Abstract

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid-phase synthesis and selective molecular sieving. The polymer is assembled in solution with real-time monitoring to ensure couplings proceed to completion, on a three-armed star-shaped macromolecule to maximize efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with side-arms at precisely defined locations that can undergo site-selective modification after polymerization. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Data availability

All data that support the findings of this study are included within the Article and its Supplementary Information, and are also available from the authors upon request.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 08 January 2019

    In the version of this Article originally published, the authors inadvertently cited ref. 10 in two places in the first paragraph. They would like to clarify that it should not have been cited in the sentence that starts “Polymer chemists have employed strategies such as single monomer insertion...” as it mistakenly implied that the IEG+ method described in ref. 10 could not produce unimolecular polymers; it can do so, as was demonstrated in ref. 10. The authors would also like to clarify that ref. 10 should not have been cited in the sentence that starts “Moreover, solid-phase synthesis is generally difficult to scale up...", as it implied that ref. 10 uses solid-phase synthesis; it does not, and is a purely liquid-phase process. The citation of ref. 10 has now been removed from these two sentences, but has been included elsewhere in the first two paragraphs of the Article as follows. In the first paragraph, at the end of the sentence “In iterative synthesis, specific monomers are added one at a time, or as multiples, to the end of a growing polymer chain, then reaction debris is separated from the chain extended polymer, and the cycle is repeated using the next monomer in the sequence10–12.”; this sentence has been further amended to indicate multiple monomers can also be added. The reference has also been added to the end of the first sentence of the second paragraph, which starts “Consequently, liquid-phase iterative synthetic methods...”, and in the third sentence of that paragraph, which now starts “For example, Johnson10, Whiting....”.

References

  1. 1.

    Seeman, N. C. DNA in a material world. Nature 421, 427–431 (2003).

  2. 2.

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

  3. 3.

    Zamfir, M. & Lutz, J.-F. Ultra-precise insertion of functional monomers in chain-growth polymerizations. Nat. Commun. 3, 1138 (2012).

  4. 4.

    Srichan, S., Mutlu, H., Badi, N. & Lutz, J.-F. Precision PEGylated polymers obtained by sequence-controlled copolymerization and postpolymerization modification. Angew. Chem. Int. Ed. 53, 9231–9235 (2014).

  5. 5.

    Nakatani, K., Ogura, Y., Koda, Y., Terashima, T. & Sawamoto, M. Sequence-regulated copolymers via tandem catalysis of living radical polymerization and in situ transesterification. J. Am. Chem. Soc. 134, 4373–4383 (2012).

  6. 6.

    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).

  7. 7.

    Engelis, N. G. et al. Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion polymerization. Nat. Chem. 9, 171–178 (2017).

  8. 8.

    McHale, R., Patterson, J. P., Zetterlund, P. B. & O’Reilly, R. K. Biomimetic radical polymerization via cooperative assembly of segregating templates. Nat. Chem. 4, 491–497 (2012).

  9. 9.

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

  10. 10.

    Barnes, J. C. et al. Iterative exponential growth of stereo-and sequence-controlled polymers. Nat. Chem. 7, 810–815 (2015).

  11. 11.

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

  12. 12.

    Solleder, S. C., Schneider, R. V., Wetzel, K. S., Boukis, A. C. & Meier, M. A. R. Recent progress in the design of monodisperse, sequence-defined macromolecules. Macromol. Rapid Commun. 38, 1600711 (2017).

  13. 13.

    Merrifield, R. B. Solid phase synthesis. Science 232, 341–347 (1986).

  14. 14.

    Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).

  15. 15.

    Svec, F. & Fréchet, J. M. J. New designs of macroporous polymers and supports: from separation to biocatalysis. Science 273, 205–211 (1996).

  16. 16.

    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).

  17. 17.

    Bidd, I. & Whiting, M. C. The synthesis of pure n-paraffins with chain-lengths between one and four hundred. J. Chem. Soc. Chem. Commun. 543–544 (1985).

  18. 18.

    Pfeifer, S., Zarafshani, Z., Badi, N. & Lutz, J.-F. Liquid-phase synthesis of block copolymers containing sequence-ordered segments. J. Am. Chem. Soc. 131, 9195–9197 (2009).

  19. 19.

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

  20. 20.

