Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Iterative exponential growth of stereo- and sequence-controlled polymers

Abstract

Chemists have long sought sequence-controlled synthetic polymers that mimic nature's biopolymers, but a practical synthetic route that enables absolute control over polymer sequence and structure remains a key challenge. Here, we report an iterative exponential growth plus side-chain functionalization (IEG+) strategy that begins with enantiopure epoxides and facilitates the efficient synthesis of a family of uniform >3 kDa macromolecules of varying sequence and stereoconfiguration that are coupled to produce unimolecular polymers (>6 kDa) with sequences and structures that cannot be obtained using traditional polymerization techniques. Selective side-chain deprotection of three hexadecamers is also demonstrated, which imbues each compound with the ability to dissolve in water. We anticipate that these new macromolecules and the general IEG+ strategy will find broad application as a versatile platform for the scalable synthesis of sequence-controlled polymers.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Traditional solid/solution-phase syntheses versus IEG+.
Figure 2: 1H NMR characterization.
Figure 3: MALDI mass spectra and GPC traces.
Figure 4: Syntheses of isotactic hexadecamers.
Figure 5: MALDI mass spectra and GPC traces of the isotactic, alternating sequence IEG+ oligotriazoles.
Figure 6: A 32-unit polymer consisting of a complex sequence and selective deprotection of three hexadecamers.

Similar content being viewed by others

References

  1. Van Hest, J. C. M. & Tirrell, D. A. Protein-based materials, toward a new level of structural control. Chem. Commun. 1897–1904 (2001).

  2. Lutz, J.-F. Sequence-controlled polymerizations: the next Holy Grail in polymer science? Polym. Chem. 1, 55–62 (2010).

    Article  CAS  Google Scholar 

  3. Lutz, J.-F., Ouchi, M., Liu, D. R. & Sawamoto, M. Sequence-controlled polymers. Science 341, 1238149 (2013).

    Article  Google Scholar 

  4. Merrifield, R. B. Solid phase peptide synthesis. 1. Synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149–2154 (1963).

    Article  CAS  Google Scholar 

  5. Wojcik, F., Ponader, D., Mosca, S. & Hartmann, L. Recent advances in solid phase polymer synthesis: polyamides from tailor-made building blocks. ACS Symp. Ser. 1170, 85–101 (2014).

    Article  CAS  Google Scholar 

  6. Serpell, C. J., Edwardson, T. G. W., Chidchob, P., Carneiro, K. M. M. & Sleiman, H. F. Precision polymers and 3D DNA nanostructures: emergent assemblies from new parameter space. J. Am. Chem. Soc. 136, 15767–15774 (2014).

    Article  CAS  Google Scholar 

  7. Zuckermann, R. N., Kerr, J. M., Kent, S. B. H. & Moos, W. H. Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 114, 10646–10647 (1992).

    Article  CAS  Google Scholar 

  8. Chan-Seng, D. & Lutz, J.-F. Solid-phase synthesis as a tool for the preparation of sequence-defined oligomers based on natural amino acids and synthetic building blocks. ACS Symp. Ser. 1170, 103–116 (2014).

    Article  CAS  Google Scholar 

  9. Roy, R. K. et al. Design and synthesis of digitally encoded polymers that can be decoded and erased. Nature Commun. 6, 7237 (2015).

    Article  Google Scholar 

  10. Ida, S., Ouchi, M. & Sawamoto, M. Template-assisted selective radical addition toward sequence-regulated polymerization: lariat capture of target monomer by template initiator. J. Am. Chem. Soc. 132, 14748–14750 (2010).

    Article  CAS  Google Scholar 

  11. Niu, J., Hili, R. & Liu, D. R. Enzyme-free translation of DNA into sequence-defined synthetic polymers structurally unrelated to nucleic acids. Nature Chem. 5, 282–292 (2013).

