PolymerChemistry

COMMUNICATION

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Department of Materials, Swiss Federal I

Zurich, Switzerland. E-mail: anzar.khan@m

+41 44 633 6474

† Electronic supplementary informatiocharacterization details are provided. See

Cite this: Polym. Chem., 2013, 4, 2440

Received 25th January 2013Accepted 26th February 2013

DOI: 10.1039/c3py00136a

www.rsc.org/polymers

2440 | Polym. Chem., 2013, 4, 2440–

Protecting-group-free synthesis of chain-endmultifunctional polymers by combining ATRP withthiol–epoxy ‘click’ chemistry†

Ikhlas Gadwal and Anzar Khan*

By combining ATRP polymerizationwith thiol–epoxy ‘click’ chemistry,

a general, efficient, and protection/deprotection-free route is

developed for the preparation of chain-end multifunctional

polymers.

Introduction

Chain-end functionalization of synthetic polymers is an estab-lished route to functional so materials.1–13 Such end-func-tionalized polymers are useful in many applications. Forexample, attachment of a radioactive label can render themuseful for biomedical purposes while appropriate substitutioncan make them excellent dispersing agents.10,11 It is interestingto note, therefore, that current synthetic approaches that do notinvolve functional group transformations and protection/deprotection protocols are limited to installation of a single typeof functionality at the polymer chain-end.1–9,12,13 This short-coming needs to be addressed as chemically heterogeneousmultifunctionalization is expected to increase the range ofpossible applications as well as performance of the function-alized materials.14,15 To this end, we describe a general andefficient synthetic scheme, free from the usual protection/deprotection requirement of organic synthesis, for installationof two different types of functional groups at a polymer chain-end (Scheme 1). This strategy also allows for total control overthe number of the chain-end functionalities (Scheme 1).

In the present strategy, functional group tolerance of theATRP16–19 process is exploited for the preparation of epoxy end-functional polymers (Step I in Scheme 1).20,21 The rst chemicalalteration of the epoxide group is achieved through the thiol–epoxy ‘click’ reaction.22–24 This high yielding and simple process

nstitute of Technology (ETH), CH-8093

at.ethz.ch; Fax: +41 44 633 1390; Tel:

n (ESI) available: Synthesis andDOI: 10.1039/c3py00136a

2444

allows for the introduction of a thiol unit at the polymer chain-end under ambient conditions (Step II in Scheme 1). Moreimportantly, a reactive hydroxyl group is revealed uponcompletion of the coupling process. Transformation of thehydroxyl moiety into an ester group then furnishes the doublyfunctionalized structures (Step III in Scheme 1).21–23 Thesupremacy of the present strategy, when compared to knownend-functionalization routes,1–9,13,25 arises due to two factors: (i)tolerance of the reactive epoxide sites by the ATRP process and(ii) the cascade25 nature of the thio-ether formation and theesterication reaction. These factors eliminate the need forprotection/deprotection protocols that would otherwise benecessary, and would at least double the number of the requiredsynthetic steps in generating such well-dened multifunctionalstructures.

Results and discussion

To meet the aforementioned goal, ATRP initiators having one,two, and three epoxide groups were designed (Scheme 1).Synthesis of initiator 1 was achieved through esterication ofthe commercially available glycidol with bromoisobutyrylbromide (Scheme 2 and Fig. 1). To obtain initiators 2 and 3carrying multiple epoxides, commercially available andhydroxyl substituted olens, 2a and 3a, were used. In the rststep, the unsaturated double bonds were subjected to anepoxidation reaction (Scheme 2). This yielded hydroxylsubstituted epoxy molecules 2b and 3b. Esterication of thehydroxyl group with bromoisobutyryl bromide then furnishedinitiators 2 and 3 (Scheme 2).

Initiators 1, 2, and 3 were used for the polymerization ofmethyl methacrylate monomer via the ATRP process. Thisafforded epoxide end-functional poly(methyl methacrylate)(PMMA) polymers, 4 (Mn ¼ 12 kDa), 5 (Mn ¼ 22 kDa), and 6(Mn ¼ 17 kDa) (Fig. 2). The rst functionalization of the epoxideunit(s) in polymers 4–6 was carried out using 1-naph-thalenethiol in the presence of a catalytic amount of LiOH in awater and THF solvent mixture (1 : 20 v/v) under ambient

This journal is ª The Royal Society of Chemistry 2013

Scheme 1

Communication Polymer Chemistry

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conditions. Subsequent esterication reaction of the hydroxylunit in polymers 7–9 with toluoyl chloride furnished the tar-geted end-multifunctional polymers 10–12.

Fig. 3 shows the 1H-NMR spectrum of polymer 6 (A), andfunctionalized polymers 9 (B) and 12 (C). Polymer 6 showed thetypical proton resonances of the PMMA backbone in the rangeof 0.6–2.2 and 3.3–3.9 ppm. The epoxy proton signals could belocated at 2.6, 2.8, and 3.1 ppm. Upon rst modication, theepoxy proton signals disappeared completely and typical

This journal is ª The Royal Society of Chemistry 2013

aromatic proton resonances from the naphthalene groupemerged in the range of 7.3–8.4 ppm. Area integration analysisin 1H-NMR spectroscopy suggested complete conversion of theepoxide moieties into the thio-ethers. Substitution with thenaphthalene chromophore was also apparent in UV-Vis spec-troscopy as polymer 9 exhibited broad absorption bands cen-tred on 245 and 300 nm due to the naphthyl chromophore(Fig. 4). The esterication reaction was carried out with toluoylchloride. This is due to the appearance of the toluoyl unit

Polym. Chem., 2013, 4, 2440–2444 | 2441

Scheme 2

Fig. 1 1H-NMR of the ATRP initiators 1 (A), 2 (B), and 3 (C) in CDCl3. Tetramethylsilane was used as an internal standard. Solvent signals are shown with an asterisk.

2442 | Polym. Chem., 2013, 4, 2440–2444 This journal is ª The Royal Society of Chemistry 2013

Polymer Chemistry Communication

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Fig. 2 GPC traces of the precursor polymers 4 (solid line), 5 (dotted line), and 6(dashed line) in chloroform.

Fig. 4 UV-Vis absorption spectra of polymers 6 (solid line), 9 (dashed line), and12 (dotted line) in chloroform (solution concentration was kept constant at 0.03mM).

Communication Polymer Chemistry

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methyl group in a region (�2.5 ppm) of the 1H-NMR spectrumthat is free from proton resonance signals of the polymerbackbone and end groups. This allows us to discern the extentof the hydroxyl group conversion by 1H-NMR spectroscopy.Indeed, the esterication of polymer 9 gave rise to polymer 12and area integration analysis between the proton resonances ofthe toluoyl unit (designated ‘e’ and ‘f’ in Fig. 3) and the naph-thalene group suggested complete conversion of the hydroxylunits into the desired toluoyl esters. The proton resonance

Fig. 3 1H-NMR of the precursor polymer 6 (A), and end-functionalized polymers 9 (signals are shown with an asterisk.

This journal is ª The Royal Society of Chemistry 2013

signal at 5.2 ppm could be assigned to a single proton located atthe carbon adjacent to the newly formed ester linkage. The NMRintegration analyses carried out aer each functionalizationprocess also suggested that the bromide chain-end did notparticipate in the modication reactions. In size exclusionchromatograms, no shi in the retention time was observed inprecursor polymers and their chain-end functionalizedstructures.

B) and 12 (C) in CDCl3. Tetramethylsilane was used as an internal standard. Solvent

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Polymer Chemistry Communication

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Conclusions

ATRP-based polymerization initiators carrying one, two, andthree epoxide units were designed and synthesized. ATRPpolymerization of the methyl methacrylate monomer furnishedthe epoxide-end-functional polymers. The thiol–epoxy ‘click’reaction then installed an optically active functionality andfurnished a reactive hydroxyl group at the polymer chain-end.Esterication of the hydroxyl unit with toluoyl chloride gave riseto the targeted chain-end multifunctional materials. Thenumber of the chain-end functionalities, in the presentapproach, could be varied simply by varying the number ofepoxide unit(s) on the polymerization initiator. Due to thefunctional group tolerance of the ATRP process and the cascadenature of the functionalization processes, the present strategy isfree from the typical protection/deprotection requirements oforganic synthesis.

In essence, the present strategy establishes a novel, modular,and efficient route to chain-end multifunctional polymers withchemically complex yet molecularly precise structures and isexpected to impact the current design of functional so mate-rials targeted for sophisticated applications.

Acknowledgements

The authors thank Prof. A. D. Schluter (ETH-Z) and SwissNational Science Foundation (SNSF) for nancial support.

Notes and references

1 R. P. Quirk and D. L. Pickel, Polymer Science: A ComprehensiveReference, 2012, 6, 351–412, and references therein.

2 M. A. Tasdelen, M. U. Kahveci and Y. Yagci, Prog. Polym. Sci.,2005, 36, 455–567, and references therein.

3 F. L. Verso and C. N. Likos, Polymer, 2008, 49, 1425–1434,and references therein.

4 U. Mansfeld, C. Pietsch, R. Hoogenboom, R. Becer andU. S. Schubert, Polym. Chem., 2010, 1, 1560–1598, andreferences therein.

5 R. K. Iha, K. L. Wooley, A. M. Nystrom, D. J. Burke, M. J. Kadeand C. J. Hawker, Chem. Rev., 2009, 109, 5620–5686, andreferences therein.

