Sequence-controlled methacrylic multiblock copolymers via sulfur-free raft emulsion polymerization

ABSTRACT Translating the precise monomer sequence control achieved in nature over macromolecular structure (for example, DNA) to whole synthetic systems has been limited due to the lack of

efficient synthetic methodologies. So far, chemists have only been able to synthesize monomer sequence-controlled macromolecules by means of complex, time-consuming and iterative chemical

strategies such as solid-state Merrifield-type approaches or molecularly dissolved solution-phase systems. Here, we report a rapid and quantitative synthesis of sequence-controlled

multiblock polymers in discrete stable nanoscale compartments via an emulsion polymerization approach in which a vinyl-terminated macromolecule is used as an efficient chain-transfer agent.

This approach is environmentally friendly, fully translatable to industry and thus represents a significant advance in the development of complex macromolecule synthesis, where a high level

of molecular precision or monomer sequence control confers potential for molecular targeting, recognition and biocatalysis, as well as molecular information storage. Access through your

institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print

issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to

local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT

BEING VIEWED BY OTHERS ONE-STEP SYNTHESIS OF SEQUENCE-CONTROLLED MULTIBLOCK POLYMERS WITH UP TO 11 SEGMENTS FROM MONOMER MIXTURE Article Open access 10 January 2022 CONCURRENT CONTROL OVER

SEQUENCE AND DISPERSITY IN MULTIBLOCK COPOLYMERS Article 29 November 2021 POLYMER CYCLIZATION FOR THE EMERGENCE OF HIERARCHICAL NANOSTRUCTURES Article Open access 25 June 2021 REFERENCES *

Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. _J. Am. Chem. Soc._ 85, 2149–2154 (1963). Article  CAS  Google Scholar  * Lutz, J.-F., Ouchi, M., Liu, D.

R. & Sawamoto, M. Sequence-controlled polymers. _Science_ 341, 1238149 (2013). Article  PubMed  CAS  Google Scholar  * Ouchi, M., Badi, N., Lutz, J.-F. & Sawamoto, M. Single-chain

technology using discrete synthetic macromolecules. _Nat. Chem._ 3, 917–924 (2011). Article  CAS  PubMed  Google Scholar  * Badi, N. & Lutz, J.-F. Sequence control in polymer synthesis.

_Chem. Soc. Rev._ 38, 3383–3390 (2009). Article  CAS  PubMed  Google Scholar  * Lutz, J.-F. Sequence-controlled polymerizations: the next holy grail in polymer science? _Polym. Chem._ 1,

55–62 (2010). Article  CAS  Google Scholar  * Zamfir, M. & Lutz, J.-F. Ultra-precise insertion of functional monomers in chain-growth polymerizations. _Nat. Commun._ 3, 1138 (2012).

Article  CAS  Google Scholar  * Vandenbergh, J., Reekmans, G., Adriaensens, P. & Junkers, T. Synthesis of sequence-defined acrylate oligomers via photo-induced copper-mediated radical

monomer insertions. _Chem. Sci._ 6, 5753–5761 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vandenbergh, J., Reekmans, G., Adriaensens, P. & Junkers, T. Synthesis of

sequence controlled acrylate oligomers via consecutive RAFT monomer additions. _Chem. Commun._ 49, 10358–10360 (2013). Article  CAS  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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  PubMed  Google Scholar  * 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  PubMed  Google Scholar  * Guo, Y., Zhang, J., Xie, P., Gao, X. &

Luo, Y. Tailor-made compositional gradient copolymer by a many-shot RAFT emulsion polymerization method. _Polym. Chem._ 5, 3363–3371 (2014). Article  CAS  Google Scholar  * 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). Article  CAS  PubMed 

Google Scholar  * Hartmann, L. & Börner, H. G. Precision polymers: monodisperse, monomer-sequence-defined segments to target future demands of polymers in medicine. _Adv. Mater._ 21,