    Article  CAS  Google Scholar 

  12. Lewandowski, B. et al. Sequence-specific peptide synthesis by an artificial small-molecule machine. Science 339, 189–193 (2013).

    Article  CAS  Google Scholar 

  13. Milnes, P. J. & O'Reilly, R. K. DNA-templated chemistries for sequence controlled oligomer synthesis. ACS Symp. Ser. 1170, 71–84 (2014).

    Article  CAS  Google Scholar 

  14. Burts, A. O. et al. Using EPR to compare PEG-branch-nitroxide ‘Bivalent-brush polymers’ and traditional PEG bottle-brush polymers: branching makes a difference. Macromolecules 45, 8310–8318 (2012).

    Article  CAS  Google Scholar 

  15. Zhang, J., Matta, M. E. & Hillmyer, M. A. Synthesis of sequence-specific vinyl copolymers by regioselective ROMP of multiply substituted cyclooctenes. ACS Macro Lett. 1, 1383–1387 (2012).

    Article  CAS  Google Scholar 

  16. Gutekunst, W. R. & Hawker, C. J. A general approach to sequence-controlled polymers using macrocyclic ring opening metathesis polymerization. J. Am. Chem. Soc. 137, 8038–8041 (2015).

    Article  CAS  Google Scholar 

  17. Norris, B. N. et al. Sequence matters: modulating electronic and optical properties of conjugated oligomers via tailored sequence. Macromolecules 46, 1384–1392 (2013).

    Article  CAS  Google Scholar 

  18. Solleder, S. C. & Meier, M. A. R. Sequence control in polymer chemistry through the Passerini three-component reaction. Angew. Chem. Int. Ed. 53, 711–714 (2014).

    Article  CAS  Google Scholar 

  19. Burns, M. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–188 (2014).

    Article  CAS  Google Scholar 

  20. Porel, M. & Alabi, C. A. Sequence-defined polymers via orthogonal allyl acrylamide building blocks. J. Am. Chem. Soc. 136, 13162–13165 (2014).

    Article  CAS  Google Scholar 

  21. Satoh, K., Ozawa, S., Mizutani, M., Nagai, K. & Kamigaito, M. Sequence-regulated vinyl copolymers by metal-catalysed step-growth radical polymerization. Nature Commun. 1, 6 (2010).

    Article  Google Scholar 

  22. Li, J., Stayshich, R. M. & Meyer, T. Y. Exploiting sequence to control the hydrolysis behavior of biodegradable PLGA copolymers. J. Am. Chem. Soc. 133, 6910–6913 (2011).

    Article  CAS  Google Scholar 

  23. Alfrey, T. & Lavin, E. The copolymerization of styrene and maleic anhydride. J. Am. Chem. Soc. 67, 2044–2045 (1945).

    Article  CAS  Google Scholar 

  24. Pfeifer, S. & Lutz, J. F. A facile procedure for controlling monomer sequence distribution in radical chain polymerizations. J. Am. Chem. Soc. 129, 9542–9543 (2007).

    Article  CAS  Google Scholar 

  25. Gody, G., Maschmeyer, T., Zetterlund, P. B. & Perrier, S. Rapid and quantitative one-pot synthesis of sequence-controlled polymers by radical polymerization. Nature Commun. 4, 2505 (2013).

    Article  Google Scholar 

  26. Moatsou, D., Hansell, C. F. & O'Reilly, R. K. Precision polymers: a kinetic approach for functional poly(norbornenes). Chem. Sci. 5, 2246–2250 (2014).

    Article  CAS  Google Scholar 

  27. Paynter, O. I., Simmonds, D. J. & Whiting, M. C. The synthesis of long-chain unbranched aliphatic-compounds by molecular doubling. J. Chem. Soc. Chem. Commun. 1165, 1166 (1982).