6 H. Durmaz, A. Sanyal, G. Hizal and U. Tunca, Polym. Chem.,2012, 3, 825–835, and references therein.

7 A. Sanyal, Macromol. Chem. Phys., 2010, 211, 1417–1425.8 S. Hilf and A. F. M. Kilbinger, Nat. Chem., 2009, 1, 537–546.9 (a) G. N. Grover, S. N. S. Alconcel, N. M. Matsumoto andH. D. Maynard, Macromolecules, 2009, 42, 7657–7663; (b)L. Tao, C. S. Kaddis, R. R. Ogorzalek Loo, G. N. Grover,J. A. Loo and H. D. Maynard, Macromolecules, 2009, 42,8028–8033; (c) K. L. Heredia, Z. P. Tolstyka andH. D. Maynard, Macromolecules, 2007, 40, 4772.

10 N. Tomczak, D. Janczewski, M. Han and G. J. Vancso, Prog.Polym. Sci., 2009, 34, 393–430.

11 R. Vestberg, A. M. Piekarski, E. D. Pressly, K. Y. V. Berkel,M. Malkoch, J. Gerbac, N. Ueno and C. J. Hawker, J. Polym.Sci., Part A: Polym. Chem., 2009, 47, 1237–1258.

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12 For a protecting-group-free chain-end bi-functionalizationwith chemically homogenous groups, please see:M. P. Robin, M. W. Jones, D. M. Haddleton andR. K. O'Reilly, ACS Macro Lett., 2012, 1, 222–226.

13 Foroneexampleof chain-endhetero-functionalization throughbromide-to-azide functional group transformation andsubsequent application of orthogonal click reactions, pleasesee: L. M. Campos, K. L. Killops, R. Sakai, J. M. J. Paulusse,D. Damiron, E. Drockenmuller, B. W. Messmore andC. J. Hawker,Macromolecules, 2008, 41, 7063.

14 For example, in the biomedical arena, molecular structuresthat possess multiple functional groups for tissuetargeting, cell entry, and imaging, in all-in-one system arehighly desired: (a) T. L. Mindt, C. Muller, F. Stuker,J.-F. Salazar, A. Hohn, T. Mueggler, M. Rudin andR. Schibli, Bioconjugate Chem., 2009, 20, 1940–1949; (b)X. Li, J. Guo, J. Asong, M. A. Wolfert and G.-J. Boons, J. Am.Chem. Soc., 2011, 133, 11147–11153; (c) D. M. Beal andL. H. Jones, Angew. Chem., Int. Ed., 2012, 51, 6320–6326.

15 For protective-group free multifunctionalization ofpolymers, please see: A. Saha, S. De, M. C. Stuparu andA. Khan, J. Am. Chem. Soc., 2012, 134, 17291–17297.

16 (a) T. E. Patten, J. Xia, T. Abernathy and K. Matyjaszewski,Science, 1996, 272, 866–868; (b) J.-S. Wang andK. Matyjaszewski, J. Am. Chem. Soc., 1995, 117, 5614–5615;(c) K. Matyjaszewski, T. E. Patten and J. Xia, J. Am. Chem.Soc., 1997, 119, 674–680.

17 (a) K. Matyjaszewski and J. Xia, Chem. Rev., 2001, 101, 2921–2990; (b) N. V. Tsarevsky and K. Matyjaszewski, Chem. Rev.,2007, 107, 2270–2299.

18 P. L. Golas and K. Matyjaszewski, Chem. Soc. Rev., 2010, 39,1338–1354.

19 For synthesis of polymers with reactive chain-ends via ATRP,please see: (a) K. Matyjaszewski, Y. Nakagawa andS. G. Gaynor, Macromol. Rapid Commun., 1997, 18, 1057–1066; (b) Y. Nakagawa and K. Matyjaszewski, Polym. J.,1998, 30, 138–141.

20 For synthesis of polymers with an epoxy chain-end via ATRP,please see: (a) N. V. Tsarevsky, S. A. Bencherif andK. Matyjaszewski, Macromolecules, 2007, 40, 4439–4445; (b)X. Zhang, J. Xia and K. Matyjaszewski, Macromolecules,2000, 33, 2340; (c) M. Degirmenci, O. Izgin, A. Acikses andN. Genli, React. Funct. Polym., 2010, 70, 28–34.

21 For synthesis of random copolymers and block copolymerscarrying an epoxide unit at each repeat unit via ATRP,please see: S. De, C. Stelzer and A. Khan, Polym. Chem.,2012, 3, 2342–2345.

22 S. De and A. Khan, Chem. Commun., 2012, 48, 3130–3132.23 A. Brandle and A. Khan, Polym. Chem., 2012, 3, 3224–3227.24 For use of the thiol–epoxy reaction in the synthesis of

hyperbranched polymers, please see: S. Li, J. Han andC. Gao, Polym. Chem., 2013, 4, 1774–1787.

25 For use of cascade reactions in post-polymerizationmodication of polymers, please see: M. Malkoch,R. J. Thibault, E. Drockenmuller, M. Messerschmidt,B. Voit, T. P. Russell and C. J. Hawker, J. Am. Chem. Soc.,2005, 127, 14942.

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