    Szweda, R., Chendo, C., Charles, L., Baxter, P. N. W. & Lutz, J.-F. Synthesis of oligoarylacetylenes with defined conjugated sequences using tailor-made soluble polymer supports. Chem. Commun. 53, 8312–8315 (2017).

  21. 21.

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

  22. 22.

    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).

  23. 23.

    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).

  24. 24.

    Solleder, S. C., Zengel, D., Wetzel, K. S. & Meier, M. A. R. A scalable and high-yield strategy for the synthesis of sequence-defined macromolecules. Angew. Chem. Int. Ed. 55, 1204–1207 (2016).

  25. 25.

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

  26. 26.

    Porel, M., Thornlow, D. N., Phan, N. N. & Alabi, C. A. Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction. Nat. Chem. 8, 590–596 (2016).

  27. 27.

    Oh, D., Ouchi, M., Nakanishi, T., Ono, H. & Sawamoto, M. Iterative radical addition with a special monomer carrying bulky and convertible pendant: a new concept toward controlling the sequence for vinyl polymers. ACS Macro Lett. 5, 745–749 (2016).

  28. 28.

    Hibi, Y., Ouchi, M. & Sawamoto, M. A strategy for sequence control in vinyl polymers via iterative controlled radical cyclization. Nat. Commun. 7, 11064 (2016).

  29. 29.

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

  30. 30.

    Bootwicha, T., Feilner, J. M., Myers, E. L. & Aggarwal, V. K. Iterative assembly line synthesis of polypropionates with full stereocontrol. Nat. Chem. 9, 896–902 (2017).

  31. 31.

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

  32. 32.

    Amir, F., Jia, Z. & Monteiro, M. J. Sequence control of macromers via iterative sequential and exponential growth. J. Am. Chem. Soc. 138, 16600–16603 (2016).

  33. 33.

    Bayer, E. & Mutter, M. Liquid phase synthesis of peptides. Nature 237, 512–513 (1972).

  34. 34.

    Harris, J. M. (ed.) Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (Springer, New York, 1992).

  35. 35.

    Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010).

  36. 36.

    French, A. C., Thompson, A. L. & Davis, B. G. High-purity discrete PEG-oligomer crystals allow structural insight. Angew. Chem Int. Ed. 48, 1248–1252 (2009).

  37. 37.

    Maranski, K., Andreev, Y. G. & Bruce, P. G. Synthesis of poly(ethylene oxide) approaching monodispersity. Angew. Chem. Int. Ed. 53, 6411–6413 (2014).

  38. 38.

    Székely, G., Schaepertoens, M., Gaffney, P. R. J. & Livingston, A. G. Iterative synthesis of monodisperse PEG homostars and linear heterobifunctional PEG. Polym. Chem. 5, 694–697 (2014).

  39. 39.

    Zhang, H. et al. Highly efficient synthesis of monodisperse poly(ethylene glycols) and derivatives through macrocyclization of oligo(ethylene glycols). Angew. Chem. Int. Ed. 54, 3763–3767 (2015).

  40. 40.

    Khanal, A. & Fang, S. Solid phase stepwise synthesis of polyethylene glycols. Chem. Eur. J. 23, 15133–15142 (2017).

  41. 41.

    Karan, S., Jiang, Z. & Livingston, A. G. Sub-10 nm polyamide nanofilms with ultrafast solvent transport for molecular separation. Science 348, 1347–1351 (2015).

  42. 42.

    Jimenez-Solomon, M. F., Song, Q., Jelfs, K. E., Munoz-Ibanez, M. & Livingston, A. G. Polymer nanofilms with enhanced microporosity by interfacial polymerization. Nat. Mater. 15, 760–767 (2016).

  43. 43.

    Marchetti, P., Jimenez Solomon, M. F., Szekely, G. & Livingston, A. G. Molecular separation with organic solvent nanofiltration: a critical review. Chem. Rev. 114, 10735–10806 (2014).

  44. 44.

    Koros, W. J. & Zhang, C. Materials for next-generation molecularly selective synthetic membranes. Nat. Mater. 16, 289–297 (2017).

  45. 45.

    König, N. F., Al Ouahabi, A., Poyer, S., Charles, L. & Lutz, J.-F. A simple post-polymerization modification method for controlling side-chain information in digital polymers. Angew. Chem. Int. Ed. 56, 7297–7301 (2017).

  46. 46.

