Synthesis of sheet-coil-helix and coil-sheet-helix triblock copolymers by combining ROMP with palladium-mediated isocyanide polymerization

Scott K. Pomarico a, Diane S. Lye a, Elizabeth Elacqua *ab and Marcus Weck *a
aDepartment of Chemistry and Molecular Design Institute, New York University, New York, NY, USA. E-mail: mw125@nyu.edu
bDepartment of Chemistry, The Pennsylvania State University, University Park, PA, USA. E-mail: eze31@psu.edu

Received 18th September 2018 , Accepted 8th November 2018

First published on 14th November 2018


We report a synthetic route to construct architecturally well-defined triblock copolymers, in particular copolymers featuring secondary structures that form sheet-coil-helix and coil-sheet-helix motifs, through a macroinitiation strategy that combines sequential ring-opening metathesis polymerization (ROMP) with palladium-mediated isocyanide polymerization. Throughout the triblock copolymer fabrication, the individual blocks retained their secondary structures as evidenced by circular dicroism (CD) and fluorescence spectroscopies. Our strategy introduces a facile way to create complex ABC triblock copolymers that contain architecturally-diverse backbones, whilst retaining the ability to control sequence: sheet-coil-helix or coil-sheet-helix.


Nature's design of proteins features intricate building blocks comprised of distinct secondary structure elements including sheets, helices, and coils. The combination of these diverse topologies within the larger macrostructure endows the protein with function. Synthetic copolymers containing structural segments analogous to the ones found in Nature's biomacromolecules have garnered interest in the fields of polymer and materials science.1–9 Copolymers that result from the combination of synthetic polymers with secondary structures are able to act as mimics, on a basic level, of some of the common domains found in proteins. Numerous examples of diblock and triblock copolymers composed of helices, sheets, and coils have been reported.1,2,9–14 However, a covalent system that combines sheet, helix, and coil blocks in one linear system has not yet been realized, owing to synthetic challenges that are presented when working with the monomers needed to form these three discrete secondary structures. Specifically, the desired monomers are not polymerizable using a single polymerization method. The present work introduces a new methodology that combines controlled polymerization methods, thereby creating two specific covalent triblock motifs (Scheme 1).
image file: c8py01361f-s1.tif
Scheme 1 Strategy to synthesize covalent sheet-coil-helix (red-grey-blue) and coil-sheet-helix (grey-red-blue) triblock copolymers. Sequential ROMP is first performed to synthesize sheet-coil and coil-sheet diblock copolymers. A dual-functional CTA (Pd-CTA) is then added to terminate the polymerizations creating the diblock macroinitiators. Finally, the palladium-mediated polymerization of the isocyanide monomer takes place to form the final ABC and BAC triblock copolymers.

The synthesis of triblock copolymers featuring three different architecturally well-defined building blocks, namely coils, sheets, and helices, can be performed using a supramolecular sequencing technique that involves the targeted assembly of mixed telechelic polymers.13 Methods to engineer covalent triblock copolymers featuring such motifs, however, have not been realized. To date, only triblocks that possess two secondary structure elements (an ABA copolymer, for example) using a copolymerization methodology have been reported.1,2,5,6,9 In order to achieve well-defined block copolymers, the chosen monomers need to be compatible and polymerizable using the same method (e.g., radical vs. ring-opening vs. cationic).

Techniques to string together synthetically-incompatible polymer blocks are limited to post-polymerization ligation15,16 or macroinitiation.17,18 Post-polymerization ligation allows for two or more distinct polymers to be covalently linked by taking advantage of azide-alkyne15,16,19,20/cyclooctyne21 click reactions, as well as other strategies15,19,22 that facilitate polymer termini functionalization.