3425–3431 (2009). Article  CAS  PubMed  Google Scholar  * 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  * 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). Article  CAS  PubMed  Google Scholar  * Ueda,

M. Sequence control in one-step condensation polymerization. _Prog. Polym. Sci._ 24, 699–730 (1999). Article  CAS  Google Scholar  * Bayer, E. & Mutter, M. Liquid phase synthesis of

peptides. _Nature_ 237, 512–513 (1972). Article  CAS  PubMed  Google Scholar  * Barnes, J. C. et al. Iterative exponential growth of stereo- and sequence-controlled polymers. _Nat. Chem._ 7,

810–815 (2015). Article  CAS  PubMed  Google Scholar  * Soeriyadi, A. H., Boyer, C., Nyström, F., Zetterlund, P. B. & Whittaker, M. R. High-order multiblock copolymers via iterative

Cu(0)-mediated radical polymerizations (SET-LRP): toward biological precision. _J. Am. Chem. Soc._ 133, 11128–11131 (2011). Article  CAS  PubMed  Google Scholar  * Anastasaki, A. et al. High

molecular weight block copolymers by sequential monomer addition via Cu(0)-mediated living radical polymerization (SET-LRP): an optimized approach. _ACS Macro Lett._ 2, 896–900 (2013).

Article  CAS  Google Scholar  * Anastasaki, A. et al. Photoinduced sequence-control via one pot living radical polymerization of acrylates. _Chem. Sci._ 5, 3536–3542 (2014). Article  CAS 

Google Scholar  * Anastasaki, A. et al. Photoinduced synthesis of α,ω-telechelic sequence-controlled multiblock copolymers. _Macromolecules_ 48, 1404–1411 (2015). Article  CAS  Google

Scholar  * Alsubaie, F., Anastasaki, A., Wilson, P. & Haddleton, D. M. Sequence-controlled multi-block copolymerization of acrylamides via aqueous SET-LRP at 0 °C. _Polym. Chem._ 6,

406–417 (2015). Article  CAS  Google Scholar  * Zhang, Q. et al. Sequence-controlled multi-block glycopolymers to inhibit DC-SIGN-gp120 binding. _Angew. Chem. Int. Ed._ 52, 4435–4439 (2013).

Article  CAS  Google Scholar  * Vandenbergh, J. & Junkers, T. Alpha and omega: importance of the nonliving chain End in RAFT multiblock copolymerization. _Macromolecules_ 47, 5051–5059

(2014). Article  CAS  Google Scholar  * Chuang, Y.-M., Ethirajan, A. & Junkers, T. Photoinduced sequence-controlled copper-mediated polymerization: synthesis of decablock copolymers.

_ACS Macro Lett._ 3, 732–737 (2014). Article  CAS  Google Scholar  * Gody, G., Maschmeyer, T., Zetterlund, P. B. & Perrier, S. Rapid and quantitative one-pot synthesis of

sequence-controlled polymers by radical polymerization. _Nat. Commun._ 4, 2505 (2013). Article  PubMed  CAS  Google Scholar  * Martin, L., Gody, G. & Perrier, S. Preparation of complex

multiblock copolymers via aqueous RAFT polymerization at room temperature. _Polym. Chem._ 6, 4875–4886 (2015). Article  CAS  Google Scholar  * Junkers, T. & Wenn, B. Continuous photoflow

synthesis of precision polymers. _React. Chem. Eng._ 1, 60–64 (2016). Article  CAS  Google Scholar  * Wenn, B., Martens, A. C., Chuang, Y. M., Gruber, J. & Junkers, T. Efficient

multiblock star polymer synthesis from photo-induced copper-mediated polymerization with up to 21 arms. _Polym. Chem._ 7, 2720–2727 (2016). Article  CAS  Google Scholar  * Boyer, C.,

Soeriyadi, A. H., Zetterlund, P. B. & Whittaker, M. R. Synthesis of complex multiblock copolymers via a simple iterative Cu(0)-mediated radical polymerization approach. _Macromolecules_

44, 8028–8033 (2011). Article  CAS  Google Scholar  * Zetterlund, P. B., Thickett, S. C., Perrier, S., Bourgeat-Lami, E. & Lansalot, M. Controlled/living radical polymerization in

dispersed systems: an update. _Chem. Rev._ 115, 9745–9800 (2015). Article  CAS  PubMed  Google Scholar  * Truong, N. P. et al. Facile production of nanoaggregates with tuneable morphologies

from thermoresponsive P(DEGMA-co-HPMA). _Polym. Chem._ 7, 430–440 (2016). Article  CAS  Google Scholar  * Moad, C. L., Moad, G., Rizzardo, E. & Thang, S. H. Chain transfer activity of

ω-unsaturated methyl methacrylate oligomers. _Macromolecules_ 29, 7717–7726 (1996). Article  CAS  Google Scholar  * Hutson, L. et al. Chain transfer activity of ω-unsaturated methacrylic

oligomers in polymerizations of methacrylic monomers. _Macromolecules_ 37, 4441–4452 (2004). Article  CAS  Google Scholar  * Suddaby, K. G., Haddleton, D. M., Hastings, J. J., Richards, S.

N. & O'Donnell, J. P. Catalytic chain transfer for molecular weight control in the emulsion polymerization of methyl methacrylate and methyl methacrylate−styrene. _Macromolecules_

29, 8083–8091 (1996). Article  CAS  Google Scholar  * Kukulj, D., Davis, T. P., Suddaby, K. G., Haddleton, D. M. & Gilbert, R. G. Catalytic chain transfer for molecular weight control in

the emulsion homo- and copolymerizations of methyl methacrylate and butyl methacrylate. _J. Polym. Sci. A_ 35, 859–878 (1997). Article  CAS  Google Scholar  * Haddleton, D. M., Maloney, D.

R., Suddaby Adam Clarke, K. G. & Richards, S. N. Radical-addition-fragmentation and co-polymerization of methyl methacrylate macromonomers from catalytic chain transfer polymerization

(CCTP). _Polymer_ 38, 6207–6217 (1997). Article  CAS  Google Scholar  * Haddleton, D. M., Maloney, D. R. & Suddaby, K. G. Competition between β-scission of macromonomer-ended radicals

and chain transfer to cobalt(II) in catalytic chain transfer polymerization (CCTP). _Macromolecules_ 29, 481–483 (1996). Article  CAS  Google Scholar  * Krstina, J. et al. Narrow

polydispersity block copolymers by free-radical polymerization in the presence of macromonomers. _Macromolecules_ 28, 5381–5385 (1995). Article  CAS  Google Scholar  * Gody, G., Zetterlund,

P. B., Perrier, S. & Harrisson, S. The limits of precision monomer placement in chain growth polymerization. _Nat. Commun._ 7, 10514 (2016). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Heuts, J. P. A. & Smeets, N. M. B. Catalytic chain transfer and its derived macromonomers. _Polym. Chem._ 2, 2407–2423 (2011). Article  CAS  Google Scholar  * Buback, M.,

Kurz, C. H. & Schmaltz, C. Pressure dependence of propagation rate coefficients in free-radical homopolymerizations of methyl acrylate and dodecyl acrylate. _Macromol. Chem. Phys._ 199,

1721–1727 (1998). Article  CAS  Google Scholar  * Beuermann, S. et al. Critically evaluated rate coefficients for free-radical polymerization, 2. Propagation rate coefficients for methyl

methacrylate. _Macromol. Chem. Phys._ 198, 1545–1560 (1997). Article  CAS  Google Scholar  * Zammit, M. D., Coote, M. L., Davis, T. P. & Willett, G. D. Effect of the ester side-chain on

the propagation kinetics of alkyl methacrylates. An entropic or enthalpic effect? _Macromolecules_ 31, 955–963 (1998). Article  CAS  Google Scholar  * Truong, N. P., Dussert, M. V.,

Whittaker, M. R., Quinn, J. F. & Davis, T. P. Rapid synthesis of ultrahigh molecular weight and low polydispersity polystyrene diblock copolymers by RAFT-mediated emulsion

polymerization. _Polym. Chem._ 6, 3865–3874 (2015). Article  CAS  Google Scholar  * Gilbert, R. G. _Emulsion Polymerization: A Mechanistic Approach_ (Academic, 1995). Google Scholar  *

Chang, C.-W., Bays, E., Tao, L., Alconcel, S. N. S. & Maynard, H. D. Differences in cytotoxicity of poly (PEGA)s synthesized by reversible addition–fragmentation chain transfer

polymerization. _Chem. Commun._ 3580–3582 (2009). * Pissuwan, D., Boyer, C., Gunasekaran, K., Davis, T. P. & Bulmus, V. In vitro cytotoxicity of RAFT polymers. _Biomacromolecules_ 11,

412–420 (2010). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors acknowledge financial support from the University of Warwick, the Australian Research

Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology (CE140100036) and Lubrizol (to N.G.E.). D.M.H. is a Wolfson/Royal Society Research Fellow. The authors

acknowledge the facilities and personnel (A.A., M.R.W., T.P.D. and D.M.H.) enabled by the Monash–Warwick Alliance. AUTHOR INFORMATION Author notes * Nikolaos G. Engelis and Athina

Anastasaki: These authors contributed equally to this work AUTHORS AND AFFILIATIONS * Chemistry Department, University of Warwick, Library Road, Coventry, CV4 7AL, UK Nikolaos G. Engelis, 

Athina Anastasaki, Gabit Nurumbetov, Vasiliki Nikolaou, Ataulla Shegiwal, Thomas P. Davis & David M. Haddleton * ARC Centre of Excellence in Convergent Bio-Nano Science and Technology,

Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 399 Royal Parade, Parkville, 3152, Victoria, Australia Athina Anastasaki, Nghia P. Truong, Michael R.

Whittaker, Thomas P. Davis & David M. Haddleton Authors * Nikolaos G. Engelis View author publications You can also search for this author inPubMed Google Scholar * Athina Anastasaki

View author publications You can also search for this author inPubMed Google Scholar * Gabit Nurumbetov View author publications You can also search for this author inPubMed Google Scholar *

Nghia P. Truong View author publications You can also search for this author inPubMed Google Scholar * Vasiliki Nikolaou View author publications You can also search for this author

inPubMed Google Scholar * Ataulla Shegiwal View author publications You can also search for this author inPubMed Google Scholar * Michael R. Whittaker View author publications You can also

search for this author inPubMed Google Scholar * Thomas P. Davis View author publications You can also search for this author inPubMed Google Scholar * David M. Haddleton View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS A.A., D.M.H. and T.P.D. conceived and designed the experiments. N.G.E. and A.A. performed the

experiments. N.G.E., A.A., and V.N. analysed the data with input from G.N, N.P.T., A.S. and M.R.W. A.A. and N.G.E. co-wrote the paper. All authors discussed the results and commented on the

manuscript. A.A. and N.G.E. contributed equally to this work. CORRESPONDING AUTHORS Correspondence to Athina Anastasaki, Thomas P. Davis or David M. Haddleton. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary information (PDF 2168 kb) RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Engelis, N., Anastasaki, A., Nurumbetov, G. _et al._ Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion

polymerization. _Nature Chem_ 9, 171–178 (2017). https://doi.org/10.1038/nchem.2634 Download citation * Received: 22 February 2016 * Accepted: 02 September 2016 * Published: 17 October 2016

* Issue Date: February 2017 * DOI: https://doi.org/10.1038/nchem.2634 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry,

a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative