Sequence Controlled Polymers from a Novel β‐Cyclodextrin Core

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COMMUNICATION 1700501 (1 of 5) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mrc-journal.de Sequence Controlled Polymers from a Novel β-Cyclodextrin Core Yamin Abdouni, Gökhan Yilmaz, and C. Remzi Becer* Y. Abdouni, Dr. G. Yilmaz, Dr. C. R. Becer School of Engineering and Materials Science Queen Mary University of London London E1 4NS, UK E-mail: [email protected] The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/marc.201700501. DOI: 10.1002/marc.201700501 In 2001 Haddleton and co-workers introduced β-cyclodextrin (a homo- chiral cyclic oligosaccharide containing 7 glucopyranose units and thus 21 free hydroxyl groups), as a multifunctional core initiator for the preparation of well- defined star-shaped polymers via copper mediated controlled radical polymeriza- tions. [8] However, more recent publica- tions have shown that full substitution of the 21 hydroxyl groups is not achieved and that a mixture of star initiators is obtained. [9] More recently, the group of Li employed a less substituted version of this β-cyclodextrin core initiator with only 4 initiating sites on average. [10–12] Addition- ally, it is very important to control the number of arms and also one-side initiated polymerization from beta-cyclodextrin (CD) in order to achieve efficient host–guest interactions and also cellular transfection which are highly desired properties for the development of specific biological applications. [13,14] Stenzel and co-workers introduced the use of a β-cyclodextrin derived star reversible addition-fragmenta- tion chain transfer radical polymerization (RAFT) agent for the synthesis of spherical glycopolymer architec- tures. [15,16] The interesting feature about this multifunctional β-cyclodextrin derived RAFT agent is that only the top face of the β-cyclodextrin is converted to RAFT agents, whereas the bottom face is not. This leaves the possibility for small mole- cules to access the hydrophobic core for potential host–guest complexations. Although RAFT has proven to be a very useful technique in the preparation of extremely well-defined multi- block copolymers by the group of Perrier, it was found not suitable for the synthesis of core-first star-shaped polymers as it is prone to many termination reactions. [17–20] As mentioned vide supra, copper mediated controlled radical polymerizations offer an elegant way of achieving interesting architectures. The group of Haddleton has used these tech- niques for the synthesis of sequence controlled polymers both in dimethyl sulfoxide (DMSO) and in aqueous systems. [21–23] Encouraged by these results, our group was recently able to prepare star-shaped polymers via SET-LRP in DMSO and pent- ablock star shaped polymers in less than 90 min via aqueous SET-LRP starting from a water soluble glycerol core. [24,25] Inspired by these findings and the interesting features a β-cyclodextrin core could provide, we have developed a novel β-cyclodextrin derived SET-LRP star initiator (β-CD initiator). This work describes the synthesis route toward this novel star initiator via “click” like reactions as well as its use for the sequence-controlled polymerization of different acrylates. [26,27] Cyclodextrin-Centered Polymers In this work the synthesis and use of a novel β-cyclodextrin-based single electron transfer-living radical polymerization (SET-LRP) initiator are reported. Three different approaches toward the synthesis of this initiator, based on several “click”-like reactions (copper(I)-catalyzed azide-alkyne cycloaddition, nucleophilic thiol-ene reaction, and radical thiol-ene reaction), are explored and discussed. Synthesis via radical thiol-ene proves to be most successful in achieving this. The β-cyclodextrin-based initiator is subsequently used for the polymerization of several acrylates in a controlled fashion, yielding 7-arm multiblock copolymers. The achieved sequence-controlled polymers exhibit low dispersities (1.12) and are completed under 6.5 h at high monomer con- version (95%) for each block. 1. Introduction Over the last decade, there has been an increased interest in the development of more structurally complex macromolecules both in terms of monomer sequence as in overall architec- ture. [1–3] Function in nature’s macromolecules is not only deter- mined by its primary structure but also by its overall molecular architecture, displaying sophisticated properties such as molecular recognition and catalysis. For this reason, many dif- ferent nonlinear molecular architectures have been established ranging from cyclic polymers to dendritic, graft, brush, hyper- branched, and star-shaped (co)polymers. [4] These, together with advances in controlled polymerization methods at the end of the last century, have paved the way for the recent explosion of novel precision macromolecules, specifically tailored to exhibit distinct features. [5,6] Star polymers, in particular, can be prepared either via an arm- first approach, via coupling-onto, or via a core-first approach. In light of architectural precision, a core-first approach offers an enhanced control over the number of arms, as the arm-first approach usually gives a broad distribution of number of arms per molecule. [7] The coupling-onto method, on the other hand, requires a high coupling efficiency often acquired via “click” reactions after full conversion of the active chain end groups. Macromol. Rapid Commun. 2017, 1700501

Transcript of Sequence Controlled Polymers from a Novel β‐Cyclodextrin Core

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CommuniCation

1700501 (1 of 5) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

www.mrc-journal.de

Sequence Controlled Polymers from a Novel β-Cyclodextrin Core

Yamin Abdouni, Gökhan Yilmaz, and C. Remzi Becer*

Y. Abdouni, Dr. G. Yilmaz, Dr. C. R. BecerSchool of Engineering and Materials Science Queen Mary University of London London E1 4NS, UKE-mail: [email protected]

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/marc.201700501.

DOI: 10.1002/marc.201700501

In 2001 Haddleton and co-workers introduced β-cyclodextrin (a homo-chiral cyclic oligosaccharide containing 7 glucopyranose units and thus 21 free hydroxyl groups), as a multifunctional core initiator for the preparation of well-defined star-shaped polymers via copper mediated controlled radical polymeriza-tions.[8] However, more recent publica-tions have shown that full substitution of the 21 hydroxyl groups is not achieved and that a mixture of star initiators is obtained.[9] More recently, the group of Li employed a less substituted version of this β-cyclodextrin core initiator with only 4 initiating sites on average.[10–12] Addition-

ally, it is very important to control the number of arms and also one-side initiated polymerization from beta-cyclodextrin (CD) in order to achieve efficient host–guest interactions and also cellular transfection which are highly desired properties for the development of specific biological applications.[13,14]

Stenzel and co-workers introduced the use of a β-cyclodextrin derived star reversible addition-fragmenta-tion chain transfer radical polymerization (RAFT) agent for the synthesis of spherical glycopolymer architec-tures.[15,16] The interesting feature about this multifunctional β-cyclodextrin derived RAFT agent is that only the top face of the β-cyclodextrin is converted to RAFT agents, whereas the bottom face is not. This leaves the possibility for small mole-cules to access the hydrophobic core for potential host–guest complexations. Although RAFT has proven to be a very useful technique in the preparation of extremely well-defined multi-block copolymers by the group of Perrier, it was found not suitable for the synthesis of core-first star-shaped polymers as it is prone to many termination reactions.[17–20]

As mentioned vide supra, copper mediated controlled radical polymerizations offer an elegant way of achieving interesting architectures. The group of Haddleton has used these tech-niques for the synthesis of sequence controlled polymers both in dimethyl sulfoxide (DMSO) and in aqueous systems.[21–23] Encouraged by these results, our group was recently able to prepare star-shaped polymers via SET-LRP in DMSO and pent-ablock star shaped polymers in less than 90 min via aqueous SET-LRP starting from a water soluble glycerol core.[24,25]

Inspired by these findings and the interesting features a β-cyclodextrin core could provide, we have developed a novel β-cyclodextrin derived SET-LRP star initiator (β-CD initiator). This work describes the synthesis route toward this novel star initiator via “click” like reactions as well as its use for the sequence-controlled polymerization of different acrylates.[26,27]

Cyclodextrin-Centered Polymers

In this work the synthesis and use of a novel β-cyclodextrin-based single electron transfer-living radical polymerization (SET-LRP) initiator are reported. Three different approaches toward the synthesis of this initiator, based on several “click”-like reactions (copper(I)-catalyzed azide-alkyne cycloaddition, nucleophilic thiol-ene reaction, and radical thiol-ene reaction), are explored and discussed. Synthesis via radical thiol-ene proves to be most successful in achieving this. The β-cyclodextrin-based initiator is subsequently used for the polymerization of several acrylates in a controlled fashion, yielding 7-arm multiblock copolymers. The achieved sequence-controlled polymers exhibit low dispersities (≤1.12) and are completed under 6.5 h at high monomer con-version (≥95%) for each block.

1. Introduction

Over the last decade, there has been an increased interest in the development of more structurally complex macromolecules both in terms of monomer sequence as in overall architec-ture.[1–3] Function in nature’s macromolecules is not only deter-mined by its primary structure but also by its overall molecular architecture, displaying sophisticated properties such as molecular recognition and catalysis. For this reason, many dif-ferent nonlinear molecular architectures have been established ranging from cyclic polymers to dendritic, graft, brush, hyper-branched, and star-shaped (co)polymers.[4] These, together with advances in controlled polymerization methods at the end of the last century, have paved the way for the recent explosion of novel precision macromolecules, specifically tailored to exhibit distinct features.[5,6]

Star polymers, in particular, can be prepared either via an arm-first approach, via coupling-onto, or via a core-first approach. In light of architectural precision, a core-first approach offers an enhanced control over the number of arms, as the arm-first approach usually gives a broad distribution of number of arms per molecule.[7] The coupling-onto method, on the other hand, requires a high coupling efficiency often acquired via “click” reactions after full conversion of the active chain end groups.

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2. Results and Discussion

2.1. β-Cyclodextrin Initiator

For the preparation of the β-cyclodextrin based initiator three different synthesis routes were explored of which the former two have proven not to be successful (Scheme 1). The first synthesis route explored (1), was based on the copper(I)-cat-alyzed azide-alkyne cycloaddition, well-known as the “click” reaction.[28] For this, the secondary hydroxyl groups on the top face of the cyclodextrin were selectively brominated using triphenylphosphine and N-bromosuccinimide and subse-quently converted into azides via simple azide substitution in dimethylformamide (DMF). A terminal alkyne containing SET-LRP initiator was synthesized by simple substitution reac-tion between propargyl alcohol and bromoisobutyryl bromide. This SET-LRP initiator was then “clicked” to the per-(6-deoxy-6-azido)-β-cyclodextrin, but gel permeation chromatography (GPC) and NMR showed the synthesis was prone to side reac-tions. Most probably this could be ascribed to radical–radical coupling as the used conditions are very similar to those used in atom transfer radical polymerization (ATRP).[5] This can be observed through the appearance of higher molecular weight species in the GPC-chromatograms as seen in Scheme 2C.

For the second approach (2), the brominated cyclodextrin was thiolated using thiourea and subsequent hydrolysis and acidification yielded per-6-thio-β-cyclodextrin (β-CD-(SH)7).

Taking in account the oxidative instability of the thiols, this compound should be used as quickly as possible and be stored under argon. Subsequently the Michael addition was per-formed in DMF to 2-(2-bromoisobutyryloxy) ethyl acrylate as the Michael acceptor in the presence of triethylamine as a base catalyst and dimethyl phenyl phosphine as nucleophilic catalyst and as a reductant for possible disulfide bridges.[29] Although the desired compound was achieved, many side products were observed which could be ascribed to a competitive thio-bromo reaction.

The third approach proved to be the most successful (3), for this the thiolated cyclodextrin was reacted with a large excess of allyl 2-bromo-2-methylpropionate via the radical thiol-ene reaction in DMF.[30,31] To account for possible disulfide bridges, present in the starting product, two equivalents of dithiothreitol were added as a reductant 60 h prior to the thiol-ene reaction. The desired product was achieved along with minor dimer for-mation. As this product gave the best results, it was further used for the synthesis of sequence-controlled polyacrylate star polymers (Scheme 2).

2.2. Sequence-Controlled Polymerization of Acrylates

The novel β-cyclodextrin based initiator was subsequently used for the SET-LRP polymerization of three different acrylates in DMSO (Scheme 3).[32] A variety of star multiblock copolymers

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Scheme 1. Schematic overview of the different approaches toward a monofacially functionalized cyclodextrin initiator.

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based on methyl acrylate (MA), ethyl acrylate, and butyl acrylate were synthesized in various compositions demonstrating the versatility of the approach.

The multiblock copolymerization was initiated with 60 repeating units of MA per arm using the ratio of [MA]: [I]: [CuBr2]: [Me6TREN] = 60: 1: 0.04: 0.19. A higher amount of

Macromol. Rapid Commun. 2017, 1700501

Scheme 2. A) Chemical structure of the three different cyclodextrin-based initiators; B) 1H NMR spectrum of β-CD initiator c in DMSO; C) DMF-GPC traces of initiators 1, 2, and 3; and D) Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) spectrum of initiator c with the isotopic distribution of the peak of interest (black) and the theoretical isotopic distribution (red).

Scheme 3. A) Representative scheme for the obtained triblock β-CD initiated copolymer P1; B) SEC traces of P1 block; and C) 1H NMR spectra dis-playing full conversion for each block.