    Google Scholar 

  28. Binauld, S., Damiron, D., Connal, L. A., Hawker, C. J. & Drockenmuller, E. Precise synthesis of molecularly defined oligomers and polymers by orthogonal iterative divergent/convergent approaches. Macromol. Rapid Commun. 32, 147–168 (2011).

    Article  CAS  Google Scholar 

  29. Brooke, G. M., Burnett, S., Mohammed, S., Proctor, D. & Whiting, M. C. Versatile process for the syntheses of very long chain alkanes, functionalised derivatives and some branched chain hydrocarbons. J. Chem. Soc. Perkin Trans. 1, 1635–1645 (1996).

    Article  Google Scholar 

  30. Zhang, J. S., Moore, J. S., Xu, Z. F. & Aguirre, R. A. Nanoarchitectures. 1. Controlled synthesis of phenylacetylene sequences. J. Am. Chem. Soc. 114, 2273–2274 (1992).

    Article  CAS  Google Scholar 

  31. Pearson, D. L., Schumm, J. S. & Tour, J. M. Iterative divergent/convergent approach to conjugated oligomers by a doubling of molecular length at each iteration. A rapid route to potential molecular wires. Macromolecules 27, 2348–2350 (1994).

    Article  CAS  Google Scholar 

  32. Schumm, J. S., Pearson, D. L. & Tour, J. M. Iterative divergent/convergent approach to linear conjugated oligomers by successive doubling of the molecular length: a rapid route to a 128-angstrom-long potential molecular wire. Angew. Chem. Int. Ed. Engl. 33, 1360–1363 (1994).

    Article  Google Scholar 

  33. Lengweiler, U. D., Fritz, M. G. & Seebach, D. Synthesis of monodisperse linear and cyclic oligo[(R)-3-hydroxybutanoates] containing up to 128 monomeric units. Helv. Chim. Acta 79, 670–701 (1996).

    Article  CAS  Google Scholar 

  34. Li, G. R., Wang, X. H. & Wang, F. S. A novel in situ deprotection/coupling and iterative divergent/convergent strategy for the synthesis of oligo(1,4-phenyleneethynylene)s. Tetrahedron Lett. 46, 8971–8973 (2005).

    Article  CAS  Google Scholar 

  35. Li, G. R., Wang, X. H., Li, J., Zhao, X. J. & Wang, F. S. Synthesis of monodisperse oligo[(1,4-phenyleneethynylene)-alt-(2,5-thiopheneethynylene)]s. Synth. Commun. 35, 115–119 (2005).

    Article  CAS  Google Scholar 

  36. Takizawa, K., Tang, C. & Hawker, C. J. Molecularly defined caprolactone oligomers and polymers: synthesis and characterization. J. Am. Chem. Soc. 130, 1718–1726 (2008).

    Article  CAS  Google Scholar 

  37. Takizawa, K., Nulwala, H., Hu, J., Yoshinaga, K. & Hawker, C. J. Molecularly defined (L)-lactic acid oligomers and polymers: synthesis and characterization. J. Polym. Sci. A 46, 5977–5990 (2008).

    Article  CAS  Google Scholar 

  38. Huang, B. & Hermes, M. E. Homogeneous polyesters of predetermined length, composition, and sequence: model synthesis of alternating glycolic-acid-co-(L)-lactic-acid oligomers. J. Polym. Sci. A 33, 1419–1429 (1995).

    Article  CAS  Google Scholar 

  39. Cai, C. Z. & Vasella, A. Oligosaccharide analogues of polysaccharides. 6. Orthogonal protecting activating groups in an improved binomial synthesis of ‘acetyleno-oligosaccharides’. Helv. Chim. Acta 79, 255–268 (1996).

    Article  CAS  Google Scholar 

  40. Liess, P., Hensel, V. & Schluter, A. D. Oligophenylene rods: a repetitive approach. Liebigs Annalen 1037–1040 (1996).

  41. Percec, V. & Asandei, A. D. Monodisperse linear liquid crystalline polyethers via a repetitive 2n geometric growth algorithm. Macromolecules 30, 7701–7720 (1997).

