Letter Cite This: ACS Macro Lett. 2018, 7, 858−862
pubs.acs.org/macroletters
Cis-Selective Metathesis to Enhance the Living Character of RingOpening Polymerization: An Approach to Sequenced Copolymers Amy L. Short,† Cheng Fang,†,§ Jamie A. Nowalk,† Ryan M. Weiss,† Peng Liu,† and Tara Y. Meyer*,†,‡ †
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, United States § Computational Modeling & Simulation Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 ‡
Downloaded via UNIV OF TOLEDO on June 29, 2018 at 18:29:34 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: The hydrolytic behavior and physical properties of a polymer are directly related to its constituent monomer sequence, yet the scalable and controllable synthesis of sequenced copolymers remains scarcely realized. To address this need, an enhanced version of entropy-driven ring-opening metathesis polymerization (ED-ROMP) has been developed. An unprecedented level of control is obtained by exploiting the kinetic and thermodynamic differences in the metathesis activity of cis- and trans-olefins embedded in large, unstrained macrocycles. First-order rate kinetics were observed, and polymer molecular weights were found to be proportional to catalyst loading. Computational analysis suggests that incorporation of a cis-olefin into the monomer backbone both introduces a thermodynamic driving force and increases the population of metathesis-active conformers. This approach offers a generally applicable method for enhancing living character in ED-ROMP.
S
Scheme 1. Advantages of SEED-ROMP Preparation of Sequenced Polyesters Relative to ED-ROMP
ynthetic copolymer structure is rarely defined at the monomer level despite evidence from biological systems that monomer sequence controls properties.1−3 Challenges inherent in the synthesis of sequenced copolymers and a lack of general understanding of structure−function relationships have inhibited progress in this area. Instead, efforts have been largely directed at creating novel monomers and controlling architecture on longer length scales. While these efforts have been fruitful, sequence engineering would expand exponentially the library of polymers available to address needs in fields like energy, medicine, environmental science, and nanotechnology.4,5 Herein, we report a new method for preparing macromolecules with repeating sequences, which we term selectivity enhanced entropy-driven ring-opening metathesis polymerization (SEED-ROMP). This general strategy involves embedding a preformed sequence into a large cyclic macromonomer equipped with a reactive unit that can be systematically cleaved. Upon cleavage, the opened rings join with other units in a controlled manner to form long chains that incorporate sequenced units (Scheme 1). This strategy offers a unique combination of advantages: first, the polymerization reaction is general and does not depend on the chemical behavior of the constituent monomers. Second, the reactions are scalable to gram quantities, and third, the living character of this approach imparts a high degree of molecular weight control, low dispersity, and access to block copolymers. The idea of opening rings to generate sequenced polymers has been previously explored,6,7 and other notable strategies © XXXX American Chemical Society
for introducing sequence into copolymers include: template approaches,8,9 iterative methods,10−13 step-growth assembly of macromonomers,14−17 and multicomponent reactions.18−20 Limitations of existing methodologies include the lack of molecular weight control, the narrow range of acceptable monomers, and/or the inclusion of property-dominating linker groups. In recent years, our group’s efforts have focused on the development of synthetic routes to periodic copolymers.6,7 We have been particularly interested in poly(lactic-co-glycolic Received: June 21, 2018 Accepted: June 27, 2018
858
DOI: 10.1021/acsmacrolett.8b00460 ACS Macro Lett. 2018, 7, 858−862
Letter
ACS Macro Letters Scheme 2. Cis-Selective Ring-Closing Metathesis and SEED-ROMP to Generate a Sequenced Copolymer