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monomers per arm was chosen for the first block, as it was found that using a smaller amount would result in elevated levels of terminating radical–radical coupling. As seen in Figure S11.1 of the Supporting Information, a shoulder at higher molecular weight was observed by GPC analysis. The main reason behind this could be that the close proximity of the growing chains leads to increased termination reactions. The use of more monomer for the first block resulted in a higher chance of monomer addition instead of radical–radical cou-pling, which leads to monomer propagation until the active chains are distant enough from each other. Typically a Schlenk tube was charged with same ratio of first block monomer MA, preactivated Cu(0) wire (5 cm), CuBr2, and Me6TREN in DMSO (1 mL) and then the mixture was degassed by gentle bubbling of argon gas for 30 min. Pre-degassed β-CD initiator in 1 mL was then added via gas tight syringe sequen-tially. The Schlenk tube was sealed and the reaction mixture was allowed to polymerize at 25 °C. After a polymerization time of 1.5 h, NMR evidenced that the poly-merization reaction was terminated. The second block solution of 10 repeating units of ethyl acrylate (EA) per arm was then degassed with argon for 20 min and subsequently transferred via cannula to the Schlenk tube under argon protection and allowed to polymerize which was finished after 1.5 h. Finally a third block of 10 repeating units of butyl acrylate (BA) per arm was added, for which the polymerization was finished after 2.5 h.

Furthermore, to assess the limits of applicability of our system, one more chain extension was carried out using MA for P1. Even though nearly 90% conversion was obtained in 3 h, a considerable coupling termination between two or more star polymers was observed via GPC at much higher molecular weight with high dispersities (Đ) (Figure S11.2, Supporting Information). Even though more experiments have been car-ried out to optimize the chain extension for the fourth block, unfortunately, it has not been successful to manage due to a higher occurrence of coupling process among star–star at low degree of polymerization ratios.

The obtained polymers were very well defined, demon-strating low polydispersities and radical–radical coupling and no tailing was observed (see the Supporting Informa-tion). As previously described, four different multiblock copolymers were synthesized (Table 1), demonstrating the versatility of the approach. We were able to keep the Đ of the multiblock copolymers below 1.12 with each block fin-ished under 2.5 h at monomer conversions over 95% and a total polymerization time under 6.5 h. Number average molar masses (Mn) and dispersities were determined via tetrahydrofuran (THF) GPC relative to polymethyl meth-acrylate (PMMA) standards. As often found for star poly-mers, measured molar masses were lower than theoretical molar masses.

3. Conclusions

In conclusion, we have investigated several synthesis routes toward monofacially functionalized β-cyclodextrin based SET-LRP star initiators. It was found that the radical thiol-ene reac-tion proved to be most successful in achieving this (3). The other two synthesis routes not only gave too many side reac-tions, but the first synthesis route also produces copper residues that can further interfere in the copper mediated polymerization processes. Furthermore we have demonstrated that this novel β-cyclodextrin based initiator can be used for the synthesis of core-first 7-arm multiblock star shaped polymers based on dif-ferent acrylates. All synthesized multiblock copolymers have excellent dispersities (≤1.12), even at high monomer conver-sions and were completed under 6.5 h. As the hydrophobic cavity of the β-cyclodextrin core should still be accessible, we hope to have drawn a basis for novel macrohost–guest reactions.

Supporting InformationSupporting Information is available from the Wiley Online Library or from the author.

AcknowledgementsThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 642083. This project is also supported by EPSRC (EP/P009018/1).

Conflict of InterestThe authors declare no conflict of interest.

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Table 1. Summary of monomer conversions, number average molar masses (Mn), and molar mass distributions (Đ) of the synthesized triblock copolymers.

Code Polymer ρa) [%] Mn,Theob)

[g mol−1]Mn,GPC

c) [g mol−1]

Đ Time [h]

MA EA BA

P1 P((MA)420-b-(EA)70)-b-(BA)70) 99 – – 38 800 35 600 1.06 1.5

– 98 – 45 800 43 500 1.07 1.5

– – 96 54 750 51 200 1.12 2

P2 P((MA)420-b-(BA)70)-b-(EA)70) 99 – – 38 800 35 300 1.06 1.5

– – 97 47 800 45 700 1.09 2

– 97 – 54 750 50 900 1.11 2.5

P3 P((EA)420-b-(MA)70)-b-(BA)70) – 99 – 44 700 41 900 1.07 1.5

98 – – 50 750 48 400 1.08 2

– – 95 59 700 56 200 1.11 2.5

P4 P((EA)420-b-(BA)70)-b-(MA)70) – 99 – 44 700 41 700 1.08 1.5

– – 96 53 600 51 100 1.10 2.5

96 – – 59 500 56 600 1.12 2.5

a)Conversion (ρ) obtained from 1H NMR; b)Mn,Theo = ([M]o/[CD-initiator]o × conversion × Mmon) + MCD-init; c)Determined by THF GPC (relative to PMMA standard).

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Macromol. Rapid Commun. 2017, 1700501

Keywordsβ-cyclodextrin initiator, sequence-controlled polymers, SET-LRP, star polymers

Received: July 24, 2017Revised: September 5, 2017

Published online:

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