demonstrated through quenching aliquots at different times during the reaction of P1-[Ru] with the 4-arm PEG enyne terminator (Figure 7). Following the reaction by SEC suggests that the coupling reaction has already significantly progressed at 2 minutes, as a significantly larger molecular weight species appears. As the remaining P1-[Ru] is consumed, this peak continues to shift to higher molecular weight and narrows in dispersity. Complete reaction is achieved in under an hour, as no further change in the 4-arm P1-b-PEO peak is observed after this time. To obtain more quantitative data, the kinetics between G3 and the tosyl enyne terminator 4-Ts were measured and found to not be entirely second order, as the rate appears to decreases slightly during

In conclusion, a new and highly efficient strategy for the conjugation of small and macro-molecules to living metathesis polymers has been developed that reveals the latent power of the ruthenium alkylidene. By leveraging the terminal alkyne as a directing group for metathesis, an otherwise unfavorable cross-metathesis reaction can be promoted to rapidly install diverse functionalities onto the end of ROMP-derived polymers, while also removing the ruthenium catalyst as an unreactive chelate. This method is compatible with many types of functional groups and is operationally straightforward to execute. Furthermore, it is the first method that can directly couple a living polymer to other macromolecules under mild conditions. This alters the traditional synthetic paradigms in which post-polymerization modification is needed for macromolecular coupling and will serve to greatly streamline functional materials synthesis using metathesis methods. Given the established compatibility of ruthenium metathesis in aqueous environments, there are clear opportunities for direct conjugation to biomacromolecules, as well as for the functionalization of nanoparticles and surfaces leading to diverse applications in materials science.27

Additional information Supplementary information, synthetic details and spectral data are available in the online version of the paper. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION 6


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Journal of the American Chemical Society Corresponding Author *[email protected]

Competing financial interests The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by start-up funds generously provided by the Georgia Institute of Technology. We acknowledge support from Science and Technology of Material Interfaces (STAMI) at GT for use of the shared characterization facility. We thank the Finn Lab for generous sharing of chemicals and also thank David Bostwick for assistance in MALDI analysis.

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