acid)s (PLGAs) and other poly(α-hydroxyacid)s with applications in biological engineering.21 By employing a stepgrowth condensation method referred to as segmer assembly polymerization (SAP), we have previously prepared a library of PLGAs with stereopure periodic repeat units. In studying these polymers, we have observed a strong correlation between sequence and properties, particularly with regard to hydrolytic degradation.22−25 Despite our success in establishing the link between sequence and properties in these SAP-produced polymers, the limitations inherent in a step-growth polymerization, particularly the lack of molecular weight control, inspired us to develop new methodologies. We first investigated and reported the use of the most basic variant of entropy-driven ring-opening metathesis polymerization (ED-ROMP), which is distinguished from ring-opening metathesis polymerization (ROMP) through its use of large, strainless monomers which offer no enthalpic driving force.26−28 Instead, ED-ROMP exploits differences in translational and conformational entropy to drive the ring−chain equilibrium toward polymeric chains.29 Molecular weight can be influenced through the regulation of concentration, temperature, and monomer-to-initiator ratios. In our previously reported ED-ROMP studies,30 we successfully polymerized a series of macrocyclic oligomers that carried within them sequences of α-hydroxy acids. This method produced materials with perfect sequence retention, a moderate degree of molecular weight control, and reasonably low dispersities (ca. 1.3).30 We sought to optimize the method further by shifting the mechanism from one dependent on ring−chain equilibria to one with significant living character. We hypothesized that this could be accomplished by the simple replacement of the default trans-olefin macromonomer with a cis-olefin. This selectivity-enhanced ED-ROMP, which we term SEED-ROMP, would be expected to improve molecular weight control, decrease dispersities, and allow for the formation of block copolymers. To test this hypothesis a macrocyclic monomer bearing a cisolefin linker was prepared. The palindromic α,ω-diolefin Eg(LGL-P)2 precursor was prepared as described previously.30 The internal olefin was installed using the Grubbs’ cis-selective nitrato catalyst (GN). The macrocyclic cis-cyclic-Eg-(LGL-P)2 was obtained in high yields and with high selectivity (Scheme 2) in reactions up to a 1.4 g scale with 87−90% cis-selectivity. The cis-macromonomer was polymerized with 1.25 mol % Grubbs’ second-generation catalyst (G2) at high concentration (0.7 M). The polymerization rate and control exceeded those observed with the corresponding trans-monomer (Figures 1A: cis; S1: cis vs trans).30 The reaction solution became an immobile gel after 2 min, and conversion reached 89% after only 10 min. In contrast, the trans-macromonomer required 2 h to reach this conversion (Figure S1D). Rapid chain propagation followed first-order kinetics (Figure 1B). The rate of propagation for the reaction, 4.1 × 10−3 s−1,
Figure 1. SEED-ROMP of cis-cyclic-Eg(LGL-P)2. (A) Mn and dispersity over time. (B) Linear first-order kinetics fit. (C) Mn as a function of catalyst loading. (D) SEC traces of SEED-ROMP polymer and chain extension.
was determined by assuming saturation conditions,31 according to eq 1.
ij [M]o yz zz = k [Ru]t lnjjj pr j [M]t zz (1) k { A linear correlation of the integrated rate equation was observed until equilibrium conversion was achieved (t = 600 s). The rate obtained is within the range expected.31 NMR spectroscopy proved useful in tracking the progress of the reaction including cis:trans ratios in both the monomer and the polymer (Figure S2). As predicted, the rate of consumption of cis-cyclic-Eg-(LGL-P)2 far exceeded that of trans-cyclic-Eg(LGL-P)2. Although the monomer was enriched in cis-olefin at the onset of polymerization (87% cis), this isomer proved far more reactive, and after 10 min the cis-content of the remaining monomer decreased to 35%. Polymer molecular weights exceeded 60 kDa, and secondary metathesis was significantly reduced as can be seen from the narrow dispersity (Đ = 1.1). Consistent with a chain mechanism, conversion was linear with time. Molecular weight 859
DOI: 10.1021/acsmacrolett.8b00460 ACS Macro Lett. 2018, 7, 858−862
Letter
ACS Macro Letters
Figure 2. Computational study on the conformations and reactivity of cis- and trans-macromonomers. (A) Optimized transition states of model substrates. (B) Molecular dynamic simulations of cis- and trans-macromonomers. (C) Representative active and inactive conformers of cis- and trans-macromonomers.
