Cyclodextrin-centred star polymers synthesized via a combination of thiol-ene click and ring opening polymerization

Article abstract of DOI:10.1039/c2cc33742h

The synthesis of cyclodextrin-centred star polymers via thiol-ene addition of per-6-thio-β-cyclodextrin (CD-(SH)₇) with vinyl terminated polymers is described. The obtained thiol-ene product was employed as an initiator for ring opening polymerization (ROP) of ε-caprolactone (ε-CL).

Full text of DOI:10.1039/c2cc33742h

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COMMUNICATION
Cyclodextrin-centred star polymers synthesized via a combination of
thiol-ene click and ring opening polymerizationw
Qiang Zhang, Guang-Zhao Li, C. Remzi Becer* and David M. Haddleton*
Received 24th May 2012, Accepted 12th June 2012
DOI: 10.1039/c2cc33742h
The synthesis of cyclodextrin-centred star polymers via thiol-ene
addition of per-6-thio-b-cyclodextrin (CD-(SH)7) with vinyl
terminated polymers is described. The obtained thiol-ene product
was employed as an initiator for ring opening polymerization
(ROP) of e-caprolactone (e-CL).
coupled to CD–(SH)7 by thiol-ene click reaction. Furthermore,
ROP of e-CL using the thiol-ene product as an initiator was
also investigated.
The hydroxyl groups on the primary face of b-CD can be
selectively transformed to iodine atoms via reaction with PPh3/I2
with a subsequent conversion into thiol groups via a one pot
reaction with thiourea (Scheme 1). The obtained CD–(SH)7 was
then reacted with different (meth)acrylic monomers and vinyl
terminated polymers synthesized by catalytic chain transfer
polymerization (CCTP), Scheme 2. Reactions were performed
in DMSO with either DMPP or HA as catalyst accelerating the
rate and increasing the conversion.23,24
Addition of MA with CD–(SH)7 followed by 1H NMR
showed the disappearance of triplet from the thiol groups at
2.13 ppm and new peaks at 2.5–2.6 ppm (S–CH2–CH2),
2.7–2.8 ppm (S–CH2–CH2) and 3.6 ppm (O–CH3), confirming
the success of the thiol-ene reaction. 13C NMR showed the
C–6’s shift from 26.0 ppm (CD–(SH)7) to 34.1 ppm
(CD–(S–MA)7) after reaction and also the appearance of new
peaks at 171.8 ppm (CQO), 51.4 ppm (O–CH3), 33.1 ppm
(CH2–CQO) and 27.7 ppm (S–CH2) (Fig. S3w). SEC analysis
(Fig. 1) showed the molecular weight (MW) increasing after the
Cyclodextrins (CD) are cyclic oligosaccharides composed of
a-1, 4-linked D-glucopyranose units and have been used in drug
delivery due to the ability to form inclusion complexes with guest
molecules.1–4 Modification of CD has offered polymer chemists
opportunities to prepare well-defined CD-centred star polymers
via core-first approach from different controlled radical poly-
merization techniques including ATRP,5 RAFT6 and NMP.7
Since the introduction of click chemistry, by Sharpless et al.,8
Cu(I)-catalysed azide-alkyne cyclodextrin (CuAAC) reaction has
been employed in modification of CD. Synthesis of seven-arm
star-shaped poly(e-CL) was first reported via CuAAC reaction of
per-6-azido-b-cyclodextrin with excess low molecular weight
acetylene poly(e-CL).9 A similar strategy was then used to
prepare well-defined multi-arm CD-centred star polymers10–12
and stimuli-responsive Janus-type copolymers.13 CuAAC has
also proved to be highly efficient in the construction of polymers
with covalently attached CD for small molecule and drug delivery
use.14–17 The thiol-ene reaction has attracted interest due to its facile
and versatile process that fulfils the basic requirements of a click
reaction.18 However, the reports on the modification of CD via
thiol-ene reaction are limited. b-CD based carbohydrate glycol
cluster compounds were prepared by the photoaddition reaction
of thiol sugars to allyl ether groups on modified CDs with moderate
yields.19,20 The sodium salt of CD–(SH)7 was used for the Michael
addition reaction with maleimide functionalized dextran to form a
crosslinked hydrogel.21 Mono thiol-functionalized CD was also
used for similar thiol-maleimide conjugation reaction in phosphate
buffered saline solution.22
Scheme 1 Schematic representation of the synthetic approach to azido
and thiol functionalized b-CD.
In this current work, we report the modification of b-CD via
base catalyzed Michael addition using (meth)acrylic monomers
and vinyl terminated polymers precursors. These precursors were
Department of Chemistry, University of Warwick, Coventry,
CV4 7AL, UK. E-mail: C.R.Becer@warwick.ac.uk,
D.M.Haddleton@warwick.ac.uk; Fax: +44(0)24 7652 4112;
Tel: +44(0)24 7652 3256
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc33742h
Scheme 2 Reagents employed in this study; CD–(SH)7, (meth)acrylic
monomers, vinyl terminated polymers and catalysts.
c
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Chem. Commun., 2012, 48, 8063–8065 8063

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Fig. 1 DMF eluent SEC traces of CD–(SH)7, CD–(S–MA)7 and
PCL-CD–(S–MA)7.
Fig. 3 MALDI-ToF MS spectra obtained for (a) CD–(S–PEGMEA480)7
and (b) CD–(S–PDEGMEMA)7.
after reaction. Although it tends to be difficult to get a high
resolution MALDI-ToF MS spectrum (Fig. 3a) for CD-centred
star polymers, polymer peaks which belong to the thiol-ene
products at higher MW region than PEGMEA480 could be
found, which proved the success and efficiency of thiol-ene
reaction between CD–(SH)7 and acrylic polymer.
The thiol-ene reaction is highly efficient in modifying
unsaturated CCTP polymers.25 To investigate the possibility
of CCTP polymers for the thiol-ene reaction with CD–(SH)7, a
CCTP MMA dimer (diMMA) was first attempted. NMR,
SEC and MALDI-ToF MS (Fig. 2) analysis confirmed the
formation of desired diMMA modified CD after 24 h.
A linear vinyl terminated PDEGMEMA (Mn = 900 g molÀ1
,
Fig. 2 MALDI-ToF MS spectra obtained for CD–(SH)7, CD–(S–MA)7,
CD–(S–MMA)7, CD–(S–DEGMEMA)7 and CD–(S–diMMA)7.
PDI = 1.40) was investigated using HA catalysis. Purification
1
via dialysis and analysis of the obtained polymer by H and
reaction and MALDI-ToF MS (Fig. 2) confirmed the complete
reaction of all seven thiol groups. Two other methacrylic
monomers, MMA and DEGMEMA, were also reacted with
CD–(SH)7 and both reactions also showed complete conversion
of thiol groups via NMR, SEC and MALDI-ToF MS analysis
(Fig. 2).
13C NMR (Fig. S11w) showed the disappearance of thiol groups
and signals for both PDEGMEMA and b-CD. SEC revealed
the increase of MW after reaction, although a small tail peak at
low MW area was noticed. Further analyses via MALDI-ToF
MS (Fig. 3b) confirmed peaks from the thiol-ene product.
Relatively small peaks at low MW were also observed and
attributed to the side reaction between HA and terminal vinyl
groups. The thermoresponsive behaviour of PDEGMEMA
before and after reaction was examined via UV/Vis spectro-
photometer. A temperature decrease of the cloud point from
58.8 to 50.2 1C was found after the linear polymer was reacted
with CD–(SH)7 (Fig. S12w), which was also noticed in a
previous report.10 The expected lower cloud point value for
Moreover, reaction of PEG acrylate (Mn = 480, PDI = 1.05)
with CD–(SH)7 ([thiol] : [ene] = 1 : 1) catalyzed by 5% DMPP in
DMSO was carried out. 1H NMR analysis revealed the disappear-
ance of the vinyl groups after 24 h. 1H NMR of the isolated
product confirmed the disappearance of thiol groups and appear-
ance of PEG moieties whilst 13C NMR revealed C–6’s shift and
existence of CD ring with SEC traces showing the MW increase
c
8064 Chem. Commun., 2012, 48, 8063–8065
This journal is The Royal Society of Chemistry 2012

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Different CD-centred macromolecular architectures and star
polymers have been prepared through the combination of
CCTP, ROP and thiol-ene click reaction. This versatile strategy
introduces the thiol-ene click reaction into modification of
CD for polymer synthesis and future studies will focus on
synthesis of miktoarm star polymers and polymers with
covalently attached to CD.
The authors acknowledge the financial support from the
University of Warwick and CSC (QZ, GZL). Equipment used
in this research was parted funded through Advantage West
Midlands (AWM) Science City Initiative. CRB is currently a
Science City Senior Research Fellow and DMH is a Royal
Society/Wolfson Fellow.
Scheme 3 Schematic representation of the synthesis of poly (e-CL)
initiated by CD–(S–MA)7.
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Fig. 4 1H (top) and13
CD–(S–MA)7 in DMSO-d6.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8063–8065 8065