Although post-polymerization ligation is used prominently in the syntheses of covalent diblock copolymers featuring two different secondary structures, it often suffers from non-quantitative yields, and it is usually difficult to remove unfunctionalized chains;16,19 these characteristics provide a significant bottleneck for the synthesis of ABC triblock copolymers. In contrast, a macroinitiation approach ensures full linkage of the polymer blocks.17,18 Through the unification of two strategies, namely ROMP and macroinitiation, we are able to circumvent challenges with post-polymerization modification methods, while polymerizing synthetically-incompatible monomers to realize architecturally well-defined triblock copolymers in high yields with a high degree of control.

Our design is based on the successive ROMP of sheet- and coil-forming monomers, followed by palladium-mediated polymerization of a helix-forming monomer allowing for the facile synthesis of covalent coil-sheet-helix (ABC) and sheet-coil helix (BAC) copolymers (Scheme 2). After the initial sheet or coil-forming monomer is polymerized through ROMP, the second monomer is introduced and polymerized, leading to a diblock comprised of sheet and coil structures. ROMP is then terminated by a chain-transfer agent (CTA)17 that features an isocyanide polymerization initiator.23–25 The resulting telechelic diblock copolymers, each containing coil-sheet and sheet-coil blocks, then function as macroinitiators for the polymerization of a P-helix forming monomer.26 This combination of sequential copolymerization and macroinitiation enables three different polymer chains, synthesized through two discrete polymerization types, ROMP and palladium-mediated isocyanide polymerization, to be linked covalently with high fidelity. The resulting covalent triblock copolymers feature defined blocks; the structure of each relying on monomer choice alone.


image file: c8py01361f-s2.tif
Scheme 2 Strategy to synthesize sheet-coil-helix and coil-sheet-helix triblock copolymers. The three monomers and palladium-containing CTA used to form these structures are shown at the top (NBC8, pCpd, MeIso, Pd-CTA).

Synthesis of the targeted covalent triblocks (Schemes S1 and S2) starts with sequential ROMP of norbornene octyl ester (NBC8), a coil-forming monomer,27 and a substituted [2.2]paracyclophane-1,9-diene (pCpd), a monomer that yields a rigid, conjugated polymer backbone28 resembling a sheet-like architecture.12,13,29,30 A monomer-to-initiator ([M]0/[I]0) of 100 was targeted for the polymerizations of the NBC8 monomer. For the sheet-forming pCpd block, a monomer-to-initiator ratio of 50 was chosen as pCpd polymerization leads to two repeat units per monomer.

The covalent coil-sheet macroinitiator was obtained through ROMP of the norbornene octyl ester using Grubbs’ 2nd generation initiator (G2). After 45 minutes, pCpd was added to the reaction mixture, and the temperature was raised to 68 °C to initiate the polymerization. Monomer consumption was monitored through 1H NMR spectroscopy by comparing the poly(norbornene) backbone peak integrations at 5.0–5.5 ppm to the signals at 3.5–4.3 ppm that correspond to the poly(p-phenylene vinylene) (PPV) side-chains (Fig. S1). Upon complete monomer consumption, ROMP was terminated by the addition of the bifunctional, palladium-containing CTA (Pd-CTA); this allowed for the incorporation of the palladium initiator onto every diblock copolymer chain end. To synthesize the sheet-coil diblock macroinitiator, the sequential polymerization order was reversed, and the ROMP was initiated by the use of a Hoveyda–Grubbs’ 2nd generation catalyst (HG2).30

The resulting coil-sheet and sheet-coil macroinitiators were purified by precipitation. 31P NMR spectroscopy of the macroinitiators demonstrated that both polymeric systems were functionalized with Pd-end groups and contained only one Pd species (Fig. S2 and S9). GPC analysis of the diblocks confirmed successful block copolymer formation with a monomodal trace, and an increase in molecular weight (Fig. S6 and S13 and Table 1). Block ratios of the coil-sheet and sheet-coil macroinitiators were determined by 1H NMR spectroscopic end-group analysis (Fig. S1 and S8). For calculations associated with the subsequent polymerizations of the menthol-isocyanide monomer, these 1H NMR spectroscopy results were utilized.