second aliquot of cis-cyclic-Eg-(LGLP)2 was added to an already formed SEED-ROMP chain. Coplotting of the sizeexclusion chromatography (SEC) data demonstrates an increase in Mn with no increase in dispersity (Figure 1D). The active chain ends were also competent to initiate the polymerization of a traditional strained ROMP monomer, norbornene (NBE). The resultant block copolymer exhibited
was linear over an extended range of catalyst loadings, enabling molecular weights between 40 and 75 kDa to be targeted (Figures 1C and S1C). These results are consistent with incomplete initiation but a high degree of living character, such that the number of active chain ends is proportional to catalyst loading. The presence of active catalysts on the majority of chains was further demonstrated by successful chain and block copolymer formation. In the first of these experiments, a 860
DOI: 10.1021/acsmacrolett.8b00460 ACS Macro Lett. 2018, 7, 858−862
ACS Macro Letters
■
ACKNOWLEDGMENTS The authors acknowledge the NSF CHE-1410119 and the University of Pittsburgh for financial support. Support for MALDI-TOF MS instrumentation was provided by a grant from the NSF (CHE-1625002).
an approximate DPSEED‑ROMP of 100 and DPNBE of 117 (Figure S3). The underlying source of selectivity enhancement that occurs during SEED-ROMP is presumably related in part to the improved rate of reaction with the cis-macromonomer relative to the trans-macromonomer.32 The origin of this preference was investigated computationally. Although metathesis of acyclic olefins suffers poor kinetic cis:trans selectivity,33 we surmised the macrocyclic structure could alter the steric environment around the double bond. If a macromonomer prefers to orient both substituents onto the same face of the double bond, the olefin will be more exposed to the Ru catalyst, and therefore a faster metathesis rate is expected. We performed 20 ns molecular dynamics (MD) simulations of cis- and trans-cyclic-Eg-(LGL-P)2 to investigate the conformational flexibility of the two macromonomers. Snapshots of the MD simulations revealed both active conformers in which the two olefin substituents are placed on the same face of the double bond and inactive conformers with the two olefin substituents on opposite faces (Figure 2C). The inactive conformers can be identified by greater deviations from the reactive geometry of the olefin in the metathesis transition states (Figure 2A). The atomic RMSD of the highlighted carbon atoms from the MD snapshots was plotted over time (Figure 2B). The cis-macromonomer has smaller deviation from the reactive conformation which indicates the cis-double bond is more exposed to the Ru catalyst. Thus, the living character results from the higher reactivity of the cisolefin relative to the trans which increases the rate propagation (kpr) relative to the rate of competing secondary metathesis (ktr).34−37 Thermodynamically, the conversion from the higher energy cis to the more stable trans geometry also adds a small enthalpic driving force. In conclusion, the simple switch from a trans to a cis double bond in the metathesis linker of the sequenced macrocycle adds significant living character to what would otherwise be a solely entropy-driven equilibrium process. Lower dispersities, improved molecular weight control, and the ability to create block copolymers result. This method is inherently general, the only requirements being that the palindromic sequence or other payload substructure is included in a macrocycle that contains a metathesizable cis-olefin and that that there are no groups present that would inhibit the catalyst.
■
■
REFERENCES
(1) Lutz, J.-F. Defining the Field of Sequence-Controlled Polymers. Macromol. Rapid Commun. 2017, 38, 1700582. (2) Swisher, J. H.; Nowalk, J. A.; Washington, M. A.; Meyer, T. Y. In Sequence-Controlled Polymers; Wiley-VCH Verlag GmbH & Co. KGaA: 2018; p 435. (3) Cole, J. P.; Hanlon, A. M.; Rodriguez, K. J.; Berda, E. B. Proteinlike structure and activity in synthetic polymers. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 191. (4) Lutz, J.-F.; Lehn, J.-M.; Meijer, E. W.; Matyjaszewski, K. From precision polymers to complex materials and systems. Nature Reviews Materials 2016, 1, 16024. (5) Lutz, J.-F.; Ouchi, M.; Liu, D. R.; Sawamoto, M. SequenceControlled Polymers. Science 2013, 341, 341. (6) Zhang, J.; Matta, M. E.; Hillmyer, M. A. Synthesis of SequenceSpecific Vinyl Copolymers by Regioselective ROMP of Multiply Substituted Cyclooctenes. ACS Macro Lett. 2012, 1, 1383. (7) Gutekunst, W. R.; Hawker, C. J. A General Approach to Sequence-Controlled Polymers Using Macrocyclic Ring Opening Metathesis Polymerization. J. Am. Chem. Soc. 2015, 137, 8038. (8) Ouchi, M.; Hibi, Y.; Arima, T.; Hayata, D.; Sawamoto, M. In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties. ACS Symp. Ser. 2014, 1170, 149. (9) Mochizuki, S.; Ogiwara, N.; Takayanagi, M.; Nagaoka, M.; Kitagawa, S.; Uemura, T. Sequence-regulated copolymerization based on periodic covalent positioning of monomers along one-dimensional nanochannels. Nat. Commun. 2018, 9, 329. (10) Soejima, T.; Satoh, K.; Kamigaito, M. Main-Chain and SideChain Sequence-Regulated Vinyl Copolymers by Iterative Atom Transfer Radical Additions and 1:1 or 2:1 Alternating Radical Copolymerization. J. Am. Chem. Soc. 2016, 138, 944. (11) 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. (12) Telitel, S.; Petit, B. E.; Poyer, S.; Charles, L.; Lutz, J.-F. Sequence-coded ATRP macroinitiators. Polym. Chem. 2017, 8, 4988. (13) Rosales, A. M.; Segalman, R. A.; Zuckermann, R. N. Polypeptoids: a model system to study the effect of monomer sequence on polymer properties and self-assembly. Soft Matter 2013, 9, 8400. (14) Li, Z.-l.; Li, L.; Du, F.-s.; Li, Z.-c. Acyclic diene metathesis polymerization of tailor-made monomers towards sequence-regulated vinyl copolymers. Chin. J. Polym. Sci. 2013, 31, 355. (15) Schulz, M. D.; Wagener, K. B. Precision Polymers through ADMET Polymerization. Macromol. Chem. Phys. 2014, 215, 1936. (16) Li, Z.-L.; Lv, A.; Du, F.-S.; Li, Z.-C. Intrachain Cyclization via Postmodification of the Internal Alkenes of Periodic ADMET Copolymers: The Sequence Matters. Macromolecules 2014, 47, 5942. (17) Martens, S.; Holloway, J. O.; Du Prez, F. E. In SequenceControlled Polymers; Wiley-VCH Verlag GmbH & Co. KGaA: 2018; p 379. (18) Lutz, J.-F. In Sequence-Controlled Polymers; Wiley-VCH Verlag GmbH & Co. KGaA: 2018; p 1. (19) Porel, M.; Thornlow, D. N.; Phan, N. N.; Alabi, C. A. Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction. Nat. Chem. 2016, 8, 590. (20) Xue, L.; Xiong, X.; Chen, K.; Luan, Y.; Chen, G.; Chen, H. Modular synthesis of glycopolymers with well-defined sugar units in the side chain via Ugi reaction and click chemistry: hetero vs. homo. Polym. Chem. 2016, 7, 4263.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00460. NMR spectra, cis vs trans comparison data, and
■
Letter
calculation details (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peng Liu: 0000-0002-8188-632X Tara Y. Meyer: 0000-0002-9810-454X Notes
The authors declare no competing financial interest. 861
DOI: 10.1021/acsmacrolett.8b00460 ACS Macro Lett. 2018, 7, 858−862
Letter
ACS Macro Letters (21) Makadia, H. K.; Siegel, S. J. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers 2011, 3, 1377. (22) Washington, M. A.; Balmert, S. C.; Fedorchak, M. V.; Little, S. R.; Watkins, S. C.; Meyer, T. Y. Monomer sequence in PLGA microparticles: Effects on acidic microclimates and in vivo inflammatory response. Acta Biomater. 2018, 65, 259. (23) Washington, M. A.; Swiner, D. J.; Bell, K. R.; Fedorchak, M. V.; Little, S. R.; Meyer, T. Y. The impact of monomer sequence and stereochemistry on the swelling and erosion of biodegradable poly(lactic-co-glycolic acid) matrices. Biomaterials 2017, 117, 66. (24) Li, J.; Rothstein, S. N.; Little, S. R.; Edenborn, H. M.; Meyer, T. Y. The Effect of Monomer Order on the Hydrolysis of Biodegradable Poly(lactic-co-glycolic acid) Repeating Sequence Copolymers. J. Am. Chem. Soc. 2012, 134, 16352. (25) Li, J.; Washington, M. A.; Bell, K. L.; Weiss, R. M.; Rothstein, S. N.; Little, S. R.; Edenborn, H. M.; Meyer, T. Y. In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; American Chemical Society: 2014; Vol. 1170, p 271. (26) Gautrot, J. E.; Zhu, X. X. Main-Chain Bile Acid Based Degradable Elastomers Synthesized by Entropy-Driven Ring-Opening Metathesis Polymerization. Angew. Chem. 2006, 118, 7026. (27) Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. TemplateDirected Ring-Closing Metathesis: Synthesis and Polymerization of Unsaturated Crown Ether Analogs. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101. (28) Ben-Haida, A.; Conzatti, L.; Hodge, P.; Manzini, B.; Stagnaro, P. An Introduction to Entropically-driven Ring-opening Polymerizations. Macromol. Symp. 2010, 297, 6. (29) Xue, Z.; Mayer, M. F. Entropy-driven ring-opening olefin metathesis polymerizations of macrocycles. Soft Matter 2009, 5, 4600. (30) Weiss, R. M.; Short, A. L.; Meyer, T. Y. Sequence-Controlled Copolymers Prepared via Entropy-Driven Ring-Opening Metathesis Polymerization. ACS Macro Lett. 2015, 4, 1039. (31) Sanford, M. S.; Love, J. A.; Grubbs, R. H. Mechanism and Activity of Ruthenium Olefin Metathesis Catalysts. J. Am. Chem. Soc. 2001, 123, 6543. (32) Pepels, M. P. F.; Hansen, M. R.; Goossens, H.; Duchateau, R. From Polyethylene to Polyester: Influence of Ester Groups on the Physical Properties. Macromolecules 2013, 46, 7668. (33) Anderson, D. R.; Ung, T.; Mkrtumyan, G.; Bertrand, G.; Grubbs, R. H.; Schrodi, Y. Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes. Organometallics 2008, 27, 563. (34) Ulman, M.; Grubbs, R. H. Relative Reaction Rates of Olefin Substrates with Ruthenium(II) Carbene Metathesis Initiators1. Organometallics 1998, 17, 2484. (35) Thomas, C. M. Stereocontrolled ring-opening polymerization of cyclic esters: synthesis of new polyester microstructures. Chem. Soc. Rev. 2010, 39, 165. (36) Keitz, B. K.; Endo, K.; Herbert, M. B.; Grubbs, R. H. ZSelective Homodimerization of Terminal Olefins with a Ruthenium Metathesis Catalyst. J. Am. Chem. Soc. 2011, 133, 9686. (37) Marinescu, S. C.; Schrock, R. R.; Müller, P.; Takase, M. K.; Hoveyda, A. H. Room-Temperature Z-Selective Homocoupling of αOlefins by Tungsten Catalysts. Organometallics 2011, 30, 1780.
862
DOI: 10.1021/acsmacrolett.8b00460 ACS Macro Lett. 2018, 7, 858−862