    Schaepertoens, M., Gaffney, P. R. J., Székely, G. & Livingston, A. G. Process for preparing polymers. Patent WO2016020696 (A1) (2016).

  47. 47.

    da Silva Burgal, J., Peeva, L., Marchetti, P. & Livingston, A. G. Controlling molecular weight cut-off of PEEK nanofiltration membranes using a drying method. J. Membrane Sci. 493, 524–538 (2015).

  48. 48.

    Gaffney, P. R. J., Livingston, A. G., Chen, R. & Dong, R. Defined monomer sequence polymers. Patent WO2017042583 (A1) (2017).

  49. 49.

    Kim, J. F., Freitas da Silva, A. M., Valtcheva, I. B. & Livingston, A. G. When the membrane is not enough: a simplified membrane cascade using organic solvent nanofiltration (OSN). Sep. Purif. Technol. 116, 277–286 (2013).

  50. 50.

    Weissman, S. A. & Zewge, D. Recent advances in ether dealkylation. Tetrahedron 61, 7833–7863 (2005).

  51. 51.

    Nishimura, S. (ed.) in Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis 572–663 (Wiley-Interscience, Hoboken, 2001).

  52. 52.

    Dunleavy, J. Sulfur as a catalyst poison. Platinum Metals Rev. 50, 110 (2006).

  53. 53.

    Okaya, S., Okuyama, K., Okano, K. & Tokuyama, H. Trichloroboron-promoted deprotection of phenolic benzyl ether using pentamethylbenzene as a non-Lewis basic cation scavenger. Org. Synth. 93, 63–74 (2016).

  54. 54.

    Matsueda, R., Higashida, S., Ridge, R. J. & Matsueda, G. R. Activation of conventional S-protecting groups of cysteine by conversion into the 3-nitro-2-pyridinesulfenyl (Npys) group. Chem. Lett. 921–924 (1982).

Download references

Acknowledgements

This work was supported financially by the Engineering and Physical Sciences Research Council (EPSRC, EP/M003949/1) and GlaxoSmithKline. The authors acknowledge the EPSRC UK National Mass Spectrometry Facility at Swansea University for MALDI–TOF–MS measurements. The authors thank R. T. Woodward for GPC analysis and C. Yu for molecular modelling. The authors thank Huntsman for provision of Jeffamines.

Author information

Affiliations

  1. Department of Chemical Engineering, Imperial College London, London, UK

    • Ruijiao Dong
    • , Ruiyi Liu
    • , Piers R. J. Gaffney
    • , Marc Schaepertoens
    • , Patrizia Marchetti
    • , Rongjun Chen
    •  & Andrew G. Livingston
  2. EPSRC UK National Mass Spectrometry Facility (NMSF), Swansea University Medical School, Swansea, UK

    • Christopher M. Williams

Authors

  1. Search for Ruijiao Dong in:

  2. Search for Ruiyi Liu in:

  3. Search for Piers R. J. Gaffney in:

  4. Search for Marc Schaepertoens in:

  5. Search for Patrizia Marchetti in:

  6. Search for Christopher M. Williams in:

  7. Search for Rongjun Chen in:

  8. Search for Andrew G. Livingston in:

Contributions

R.D., P.R.J.G., R.C. and A.G.L. conceived the project. R.D., P.R.J.G. and A.G.L. designed the experiments. R.D. carried out the synthesis and characterization of BnO-BB, N3-BB, PmbS-BB and polymers, and analysed the data. R.L. synthesized octyl-BB. R.D. conducted the DSC, TGA, UV–vis and fluorescence spectrometry measurements. R.D. and R.L. carried out organic solvent nanofiltration. R.L. performed liquid–liquid porometry and membrane screening. M.S. provided the hub molecule. P.M. prepared the PBI membranes. C.M.W. performed the MS/MS measurements. R.D. and P.R.J.G. wrote the manuscript. A.G.L. guided the project. All authors discussed the results and edited the manuscript.

Competing interests

Imperial Innovations has filed a UK patent application (no. 1516067.4) related to defined monomer sequence polymers (leading to PCT/GB2016/052801). A.G.L., P.R.J.G., R.D., R.C., P.M. and R.L. are listed as inventors. All other authors declare no competing interests.

Corresponding author

Correspondence to Andrew G. Livingston.

Supplementary information

  1. Supplementary information

    Supplementary experimental methods, synthetic procedures and compound characterization

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41557-018-0169-6