Table 1 Polymer characterization data for PNB-b-PPV-Pd, PNB-b-PPV-b-PIC-Pd, PPV-b-PNB-Pd, and PPV-b-PNB-b-PIC-Pd
Polymer [M]0/[I]0 Đ M n M w
a Đ and Mn were determined by GPC (CHCl3, poly(styrene) standards). b M w was determined by 1H NMR spectroscopic end-group analysis. c Unable to measure accurately for the poly(isocyanide) backbone from 1H NMR spectroscopy.
PPV-b-PNB-Pd 50, 100 1.47 25[thin space (1/6-em)]500 65[thin space (1/6-em)]000
PPV-b-PNB-b-PIC-Pd 50, 100, 100 1.30 39[thin space (1/6-em)]000 c
PNB-b-PPV-Pd 100, 50 1.14 16[thin space (1/6-em)]000 82[thin space (1/6-em)]000
PNB-b-PPV-b-PIC-Pd 100, 50, 100 1.51 45[thin space (1/6-em)]500 c


The pure PNB-b-PPV-Pd and PPV-b-PNB-Pd macroinitiators were then used to polymerize the menthol-based phenyl isocyanide monomer (MeIso) (Scheme 2). Isocyanide polymerizations were conducted with [M]0/[I]0 of 100. The isocyanide underwent polymerization over the course of 16 hours at 55 °C to achieve the final triblock copolymers containing architecturally well-defined building blocks, namely sheet-coil-helix and coil-sheet-helix arrangements.

After purification, GPC analyses yielded dispersities of 1.51 and 1.30 for the PNB-b-PPV-b-PIC-Pd and PPV-b-PNB-b-PIC-Pd triblocks respectively (Table 1), and peak shifts to lower retention times, corresponding to increases in molecular weight after the helical blocks were added were observed (Fig. S6 and S13). 31P NMR spectroscopic analysis of the block copolymers revealed that a single phosphorus signal is maintained at δ = 17.9 ppm, suggesting that the palladium moiety remained intact after initiation of the isocyanide monomer and purification (Fig. S5 and S12). This demonstrates the robustness of the palladium-containing macroinitiator and our macroinitiation methodology in general.

Fluorescence and circular dichroism (CD) spectroscopies were conducted to characterize whether each block had retained its secondary structure. Fluorescence spectroscopy revealed that the coil-sheet-helix and sheet-coil-helix block copolymers retained the intrinsic fluorescence of the PPV block (Fig. 1a and 2a respectively). In each iteration, both before and after macroinitiation of the isocyanide monomer, the strong signal at 546 nm in the emission spectra demonstrated that the sheet-like structure of the PPV block remained intact, despite the presence of the PNB block, which could affect the polymer's natural tendency to organize into stacked structures.


image file: c8py01361f-f1.tif
Fig. 1 Fluorescence emission spectrum of the coil-sheet-helix triblock (a), and CD spectra overlay of the coil-sheet diblock (red) and the coil-sheet-helix triblock (black) (b).

image file: c8py01361f-f2.tif
Fig. 2 Fluorescence emission spectrum of the sheet-coil-helix triblock (a), and CD spectra overlay of the coil-sheet diblock (red) and the coil-sheet-helix triblock (black) (b).

Upon introduction of the helical block through palladium-mediated isocyanide polymerization, the CD spectroscopic data (Fig. 1b and 2b) of both PNB-b-PPV-b-PIC-Pd and PPV-b-PNB-b-PIC-Pd showed the emergence of a strong positive Cotton Effect at 364 nm. This indicates that a right-handed helical structure formed after isocyanide polymerization from the sheet-coil PNB- and the coil-sheet PPV-based macroinitiators. Before addition of the isocyanide monomer, no signal was visible (Fig. 1b and 2b, red and blue traces). These CD results clearly demonstrate that the structural integrity of the helical block was maintained throughout the formation of both sheet-coil-helix and coil-sheet-helix triblock copolymers, which aligns with expectations based on our previous studies of analogous supramolecular systems.12,13

In conclusion, we have introduced a straightforward synthetic methodology to engineer covalent triblock copolymers comprised of sheet, coil, and helical blocks. Our strategy involves the engineering of a sheet-coil or coil-sheet polymer by sequential ROMP and termination with a CTA that contains an isocyanide polymerization initiator. An isocyanide monomer, known to form static right-handed helices, is then added to the PPV- and PNB-based macroinitiators to form the final sheet-coil-helix and coil-sheet-helix ABC and BAC copolymers; the successful formation of which was confirmed using GPC and 1H NMR spectroscopy. Through fluorescence and CD spectroscopies, we observed that the individual block shapes were maintained throughout the synthesis and purification steps.

The present study provides a new methodology to covalently link three distinct structures together with high fidelity whilst retaining control over sequence. This work can be extended to the formation of a diverse array of tri- and multiblock copolymers. The diblock macroinitiators can be used to polymerize or copolymerize poly(isocyanide) monomers containing different side-chains, or to copolymerize isocyanide monomers with monomers of other types.24 Alternatively, the versatile Pd-CTA can be modified with various functional groups to perform a role in other polymerization techniques. For example, a primary alcohol can be incorporated onto the palladium compound to act as an initiator for ring-opening polymerization (ROP) of lactides.31 With these potential uses in mind, future work will focus on the engineering of triblock copolymers with different motifs, as well as performing morphological and materials studies on these copolymer systems.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge financial support from the National Science Foundation under award number CHE-1506890. We also acknowledge the National Institutes of Health for the purchase of the Advance III-600 CPTCI-cryoprobe head (S10 grant, OD016343) and New York University for the purchase of the Circular Dichroism Spectropolarimeter.

Notes and references

  1. L. Huang, J. Hu, L. Lang, X. Chen, Y. Wei and X. Jing, Macromol. Rapid Commun., 2007, 28, 1559–1566 CrossRef CAS.
  2. J. Hu, G. Zhang, Y. Geng and S. Liu, Macromolecules, 2011, 44, 8207–8214 CrossRef CAS.
  3. Y. Li, T. Jiang, L. Wang, S. Lin and J. Lin, Polymer, 2016, 103, 64–72 CrossRef CAS.
  4. X. Xiao, Y.-Q. Fu, J.-J. Zhou, Z.-S. Bo, L. Li and C.-M. Chan, Macromol. Rapid Commun., 2007, 28, 1003–1009 CrossRef CAS.
  5. J.-Z. Chen, Z.-Y. Sun, C.-X. Zhang, L.-J. An and Z. Tong, J. Chem. Phys., 2008, 128, 074904 CrossRef PubMed.
  6. Y. Li, S. Lin, X. He, J. Lin and T. Jiang, J. Chem. Phys., 2011, 135, 014102 CrossRef PubMed.
  7. J. Zhang, X.-F. Chen, H.-B. Wei and X.-H. Wan, Chem. Soc. Rev., 2013, 42, 9127–9154 RSC.
  8. J. S. Rudra, P. Tripathi, D. A. Hildeman, J. P. Jung and J. H. Collier, Biomaterials, 2010, 31, 8475–8483 CrossRef CAS PubMed.
  9. O. Altintas, M. Artar, G. ter Huurne, I. K. Voets, A. R. A. Palmans, C. Barner-Kowollik and E. W. Meijer, Macromolecules, 2015, 48, 8921–8932 CrossRef CAS.
  10. N. Hosono, M. A. J. Gillissen, Y. Li, S. S. Sheiko, A. R. A. Palmans and E. W. Meijer, J. Am. Chem. Soc., 2013, 135, 501–510 CrossRef CAS PubMed.
  11. A. Croom, K. B. Manning and M. Weck, Macromolecules, 2016, 49, 7117–7128 CrossRef CAS.
  12. E. Elacqua, A. Croom, K. B. Manning, S. K. Pomarico, D. S. Lye, L. Young and M. Weck, Angew. Chem., Int. Ed., 2016, 55, 15873–15878 CrossRef CAS PubMed.
  13. E. Elacqua, K. B. Manning, D. S. Lye, S. K. Pomarico, F. Morgia and M. Weck, J. Am. Chem. Soc., 2017, 139, 12240–12250 CrossRef CAS PubMed.
  14. J. P. Cole, J. J. Lessard, K. J. Rodriguez, A. M. Hanlon, E. K. Reville, J. P. Mancinelli and E. B. Berda, Polym. Chem., 2017, 8, 5829–5835 RSC.
  15. E. Blasco, M. B. Sims, A. S. Goldmann, B. S. Sumerlin and C. Barner-Kowollik, Macromolecules, 2017, 50, 5215–5252 CrossRef CAS.
  16. A. Croom, R. Tarallo and M. Weck, J. Polym. Sci., Part A: Polym. Chem., 2016, 54, 2766–2773 CrossRef CAS.
  17. E. Elacqua, A. Croom, D. S. Lye and M. Weck, J. Polym. Sci., Part A: Polym. Chem., 2017, 55, 2991–2998 CrossRef CAS.
  18. Y. Schneider, J. D. Azoulay, R. C. Coffin and G. C. Bazan, J. Am. Chem. Soc., 2008, 130, 10464–10465 CrossRef CAS PubMed.
  19. J. Budhathoki-Uprety and B. M. Novak, Macromolecules, 2011, 44, 5947–5954 CrossRef CAS.
  20. J. F. Reuther, D. A. Siriwardane, O. V. Kulikov, B. L. Batchelor, R. Campos and B. M. Novak, Macromolecules, 2015, 48, 3207–3216 CrossRef CAS.
  21. J. A. Johnson, J. M. Baskin, C. R. Bertozzi, J. T. Koberstein and N. J. Turro, Chem. Commun., 2008, 26, 3064–3066 RSC.
  22. Y. Han, L. Yuan, G. Li, L. Huang, T. Qin, F. Chu and C. Tang, Polymer, 2016, 83, 92–100 CrossRef CAS.
  23. Y.-X. Xue, J.-L. Chen, Z.-Q. Jiang, Z. Yu, N. Liu, J. Yin, Y.-Y. Zhu and Z.-Q. Wu, Polym. Chem., 2014, 5, 6435–6438 RSC.
  24. J.-L. Chen, L. Yang, Q. Wang, Z.-Q. Jiang, N. Liu, J. Yin, Y. Ding and Z.-Q. Wu, Macromolecules, 2015, 48, 7737–7746 CrossRef CAS.
  25. M. Su, N. Liu, Q. Wang, H. Wang, J. Yin and Z.-Q. Wu, Macromolecules, 2016, 49, 110–119 CrossRef CAS.
  26. S. Asaoka, A. Joza, S. Minagawa, L. Song, Y. Suzuki and T. Iyoda, ACS Macro Lett., 2013, 2, 906–911 CrossRef CAS.
  27. T. F. A. Haselwander, W. Heitz, S. A. Krügel and J. H. Wendorff, Macromolecules, 1997, 30, 5345–5351 CrossRef CAS.
  28. D. Mäker, C. Maier, K. Brödner and U. H. F. Bunz, ACS Macro Lett., 2014, 3, 415–418 CrossRef.
  29. C.-Y. Yu and M. L. Turner, Angew. Chem., Int. Ed., 2006, 45, 7797–7800 CrossRef CAS PubMed.
  30. E. Elacqua and M. Weck, Chem. – Eur. J., 2015, 21, 7151–7158 CrossRef CAS PubMed.
  31. M. Hirata, K. Masutani and Y. Kimura, Biomacromolecules, 2013, 14, 2154–2161 CrossRef CAS PubMed.

Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c8py01361f

This journal is © The Royal Society of Chemistry 2018