    Article  CAS  Google Scholar 

  42. Sadighi, J. P., Singer, R. A. & Buchwald, S. L. Palladium-catalyzed synthesis of monodisperse, controlled-length, and functionalized oligoanilines. J. Am. Chem. Soc. 120, 4960–4976 (1998).

    Article  CAS  Google Scholar 

  43. Louie, J. & Hartwig, J. F. The largest discrete oligo(m-aniline). An exponential growth strategy using palladium-catalyzed amination of aryl sulfonates. Macromolecules 31, 6737–6739 (1998).

    Article  CAS  Google Scholar 

  44. Martin, R. E. & Diederich, F. Linear monodisperse π-conjugated oligomers: model compounds for polymers and more. Angew. Chem. Int. Ed. 38, 1350–1377 (1999).

    Article  Google Scholar 

  45. Williams, J. B., Chapman, T. M. & Hercules, D. M. Synthesis of discrete mass poly(butylene glutarate) oligomers. Macromolecules 36, 3898–3908 (2003).

    Article  CAS  Google Scholar 

  46. Zhou, C. Z., Liu, T. X., Xu, J. M. & Chen, Z. K. Synthesis, characterization, and physical properties of monodisperse oligo(p-phenyleneethynylene)s. Macromolecules 36, 1457–1464 (2003).

    Article  CAS  Google Scholar 

  47. Binauld, S., Hawker, C. J., Fleury, E. & Drockenmuller, E. A modular approach to functionalized and expanded crown ether based macrocycles using click chemistry. Angew. Chem. Int. Ed. 48, 6654–6658 (2009).

    Article  CAS  Google Scholar 

  48. Franz, N., Menin, L. & Klok, H.-A. A post-modification strategy for the synthesis of uniform, hydrophilic/hydrophobic patterned α-hydroxy acid oligomers. Eur. J. Org. Chem. 2009, 5390–5405 (2009).

    Article  Google Scholar 

  49. Koch, F. P. V., Smith, P. & Heeney, M. ‘Fibonacci's route’ to regioregular oligo(3-hexylthiophene)s. J. Am. Chem. Soc. 135, 13695–13698 (2013).

    Article  CAS  Google Scholar 

  50. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).

    Article  CAS  Google Scholar 

  51. Rostovtsev, V. V., Green, L. G., Fokin, V. V. & Sharpless, K. B. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective ‘ligation’ of azides and terminal alkynes. Angew. Chem. Int. Ed. 41, 2596–2599 (2002).

    Article  CAS  Google Scholar 

  52. 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 9, 8400–8414 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge DuPont for support of this work. J.C.B. acknowledges the Howard Hughes Medical Institute (Postdoctoral Fellow of the Life Sciences Research Foundation), and F.A.L. acknowledges the National Science Foundation (Postdoctoral Sustainability Fellowship).

Author information

Authors and Affiliations

Authors

Contributions

J.A.J. conceived of the IEG+ concept. J.A.J. and J.C.B. conceived the molecular designs and synthetic protocols. J.C.B., D.J.C.E., A.X.G., Y.J. and E.Z. carried out the syntheses. J.C.B. characterized each compound by NMR, GPC and MALDI, and J.C.B. and J.A.J. analysed the data. F.A.L. performed DSC/TGA experiments. J.C.B. and J.A.J. wrote the paper. J.C.B., D.J.C.E., A.X.G., F.A.L., Y.J., E.Z., T.F.J. and J.A.J. discussed the results and edited the manuscript.

Corresponding author

Correspondence to Jeremiah A. Johnson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 3489 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barnes, J., Ehrlich, D., Gao, A. et al. Iterative exponential growth of stereo- and sequence-controlled polymers. Nature Chem 7, 810–815 (2015). https://doi.org/10.1038/nchem.2346

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2346

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing