Synthesis of a star polymer library with a diverse range of highly functionalized macromolecular architectures

Article abstract of DOI:10.1021/ma200283c

An efficient and versatile synthetic route toward highly functionalized core cross-linked star (CCS) polymers with interesting structures and properties is presented using an alkyne CCS polymer as scaffold. The alkyne CCS polymer scaffold was initially prepared via an improved arm-first approach, through ring-opening polymerization (ROP) of 4,4′-bioxepanyl-7,7′-dione (BOD) with a poly(caprolactone-b-propargyl methacrylate) macroinitiator and stannous triflate (Sn(OTf)₂) catalyst. Highly functionalized fluorescent, saccharide and amphiphilic CCS polymers were synthesized by grafting the alkyne CCS polymer with the corresponding azido substituted compounds via copper catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC), 'click' chemistry. The resulting corona-functionalized CCS polymers were characterized via GPC, ¹H NMR spectroscopic analysis and DLS. ¹H NMR spectroscopic analysis revealed that the grafting efficiency (i.e., click efficiency) ranged from 10 to >99% and was highly dependent on the structure and functionality of the azido compounds. This equates to the grafting of 45 to 450 functional compounds onto the CCS polymer scaffolds corona. The results indicate that the click functionalization efficiency is closely related to the molecular size of the azido compounds. Other than size, factors including molecular structure, compatibility and synergistic driving forces, such as the formation of potential inclusion complexes, are also found to affect the functionalization efficiencies.

Full text of DOI:10.1021/ma200283c

ARTICLE
pubs.acs.org/Macromolecules
Synthesis of a Star Polymer Library with a Diverse Range of Highly
Functionalized Macromolecular Architectures
Jing M. Ren, James T. Wiltshire, Anton Blencowe, and Greg G. Qiao*
Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
S Supporting Information
b
ABSTRACT: An efficient and versatile synthetic route toward
highly functionalized core cross-linked star (CCS) polymers
with interesting structures and properties is presented using an
alkyne CCS polymer as scaffold. The alkyne CCS polymer
scaffold was initially prepared via an improved arm-first
approach, through ring-opening polymerization (ROP) of 4,40-
bioxepanyl-7,70-dione (BOD) with a poly(caprolactone-b-pro-
pargyl methacrylate) macroinitiator and stannous triflate
(Sn(OTf)2) catalyst. Highly functionalized fluorescent, sacchar-
ide and amphiphilic CCS polymers were synthesized by grafting the alkyne CCS polymer with the corresponding azido substituted
compounds via copper catalyzed 1,3-dipolar azideꢀalkyne cycloaddition (CuAAC), ‘click’ chemistry. The resulting corona-
1
1
functionalized CCS polymers were characterized via GPC, H NMR spectroscopic analysis and DLS. H NMR spectroscopic
analysis revealed that the grafting efficiency (i.e., click efficiency) ranged from 10 to >99% and was highly dependent on the structure
and functionality of the azido compounds. This equates to the grafting of 45 to 450 functional compounds onto the CCS polymer
scaffolds corona. The results indicate that the click functionalization efficiency is closely related to the molecular size of the azido
compounds. Other than size, factors including molecular structure, compatibility and synergistic driving forces, such as the
formation of potential inclusion complexes, are also found to affect the functionalization efficiencies.
’ INTRODUCTION
carrier, which ultimately facilitates greater cell adhesion9 and
site-specific drug delivery.10
CCS polymers represent a unique type of three-dimensional
(3D) macromolecular architecture consisting of a cross-linked
core surrounded by a number of radiating arms, typically
10ꢀ100.1 CCS polymers can often possess very high molecular
weights, while still maintaining excellent solubility characteristics
and low viscosities comparable to linear or branched polymers
with lower molecular weights.2 The distinctive rheological prop-
erties and 3D globular structure of CCS polymers has attracted
significant interest and resulted in a number of potential applica-
tions, including polymer therapeutics and drug delivery,3 cascade
reaction catalysis,4 microporous films,5 and paint additives.6
Often, the design of CCS polymers carrying high desirable
functionality and spatial control over their location is required to
meet a diverse range of application needs. In particular, in
polymer therapeutics, the synthesis of CCS polymers with high
coronal functionality would be particularly beneficial for drug
loading and conjugation of targeting moieties. Functional groups
at the periphery of nanometer-sized drug carriers could facilitate
drug encapsulation through either covalent bonding7 or non-
covalent (e.g., electrostatics8) interactions with complementary
drugs such as peptides, proteins, nucleic acids and other thera-
peutic agents. Thus, an increased functional group density offers
larger drug-loading potential. Moreover, a high number of
reactive functional sites increases the chance of success in
attachment of targeting moieties and binding agents to the
CCS polymers with high functionality, good structural control
and narrow molecular weight distributions can be readily synthe-
sized via controlled polymerization techniques,11ꢀ15 and the
arm-first approach.16ꢀ18 Functional groups can be integrated
into the periphery of CCS polymers via two discrete approaches;
end-functional star polymers can be prepared from telechelic
macroinitiators/macromonomers or block copolymer macroini-
tiators in which one block consists of a number of pendent
functionalities. The drawback of the former is that the resulting
star polymers possess a relatively low number of functionalities at
the periphery, since the number of functional units is equal
(restricted) to the number of arms. To overcome this, dendritic
macroinitiators have been used to prepare CCS polymers,19
leading to stars with up to 1100 peripheral functional groups.
However, the preparation of dendritic macroinitiators generally
involves multiple protection/deprotection steps, which require
time and labor intensive synthetic protocols, especially consider-
ing that high dendron generation is required to achieve high
functionality. In contrast, stepwise polymerization of functional
monomers to yield block copolymer macroinitiators suitable for
CCS polymer formation20 is a more promising and synthetically
Received: February 8, 2011
Revised:
March 23, 2011
Published: April 05, 2011
r
2011 American Chemical Society
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convenient route to introduce a large number of coronal
functionalities. However, this synthetic route requires the pre-
paration of desirable functional monomers before polymeriza-
tion, which may be synthetically involved.21 Furthermore,
controlled polymerization of functional monomers can be re-
stricted as a result of steric constraints and coordination/reaction
of the monomer with the catalyst, initiator or propagating
chains.22 To avoid this, protected monomers are often employed
and deprotected postpolymerization to afford the desired func-
tional polymers.21,23,24 In addition, monomers with bulky pen-
dent groups can suffer from poor conversion as a result of
polymerizationꢀdepolymerization equilibrium.25 Therefore, a
facile and efficient route which provides access to a diverse range
of highly corona-functionalized CCS polymers from a single
scaffold would be immensely invaluable.
Recently, we reported the synthesis of a CCS polymer with
high loadings of corona-isolated terminal alkyne (click) func-
tionalities.26 As a result of the efficient nature and functional
group tolerance of CuAAC chemistry,27ꢀ29 azido-substituted
compounds with a range of functionalities can be grafted onto the
alkyne CCS polymer scaffold to yield a wide variety of corona-
functionalized star polymers from a single precursor. Herein we
report the preparation of a clickable CCS polymer scaffold via an
improved synthetic approach and study the grafting of various
azido substituted compounds via CuAAC chemistry to afford
highly corona-functionalized star polymers with unique and
interesting architectures and properties. The grafting efficiency
with different azido compounds and polymers was determined
and factors affecting the click efficiency were investigated. Thus,
this report provides a valuable reference for the high density
functionalization of 3D nanostructures.
20-methyl-20-bromopropionate 1 and 4,40-bioxepanyl-7,70-dione (BOD)
were synthesized according to literature procedures.30,31
Instrumentation. Gel permeation chromatography (GPC) (THF
as eluent) was performed on a Shimadzu liquid chromatography system
fitted with a Wyatt DAWN EOS multiangle laser light scattering
(MALLS) detector (690 nm, 30 mW) and a Wyatt OPTILAB DSP
interferometric refractometer (690 nm), using three Phenomenex
Phenogel columns (500, 104, and 106 Å porosity; 5 μm bead size)
operated at 1 mL/min with column temperature set at 30 °C. GPC
(DMF as eluent) was performed on a Shimadzu liquid chromatography
system fitted with a Wyatt DAWN-HELEOS LS detector (λ = 658 nm),
Shimadzu RID-10 refractometer (λ = 633 nm) and Shimadzu SPD-20A
UVꢀvis detector, using three identical Polymer Laboratories PLgel
columns (5 μm, MIXED-C) and HPLC grade DMF with 0.05 M LiBr
(70 °C, 1 mL/min) as mobile phase. Astra software (Wyatt Technology
Corp.) was used to process the data to determine the molecular weights
either using known dn/dc values or based on the assumption of 100%
mass recovery of the polymer where the dn/dc value was unknown. 1H
NMR spectroscopic analysis was performed on a Varian Unity Plus
400 MHz spectrometer using the deuterated solvent as reference. Gas
chromatography was performed on a Shimadzu GC 17-A gas chroma-
tograph equipped with an Agilent JþW DB-5 capillary column (30 m,
5% phenyl siloxane) and coupled to a GCMS-QP50000 mass spectro-
meter (injector temperature =250 °C; initial column initial temperature
=40 °C; heat ramp =10 °C/min; final column temperature =320 °C).
Dynamic light scattering (DLS) measurements were performed using a
Malvern high performance particle sizer (HPPS) with a 3.0 mW HeꢀNe
laser operated at 633 nm. Analysis was performed at an angle of 173° and
a constant temperature of 25 ( 0.1 °C. MALDI ToF MS was performed
on a Bruker Autoflex III Mass Spectrometer operating in positive linear
mode; the analyte, matrix (DIT or DCTB) and cationisation agent (NaI
or KI) were dissolved in THF at concentrations of 10, 10, and 1 mg/mL,
respectively, and then mixed in a ratio of 10:1:1. Then 0.3 μL of this
solution was spotted onto a ground steel target plate, and the solvent was
allowed to evaporate prior to analysis. FlexAnalysis (Bruker) was used to
analyze the data. UVꢀvis spectrophotometry was performed on a Shimad-
zu UV-2101PC spectrometer using quartz cuvettes with a 1 cm path length.
Synthesis of (Trimethylsilyl)propargyl Methacrylate
(TMS-PgMA). This compound was prepared according to the literature
procedures.31ꢀ33 1H NMR (400 MHz, CDCl3):δH 0.18 (s, 9H, Si(CH3)3),
1.96 (m, 3H, CH3), 4.75 (d, 2H, OCH2), 5.61 (m, 1H, CCHH cis), 6.17 (m,
1H, CCHH trans) ppm. 13C NMR (100 MHz, CDCl3): δC ꢀ0.3
(Si(CH3)3), 18.3 (CH3), 52.9 (OCH2), 94.7 (CH2CtC), 99.1
(CH2CtC), 126.4 (CCH2), 135.7 (CCH2), 166.5 (CdO) ppm. LRMS
[Mþ]: C10H16O2Si requires 196.09; found, 196.10.
Synthesis of HO-PCL-Br Macroinitiator 2. A round-bottom
flask charged with Sn(Oct)2 (0.79 g, 1.95 mmol, 1 equiv) was evacuated
and backfilled with argon. Subsequently, CL (20.0 g, 200 mmol,
100 equiv), 2-hydroxylethyl 20-methyl-20-bromopropionate 1 (0.823 g,
3.90 mmol, 2 equiv) and toluene (180 mL) were added via syringe. The
reaction solution was stirred at 100 °C under argon for 19 h, cooled to
room temperature and then precipitated into cold MeOH (800 mL).
The precipitate was collected by vacuum filtration and dried in vacuo to
yield macroinitiator 2 as a white powder, 19.0 g (91.2%). GPC-MALLS
(THF): Mn = 5.14 kDa, PDI = 1.20; 1H NMR (400 MHz, CDCl3): δH
1.34ꢀ1.46 (m, ꢀCH2CH2CH2ꢀ), 1.61ꢀ1.72 (m, ꢀCH2CH2CH2-),
1.95 (s, ꢀCH3 end group), 2.32 (t, ꢀCH2CH2COꢀ), 3.66 (t,
ꢀCH2CH2OH end group), 4.07 (t, ꢀCH2CH2Oꢀ) ppm. Different
molecular weight macroinitiators were prepared by variation of the
monomer to initiator ratio (Table S1, Supporting Information).
Synthesis of HO-P(CL-b-TMS-PgMA)ꢀBr Macroinitiator 3.
HO-PCL-Br macroinitiator 2 (3.00 g, 0.58 mmol, Mn,GPC = 5.14 kDa,
1 equiv), TMS-PgMA (4.00 g, 20.4 mmol, 35 equiv), and PMDETA
(0.20 g, 1.20 mmol, 2 equiv) were added to a Schlenk flask and dissolved
’ EXPERIMENTAL SECTION
Materials. Anisole (anhydrous, 99.7%), 1-(chloromethyl)naphthalene
(90%), copper(I) bromide (CuBr, 98%), copper(II) bromide (CuBr2,
98%), methyl 2-bromopropionate (98%) chlorotrimethylsilane (98%),
methacryloyl chloride (97%), 2-propyn-1-ol (99%), γ-oxo-1-pyrene
butyric acid (tech.), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 98%),
tetra-n-butyl ammonium fluoride (TBAF, 1 M solution in THF),
stannous 2-ethylhexanoate (Sn(Oct)2, 95%), stannous triflate
(Sn(OTf)2, 97%), β-cyclodextrin (98%), furfuryl isocyanate (97%),
1-bromodecane (98%), N,N,N0,N00,N00-pentamethyldiethylenetriamine
(PMDETA, 99%), poly(ethylene glycol) monomethyl ether (Mn ∼1000
Da), poly(ethylene glycol) monomethyl ether (Mn ∼2000 Da), tetra-n-
butylammonium hydrogen sulfate (TBAHS) (99þ%), acetobromo-R-
D-galactose (>93%), 4-(dimethylamino)pyridine (DMAP) (99%), sodium
iodide (NaI, 99.999%), and potassium iodide (KI, g 99.99%) were all
purchased from Aldrich and used as received. Acetic acid (99.8%,
Merck), N-(3-(dimethylamino)propyl)-N0-ethylcarbodiimide hydro-
chloride (EDCI) (98þ%, Fluka), N,N-dimethylformamide (99.8%,
Merck), n-hexane (AR, Chem-Supply), ethyl acetate (AR, Chem-
Supply), methanol (MeOH, AR, Chem-Supply), thionyl chloride
(Merck), sodium azide (NaN3, 99%, Chem-Supply), silver chloride
(AgCl, 99.5%, Fluka), poly(ethylene glycol) monomethyl ether
(Mn ∼350 Da) (Fluka), 9-anthracenecarboxylic acid (purum, Fluka),
1,8,9-anthrancenetriol (DIT, puriss, Fluka) and trans-2-[3-(4-tert.-butyl-
phenyl)-2-methyl-2-propenylidene]-malononitrile (DCTB, puriss, Fluka)
were also used as received. Tetrahydrofuran (RCI Labscan, HPLC)
(THF) was distilled from sodium benzophenone ketyl. Toluene (Scharlau,
HPLC), ε-caprolactone (CL, 99þ%, Aldrich), dichloromethane (99.8%,
Merck), triethylamine (99%, Ajax) and tert-butyl acrylate (98%, Aldrich)
were distilled from calcium hydride (95%, Sigma-Aldrich). 2-Hydroxylethyl-
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in anisole (19 mL). The mixture was subsequently degassed via one
freezeꢀpumpꢀthaw cycle, backfilled with argon and CuBr (85 mg,
0.58 mmol, 1 equiv) was added under argon. The mixture was then
degassed via another two freezeꢀpumpꢀthaw cycles, backfilled with
argon and heated at 85 °C for 5 h. The reaction was stopped (TMS-
PgMA conversion =50%) by dipping the reaction solution into liquid
nitrogen. After warming to room temperature, the reaction solution was
diluted with THF (100 mL) and passed through an alumina column to
remove the copper complex. The solution was then concentrated to
∼15 mL in volume and precipitated into cold methanol (200 mL). The
precipitate was collected by vacuum filtration and dried in vacuo to afford
macroinitiator 3 as a white solid, 3.2 g (64%). GPC-MALLS (THF):
(t, 2H, J = 6.6 Hz, CH2O) ppm. 13C NMR (100 MHz, CDCl3): δC 31.4
(CH2), 48.4 (CH2N3), 59.6 (OCH2) ppm. LRMS [M ꢀ Hþ]:
C3H7N3O requires 100.11; found, 100.30.
Synthesis of 1-(Azidomethyl)naphthalene C1. 1-(Chloro-
methyl)naphthalene (2.00 g, 11.3 mmol), NaN3 (1.47 g, 22.6 mmol),
and DMF (50 mL) were heated at 65 °C for 24 h. The reaction mixture
was centrifuged to remove excess NaN3 and then the solvent was
removed in vacuo. The residue was dissolved in dichloromethane
(50 mL) and then washed with distilled water (50 mL ꢁ 3). The
organic extract was dried (MgSO4), filtered and concentrated in vacuo to
1
afford C1 as a brown powder, 1.90 g (86%). H NMR (400 MHz,
CDCl3): δH 4.78 (s, 2H, CH2N3), 7.42ꢀ7.61 (m, 4H, 4ArH), 7.86ꢀ7.92
(m, 2H, 2ArH), 8.02ꢀ8.05 (m, 1H, 1ArH) ppm. 13C NMR (100 MHz,
CDCl3): δC 52.9 (CH2N3), 123.5 (ArCH), 125.2 (ArCH), 125.2
(ArCH), 126.7 (ArCH), 127.2 (ArCH), 128.8 (ArCH), 129.4
(ArCH), 131.0 (ArCC), 131.3 (ArCC), 133.9 (ArCC) ppm. LRMS
[Mþ]: C11H9N3 requires 183.08; found, 183.30.
1
Mn = 8.66 kDa, PDI = 1.19. H NMR (400 MHz, CDCl3): δH 0.17
(s,ꢀSi(CH3)3), 0.80ꢀ1.15 (m,ꢀCH3), 1.34ꢀ1.46 (m,ꢀCH2CH2CH2ꢀ),
1.61ꢀ1.72 (m, ꢀCH2CH2CH2ꢀ), 1.75ꢀ2.10 (m, ꢀCH2Cꢀ
and s, ꢀCH3 end group), 2.32 (t, ꢀCH2CH2COꢀ), 3.66 (t,
ꢀCH2CH2OH end group), 4.07 (t, ꢀCH2CH2Oꢀ), 4.32ꢀ4.42 (m,
ꢀCH2CH2Oꢀ end group), 4.57 (s, ꢀCOOCH2ꢀ) ppm. Different
molecular weight macroinitiators were prepared by variation of the
monomer to macroinitiator ratio (Table S1, Supporting Information).
Synthesis of Alkyne Functional Stars CCS 1 and CCS 2.
Macroinitiator 3 (2.00 g, 0.289 mmol; Mn,GPC = 8.66 kDa), BOD (0.65 g,
2.89 mmol), and stannous triflate (Sn(OTf)2) (24.6 mg, 0.61 mmol)
were added to a flask, and purged with argon. 2:8 THF/toluene (20 mL)
was added and the reaction mixture was heated at 65 °C under argon for
99 h (cross-linker conversion via GC = 99þ %). The reaction mixture
was filtered, concentrated and then fractionally precipitated (SI) with
MeOH to isolate star CCS 1, 1.44 g; Mn,GPC = 300 kDa, PDI = 1.25).
The fractionated star CCS 1 (1.44 g, 2.16 mmol of alkyne-TMS groups)
and acetic acid (0.15 mL, 2.70 mmol) were dissolved in THF (24 mL)
under argon at 0 °C and a 0.2 M TBAF solution in THF (10.8 mL) was
added dropwise. The reaction solution was stirred at 0 °C for another 30
min and then at room temperature for a further 12 h. The reaction
mixture was then concentrated to ∼5 mL in volume and precipitated
into MeOH (50 mL). The precipitate was dried in vacuo to afford
the terminal alkyne star CCS 2, 1.11 g (49%). GPC-MALLS (THF):
Mn = 267 kDa, PDI = 1.30. 1H NMR (400 MHz, CDCl3): δH 0.80ꢀ1.20
(m, 3H, ꢀCH3), 1.35ꢀ1.47 (m, ꢀCH2CH2COꢀ), 1.61ꢀ1.72 (m,
ꢀCH2CH2CH2ꢀ), 1.80ꢀ2.10 (m, ꢀCH2Cꢀ), 2.32 (t, ꢀCH2CH2COꢀ),
2.53 (s, CtCH), 4.08 (t, ꢀCH2CH2Oꢀ), 4.57 (s, ꢀCOOCH2ꢀ)
ppm (Figure S1, Supporting Information).
Synthesis of 3-Azidopropyl Anthrancene-9-carboxylate
C2. Anthrancene carboxylic acid (2.22 g, 10.0 mmol) and thionyl
chloride (SOCl2) (30 mL) were added to a dried flask under argon.
The reaction mixture was refluxed under argon for 90 min and the excess
SOCl2 was removed in vacuo. The resulting residue was azeotroped with
benzene (10 mL ꢁ 3), redissolved in anhydrous THF (40 mL) and
cooled to 0 °C. Triethylamine (2.4 mL, 32.7 mmol) was added, followed
by 3-azidopropanol (0.97 g, 9.0 mmol) in anhydrous THF (30 mL)
dropwise. The reaction solution was stirred at 0 °C for 30 min, warmed
to room temperature and stirred for 48 h, and then filtered and
concentrated. The crude product was redissolved in dichloromethane
(50 mL), washed with 2 M NaOH (50 mL ꢁ 2), 2 M HCl (50 mL ꢁ 2)
and distilled water (50 mL), dried (MgSO4), filtered, and concentrated
1
in vacuo to afford C2 as a light brown solid, 2.5 g (90%). H NMR
(400 MHz, CDCl3): δH 2.09 (quin, 2H, J = 6.4 Hz, CH2), 3.45 (t, 2H, J =
5.2 Hz, OCH2), 4.67 (t, 2H, J = 5.2 Hz, CH2N3), 7.44ꢀ7.54 (m, 4H,
4ArH), 7.99ꢀ8.01 (m, 4H, 4ArH), 8.48 (s, 1H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δC 8.3 (CH2), 48.2 (CH2N3), 62.5 (OCH2), 124.7
(2ArCH), 125.6 (2ArCH), 127.2 (2ArCH), 127.7 (ArCH), 128.5
(ArCC), 128.7 (2ArCH), 129.5 (2ArCH), 131.0 (ArCH), 169.6
(CdO) ppm.
Synthesis of 3-Azidopropyl 4-Oxo-4-(pyren-4-yl) Butano-
ate C3. γ-Oxo-1-pyrenebutyric acid (1.20 g, 3.97 mmol), EDCI (0.840 g,
4.37 mmol), and DMAP (97.0 mg, 0.79 mmol) were dissolved in
anhydrous dichloromethane (24 mL) under argon. 3-Azidopropanol
(0.39 mL, 3.90 mmol) was then added and the mixture was stirred at
30 °C for 40 h. The reaction mixture was then washed with 0.05 M HCl
(100 mL ꢁ 3), dried (MgSO4), filtered and the filtrate concentrated
in vacuo. The crude product was purified via column chromatography on
silica using 2:8 hexane:dichloromethane. The desired compound (Rf =
0.06) was collected, dried (MgSO4), filtered and concentrated in vacuo
(0.1 mbar, 50 °C) to give C3 as a dark brown solid, 0.90 g (64%). 1H
NMR (400 MHz, CDCl3): δH 1.92 (quin, 2H, J = 6.4 Hz, CH2), 2.90 (t,
2H, J = 6.4 Hz, CH2CO2), 3.39 (t, 2H, J = 6.4 Hz, CH2N3), 3.53 (t, 2H,
J = 6.4 Hz, COCH2), 4.23 (t, 2H, J = 6.4 Hz, CO2CH2), 8.00ꢀ8.05 (m,
2H, 2ArH), 8.13ꢀ8.23 (m, 5H, 5ArH), 8.38 (d, 1H, J = 8.0 Hz, ArH),
8.91 (d, 1H, J = 9.6 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3): δC
28.3 (CH2CO2), 28.9 (CH2), 37.0 (OCH2), 48.3 (CH2N3), 61.7
(CO2CH2), 124.1 (ArCH), 124.3 (ArCC), 124.8 (ArCC), 125.0
(ArCH), 126.1 (ArCC), 126.3 (ArCH), 126.3 (ArCH), 126.4 (ArCH),
127.1 (ArCH), 129.5 (ArCH), 129.6 (ArCC), 129.7 (ArCH), 130.5
(ArCH), 131.1 (ArCC), 131.7 (ArCC), 133.9 (ArCC) ppm.
Synthesis of Deprotected Arm Initiator HO-P(CL-b-
PgMA)-Br (LP 1). HO-P(CL-b-TMS-PgMA)-Br macroinitiator
(Table S1, Supporting Information, entry 6) (0.50 g, 1.19 mmol of
alkyneꢀTMS groups, Mn = 11.3 kDa), and acetic acid (0.10 mL, 1.79
mmol) were dissolved in THF (12.8 mL) under argon at 0 °C and a 0.2
M TBAF solution in THF (5.8 mL) was added dropwise. The reaction
solution was stirred at 0 °C for another 30 min and then at room
temperature for a further 12 h. The reaction mixture was then concen-
trated to ∼5 mL in volume and precipitated into MeOH (20 mL). The
precipitate was dried in vacuo to afford LP 1, 0.38 g (92%). GPC-MALLS
(THF): Mn = 9.2 kDa, PDI = 1.20. 1H NMR (400 MHz, CDCl3): δH
0.80ꢀ1.20 (m, 3H, ꢀCH3), 1.35ꢀ1.47 (m, ꢀCH2CH2COꢀ),
1.61ꢀ1.72 (m, ꢀCH2CH2CH2ꢀ), 1.80ꢀ2.10 (m, ꢀCH2Cꢀ), 2.32
(t, ꢀCH2CH2COꢀ), 2.53 (s, CtCH), 3.64 (t, ꢀCH2CH2OH end
group), 4.08 (t, ꢀCH2CH2Oꢀ), 4.57 (s, ꢀCOOCH2ꢀ) ppm.
Synthesis of 3-Azidopropanol. NaN3 (2.80 g, 43.1 mmol) and
TBAHS (85.0 mg, 0.25 mmol) were dissolved in Milli-Q water (50 mL).
3-Chloropropanol (2.04 g, 21.6 mmol) was then added and the mixture
was stirred at 80 °C for 24 h. The mixture was extracted with diethyl
ether (75 mL ꢁ 3) and the organic extracts were combined, dried
(MgSO4), filtered and concentrated in vacuo to yield a clear liquid, 1.80 g
Synthesis of 3-Azidopropyl Furan-2-ylmethylcarbamate
C4. Furfuryl isocyanate (370 mg, 3.00 mmol) was dissolved in anhy-
drous THF (5 mL) in a dried Schlenk tube under argon, and 3-azido-
propanol (300 mg, 2.97 mmol) and triethylamine (21 μL, 0.14 mmol)
were added. After 24 h at 50 °C, the reaction mixture was concentrated
1
(82%). H NMR (400 MHz, CDCl3): δH 1.82 (quin, 2H, J = 6.6 Hz,
CH2), 1.91 (br s, 1H, CH2OH), 3.44 (t, 2H, J = 6.6 Hz, CH2N3), 3.74
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in vacuo, and purified via column chromatography on silica (Rf = 0.73,
1:99 methanol:dichloromethane) to afford C4 as a pale yellow oil, 420
mg (62%). 1H NMR (400 MHz, CDCl3): δH 1.88 (quin, 2H, J = 8.0 Hz,
CH2), 2.29 (t, 2H, J = 8.0 Hz, CH2N3), 4.16 (t, 2H, J = 8.0 Hz, OCH2),
4.34 (d, 2H, CH2N), 5.05 (br s, NH), 6.21 (d, 1H, ArH), 6.30 (m, 1H,
ArH), 7.34 (m, 1H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δC 28.5
(CH2), 38.9 (CH2N), 48.2 (CH2N3), 62.0 (OCH2), 107.2 (ArCH),
110.4 (ArCH), 142.2 (ArCH), 151.5 (ArCC), 156.0 (CdO) ppm.
LRMS [Mþ]: C9H12N4O3 requires 224.09; found, 224.00.
dropwise. The reaction was kept at 0 °C for 30 min and then at room
temperature for 12 h. The reaction was filtered and the filtrate was
concentrated in vacuo. The residue was dissolved in DMF (50 mL), and
NaN3 (200 mmol, 10 equiv) was added. The reaction mixture was
heated to 65 °C for 12 h, cooled to room temperature and concentrated
in vacuo. The residue was dissolved in water (200 mL) and then washed
with dichloromethane (100 mL ꢁ 2). The organic extracts were collected,
washed with water (200 mL) and saturated NaCl (200 mL ꢁ 2),
dried (MgSO4), filtered, and concentrated in vacuo to afford the
desired monoazido PEGs. 1H NMR (400 MHz, CDCl3): δH 3.37ꢀ3.41
(s, 3H, OCH3 end group, and t, 2H, CH2N3 end group), 3.45ꢀ3.85
(m, ꢀCH2Oꢀ) ppm. MALDI ToF MS: P1, Mn = 440, PDI = 1.01; P2,
Mn = 1070, PDI = 1.02; P3, Mn = 1800, PDI = 1.02 (Figure S2ꢀS4,
Supporting Information).
Synthesis of Terminal Azido-Functionalized PtBA P4. The
procedure to synthesize PtBA-N3 was adopted from the literature39 with
slight modification. Deoxygenated acetone (4.2 mL) and tBA (15 g, 117
mmol) were added to a Schlenk tube. The solution was degassed by
three freezeꢀpumpꢀthaw cycles and then CuBr (170 mg, 1.17 mmol),
CuBr2 (14 mg, 0.63 mmol) and PMDETA (250 μL, 1.18 mmol) were
added. The reaction solution was stirred at room temperature for 30 min
and then methyl 2-bromopropionate (270 μL, 2.34 mmol) was added
under argon. The reaction mixture was heated at 65 °C for 13 h
(monomer conversion via GC = 50%), cooled to room temperature
and precipitated into cold methanol (ꢀ15 °C, 600 mL). The precipitate
was collected and redissolved in DMF (50 mL). NaN3 (1.52 g, 23.4
mmol) was added and the reaction mixture was then stirred at room
temperature for 24 h. The solvent was removed in vacuo and the residue
was redissolved in dichloromethane (50 mL) and washed with saturated
NaCl (50 mL ꢁ 2) and distilled water (50 mL ꢁ 2). The organic extract
was collected, dried (MgSO4), filtered and concentrated in vacuo to
afford PtBA-N3 P4, 6.00 g (38.5%); GPC-MALLS: Mn = 5.85 kDa,
PDI = 1.12. 1H NMR (400 MHz, CDCl3): δH 1.14 (s, 3H, ꢀC(CH3)ꢀ),
1.20ꢀ2.00 (m, ꢀC(CH3)3, andꢀCH2CHꢀ), 2.00ꢀ2.50 (m,ꢀCH2CHꢀ),
2.90ꢀ3.00 (d, ꢀCH2N3 end group), 3.66 (s, ꢀOCH3 end group) ppm.
MALDI ToF MS: Mn = 3.60 kDa, PDI = 1.08. (Figure S5, Supporting
Information).
Synthesis of Highly Functionalized CCS Polymers via
CuAAC Chemistry. The general procedure for synthesizing corona-
functionalized stars CCS C1-5, CCS C7, and CCS P4 was as follows:
initially a 0.085 mM catalyst stock solution was prepared by dissolving
CuBr (0.085 mmol, 1 equiv), and PMDETA (0.085 mmol, 1 equiv) in
degassed DMF. In a Schlenk tube, alkyne star CCS 2 (0.187 μmol,
0.084mmolalkynegroups, 1 equiv)andthe azido compound (0.42mmol,
5 equiv or 0.17 mmol, 2 equiv P4 only) were dissolved in DMF (5 mL).
The mixture was degassed via two freezeꢀpumpꢀthaw cycles and
backfilled with argon, and catalyst stock solution (0.1 mL) was added.
The reaction solution was subjected to one freezeꢀpumpꢀthaw cycle,
backfilled with argon and stirred at room temperature for 48 h. The
Cu(I) catalyst was removed via addition of 1-dodecanethiol (0.088 mmol,
1 equiv) to form an insoluble copper complex (the solution immediately
became cloudy and the characteristic color of the CuBr/PMDETA
complex completely disappeared). After a further 24 h at room
temperature the reaction mixture was centrifuged to remove the
insoluble copper salts, and the supernatant was concentrated in vacuo
to ∼1ꢀ2 mL in volume and then precipitated in methanol (25 mL)
twice. The precipitate was collected via centrifugation and dried in vacuo
to give the click-functionalized stars.
Synthesis of β-Galactopyranosyl Azide C5. β-Galactopyra-
nosyl azide was preparedaccording to literature34 with slight modification.
To acetobromo-R-D-galactose (5.0 g, 12.2 mmol) in dichloromethane
(50 mL) was added NaN3 (4.40 g, 67.7 mmol), TBAHS (4.10 g,
12.2 mmol), and saturated NaHCO3 (50 mL) in sequence. The reaction
mixture was stirred vigorously at room temperature for 3 h and then
diluted with ethyl acetate (500 mL). The organic layer was washed with
saturated NaHCO3 (200 mL) and concentrated in vacuo. The residue
was dissolved in MeOH (35 mL) and a solution of 10 M KOH (9.0 mL)
was added and stirred at room temperature for 3 h. The mixture was
concentrated in vacuo and purified via column chromatography on silica
using 3:7 MeOH/dichloromethane to afford C5 as a white powder, 2.00
1
g (80%). H NMR (400 MHz, DMSO-d6): δH 3.26ꢀ3.36 (m, 3H,
2CHOH, H-2,4, CH2CH, H-5), 3.42ꢀ3.52 (m, 2H, CH2OH, H-6), 3.63
(d, 1H, CHOH, H-3), 4.31 (d, 1H, CHN3, H-1), 4.50ꢀ5.50 (m, 4H,
4OH, OH-2,3,4,6) ppm. 13C NMR (400 MHz, DMSO-d6): δC 60.8
(CH2, C-6), 68.5 (CH, C-2), 70.7 (CH, C-4), 73.7 (CH, C-3), 78.0 (CH,
C-1), 91.1 (CH, C-5) ppm.
Synthesis of Mono-6-deoxy-6-azido-β-cyclodextrin C6.
β-CD derivative C6 was prepared according to a literature procedure.35ꢀ38
β-Cyclodextrin (6.0 g, 5.29 mmol) was suspended in water (50 mL) and
8.25 M NaOH (2 mL) was added dropwise over 10 min. p-Toluene-
sulfonyl chloride (1.1 g, 5.67 mmol) in acetonitrile (30 mL) was added
dropwise, causing immediate formation of a white precipitate. After 2 h
at room temperature the precipitate was filtered off, redissolved in
anhydrous DMF (20 mL) and NaN3 (0.80 g, 12.3 mmol) was added.
After 24 h at 65 °C the reaction solution was concentrated in vacuo, and
the unwanted salts were removed via dialysis (Thermoscientific,
MWCO 1000) against water for 48 h. The resultant aqueous suspension
was collected and freeze-dried to afford a white solid, 0.6 g (10%). 1H
NMR (400 MHz, DMSO-d6): δH 3.26ꢀ3.80 (br s, 42H, 28CHO and
7CH2O), 4.44ꢀ4.55 (m, 6H, 6OH), 4.80ꢀ4.90 (m, 7H, 7CHO2),
5.60ꢀ5.80 (m, 14H, 14OH) ppm. 13C NMR (100 MHz, DMSO-d6):
δC 51.0 (CH2N3), 59.7ꢀ60.0 (m, CH2O), 70.0ꢀ72.9 (m, CHO),
81.4ꢀ82.8 (m, CHO), 101.4ꢀ102.1 (m, CHO2) ppm. MALDI ToF
MS [M þ Naþ]: C42H69N3NaO34 requires 1182.37; found, 1182.20.
Synthesis of 1-Azidodecane C7. 1-Bromodecane (5.03 g,
22.6 mmol) and NaN3 (3.00 g, 46.1 mmol) were dissolved in DMF
(50 mL) and heated at 65 °C for 24 h. After cooling to room temperature
the reaction mixture was centrifuged to remove excess NaN3 and washed
with hexane (50 mL ꢁ 3). The hexane extracts were collected, dried
(MgSO4), filtered, and concentrated in vacuo to afford C7 as a pale
yellow oil, 4.0 g (97%). 1H NMR (400 MHz, CDCl3): δH 0.87 (t, 3H,
J = 6.8 Hz, CH3), 1.25 (m, CH2), 1.58 (quin, 2H, J = 6.8 Hz,
CH2CH2N3), 3.23 (t, 2H, J = 6.8 Hz, CH2N3) ppm. 13C NMR (100
MHz, CDCl3): δC 14.2 (CH3), 22.8 (CH2), 22.9 (CH2), 26.9 (CH2),
29.0 (CH2), 29.3 (CH2), 29.5 (CH2), 29.7 (CH2), 29.7 (CH2), 51.6
(CH2N3) ppm. LRMS [Mþ]: C10H21N3 requires 183.17; found, 182.50.
Synthesis of Terminal Azido-Functionalized PEGs P1ꢀ3.
The general procedure employed for the preparation of terminal azido
functionalized PEG was as follows: PEG monomethyl ether (20 mmol,
1 equiv) was initially dried via azeotropic distillation with toluene
(100 mL ꢁ 3). Subsequently, triethylamine (24 mmol, 1.2 equiv) and
dichloromethane (80 mL) were added and the mixture was cooled to
0 °C before methanesulfonyl chloride (30 mmol, 1.5 equiv) was added
The general procedure for synthesizing corona-functionalized stars
CCS P1ꢀ3 and CCS C6 was as follows: initially a 0.085 mM catalyst
stock solution was prepared by dissolving CuBr (0.085 mmol, 1 equiv),
and PMDETA (0.085 mmol, 1 equiv) in degassed DMF. In a Schlenk
tube, alkyne star CCS 2 (0.187 μmol, 0.084 mmol of alkyne groups,
1 equiv) and the azido compound (0.17 mmol, 2 equiv) were dissolved
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in DMF (5 mL). The mixture was degassed via two freezeꢀpumpꢀthaw
cycles and backfilled with argon, and catalyst stock solution (0.1 mL)
was added under argon. The reaction solution was subjected to one
freezeꢀpumpꢀthaw cycle, backfilled with argon, and stirred at room
temperature for 48 h. The Cu(I) catalyst was removed via addition of
1-dodecanethiol (0.088 mmol, 1 equiv) to form an insoluble copper
complex. After a further 24 h at room temperature, the reaction mixture
was centrifuged to remove the insoluble copper salts. The supernatant
was dialyzed (Thermoscientific, MWCO = 3500) against water for
4 days and freeze-dried to afford the click-functionalized stars.
Scheme 1. Synthetic Routes for the Preparation of Highly
Corona-Functionalized CCS Polymers via Sequential ROP,
ATRP, and CuAAC Chemistrya
Synthesis of Highly Functionalized Linear Polymers via
CuAAC Chemistry. The general procedure for synthesizing linear
polymers (LP C2, LP C6, and LP P2) with high pendent functionality
was as follows: initially a 150 mM catalyst stock solution was prepared by
dissolving CuBr (150 mmol, 1 equiv) and PMDETA (150 mmol,
1 equiv) in degassed DMF. In a Schlenk tube, deprotected macroini-
tiator LP 1 (5.43 μmol, 0.147 mmol alkyne groups, 1 equiv) and the
azido compound (0.29 mmol, 2 equiv or 0.74 mmol, 5 equiv C2 only) were
dissolved in DMF (4 mL). The mixture was degassed via two freezeꢀ
pumpꢀthaw cycles, backfilled with argon and catalyst stock solution
(0.1 mL) was added. The reaction solution was subjected to one
freezeꢀpumpꢀthaw cycle, backfilled with argon and stirred at room
temperature for 48 h. The Cu(I) catalyst was removed via addition of
1-dodecanethiol (0.150 mmol, 1 equiv) to form an insoluble copper
complex (the solution immediately became cloudy and the characteristic
color of the CuBr/PMDETA complex completely disappeared). After a
further 24 h at room temperature the reaction mixture was centrifuged to
remove the insoluble copper salts. For the synthesis of LP C6 and LP P2,
the supernatant was dialyzed (Thermoscientific, MWCO = 3500)
against water for 4 days and freeze-dried to afford the grafted linear
polymer. For LP C2, the supernatant was concentrated in vacuo to
∼1ꢀ2 mL in volume and then precipitated in methanol (25 mL) twice.
The precipitate was collected via centrifugation and dried in vacuo to give
the grafted linear polymer. GPC-MALLS (THF): LP C2 Mn = 43.4 kDa,
PDI = 1.52. GPC-MALLS (DMF): LP C6 Mn = 26.7 kDa, PDI = 1.15;
LP P2 Mn = 39.7 kDa, PDI = 1.27.
’ RESULTS AND DISCUSSION
Improved Synthesis of “Clickable” CCS Polymer Scaffold.
In our previous publication two issues were encountered during
the preparation of alkyne CCS polymers, including poor macro-
initiator-to-star conversion and starꢀstar coupling.26 Therefore,
a new synthetic strategy was developed to overcome these
problems. Initially, the alkyne CCS polymer scaffold was pre-
pared via the arm-first approach to act as a versatile platform for
the preparation of a diverse library of highly functionalized stars
with tunable structures and properties (Scheme 1). In the arm
formation step, macroinitiator 3 was first synthesized via ROP of
ε-caprolactone (CL) and subsequent atom transfer radical
polymerization (ATRP) of trimethylsilyl propargyl methacrylate
(TMS-PgMA) using the asymmetric difunctional initiator 2-hy-
droxyethyl 20-methyl-20-bromopropionate 1 (Scheme 1, routes
(i) and (ii), respectively). In the star formation step (Scheme 1,
route (iii), ROP of 4,40-bioxepanyl-7,70-dione (BOD) cross-
linker using macroinitiator 3 and Sn(OTf)2 as catalyst yielded
star CCS 1 with TMS protected alkyne functionalities. The TMS
protecting groups on the corona of CCS 1 were removed using
TBAF (Scheme 1, route (iv) to afford CCS 2 with clickable
terminal alkyne groups suitable for the subsequent CuAAC
functionalization.
a Key: (i) formation of poly(ε-caprolactone) macroinitiator (HO-PCL-
Br) 2 through ROP of CL using initiator 1; (ii) synthesis of poly(ε-
caprolactone-b-trimethylsilyl propargyl methacrylate) macroinitiator
(HO-P(CL-b-TMS-PgMA)-Br) 3 through ATRP of TMS-PgMA using
macroinitiator 2; (iii) preparation of alkyne functionalized star CCS 1
via the arm-first approach and ROP of BOD cross-linker with macro-
initiator 3; (iv) deprotection of TMS-protected CCS 1 using TBAF in
acetic acid to afford terminal alkyne functionalized star CCS 2; (v)
corona functionalization of CCS 2 via CuAAC chemistry using CuBr/
PMDETA as the catalyst.
macroinitiators 2 and 3 with various degrees of polymerization;
the theoretical and determined molecular weight characteristics
and monomer unit ratios indicated good control of the polym-
erization was observed in all cases (Table S1, Supporting
Information). A TMS protected PgMA monomer was employed
to minimize potential side reactions, including propagating
radical addition to terminal alkyne moieties (leading to branched
In the arm formation step, ROP and ATRP were repeated
several times with various monomer to initiator ratios as to afford
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leads to cyclization of the arm macroinitiators resulting in loss
of their active hydroxyl terminus, thus preventing them from
participating in ROP and integration into the CCS polymers.
Intermolecular transesterification at high BOD conversions
would result in active hydroxyl initiating sites in the core
of preformed CCS polymers attacking ester moieties of adjacent
CCS polymers, which is believed to be the major cause of
starꢀstar coupling. Lowering the reaction temperature would
suppress both types of transesterification and allow high macro-
initiator-to-star conversions with minimal starꢀstar coupling.
Sn(OTf)2 has been reported42,43 to be capable of catalyzing ROP
of lactones at low temperatures and fast reaction rates. The
results obtained in this study suggest Sn(OTf)2 is a superior
catalyst for the synthesis of alkyne functionalized CCS polymers.
The crude CCS polymer was purified via fractional precipitation
to afford the fractionated star CCS 1 with a Mn of 300 kDa and
low PDI of 1.25 (Figure 1, curve (iv)). From the molecular
weight and conversion data the average number of arms (f)
incorporated into each CCS polymer was calculated to be 25 with
each arm containing ∼18 pendent TMS protected alkyne
groups; thus, each star possess ∼450 alkyne groups (SI). Even
after multiple fractional precipitations, clean separation of CCS 1
could not be achieved as evidenced from a shoulder at high
retention time(Figure1(iv)), whichcorrespondstounincorporated
polymer. Following the isolation of CCS 1, the alkyne groups on the
corona were deprotected to afford alkyne star CCS 2 (Scheme 1,
route (iv)) with a Mn of 267 kDa, which correlates well with the
theoretical value of 265 kDa (Figure 1, curve (v)), based upon the Mn
of CCS 1 and number of alkyne groups per star. GPC and 1H NMR
spectroscopic analysis (Figure S1, Supporting Information) indicate
that no degradation of the PCL components occurs under the acidic
deprotection conditions. Deconvolution of the GPC RI chromato-
gram of CCS 2 (Figure 1, curve (v) provided an estimate of 70%
deprotected CCS polymer and 30% unincorporated polymer. The
30% unincorporated polymer is likely to originate from “arm”
macroinitiator 3 that has been chain extended1 with BOD but not
incorporated into CCS polymers (i.e., P(BOD-b-CL-b-TMS-
PgMA)). There are two possible causes for the presence of uncon-
verted P(BOD-b-CL-b-TMS-PgMA): (i) during the ROP-mediated
CCS formation some of the BOD chain extended macroinitiators
P(BOD-b-CL-b-TMS-PgMA) are terminally inactive,44,45 due to
insufficient Sn(II) catalyst being available to complex with the
hydroxyl group of the macroinitiator and initiate cross-linking, as
the Sn(II) catalysts are mostly trapped in the core of the preformed
CCS polymers, and (ii) the inactive macroinitiators with pendent
cross-linkable functionality cannot diffuse effortlessly into the pre-
formed CCS polymers and are therefore not incorporated due to
steric restrictions;1,44 thus, prolonged polymerization times would be
required to convert all the unreacted macroinitiators. The unincor-
porated P(BOD-b-CL-b-TMS-PgMA) present in the crude CCS
cannot be completely isolated via fractional precipitation (Figure 1
(iv)) and this most likely results in the 30% unincorporated polymer
in the final alkyne CCS polymer product (Figure 1, curve (v)).
Synthesis of Azido-Substituted Compounds. Following the
improved synthesis of the alkyne CCS polymer scaffold CCS 2, a
range of azido substituted derivatives (Figure 2) were prepared to
demonstrate the versatility of the click approach toward the
preparation of a library of highly corona-functionalized stars and
to assess factors affecting the ‘click’ efficiency.
Figure 1. GPC (THF) refractive index (RI) chromatograms of (i) HO-
PCL-Br macroinitiator 2 ([1]:[Sn(Oct)2]:[CL] = 2:1:80, 110 °C in
toluene) (Table S1, Supporting Information, entry 2); (ii) HO-P(CL-b-
TMS-PgMA)-Br macroinitiator 3 ([2]:[CuBr]:[PMDETA]:[TMS-
PgMA] = 1:1:2:35, 80 °C in anisole) (Table S1, Supporting Information,
entry 4); (iii) crude CCS 1 ([3]:[Sn(OTf)2]:[BOD] = 10:1:100, 65 °C
in 1:4 THF:Toluene); (iv) fractionated CCS 1; (v) deprotected CCS 2
polymer consisting of 70% CCS polymer and 30% unincorporated
polymer as determined by deconvolution of the RI chromatograms
using Gaussian functions.
or cross-linked products at high monomer conversions23,32) and
strong coordination of terminal alkynes to Cu(I) complexes
(such as those commonly used as ATRP catalysts).40,41 Polymers
prepared from each synthetic step were characterized via GPC
1
(Figure 1) and H NMR spectroscopic analysis (Figure S1,
Supporting Information). The GPC results show a decrease in
elution times corresponding to molecular weight increases across
each synthetic stage. Low polydispersities (PDI < 1.30) were
observed for all polymers prepared indicating narrow molecular
weight distributions and controlled polymeric architectures were
generated in all cases.
In the star-formation step, stannous triflate (Sn(OTf)2) was
used as the catalyst for ROP of the BOD cross-linker, allowing
the alkyne star CCS 1 to be prepared under milder reaction
conditions at a temperature of 65 °C. In comparison to the
previously reported synthesis using stannous 2-ethylhexanoate
(Sn(Oct)2) as the catalyst at 100 °C,26 Sn(OTf)2 provides
significantly improved macroinitiator-to-star conversions from
40% to 60%, and reduced the amount of the starꢀstar coupling
from approximately 15% to <1% (Figure 1, curve (iii)). Overall,
the new Sn(OTf)2 catalytic system utilized increased the yield of
the CCS polymers from 31% to 50% due to the elimination of
high molecular weight starꢀstar coupled products.26 These
results indicate that Sn(OTf)2 and the lower reaction tempera-
ture suppresses transesterification during ROP,42,43 minimizing
intramolecular backbiting of terminal hydroxyl groups and
intermolecular transesterification. Intramolecular backbiting
The azido-substituted compounds prepared in this study can be
divided into four main classes: (i) polycyclic aromatic hydrocar-
bons, including 1-(azidomethyl)-naphthalene C1, 3-azidopropyl
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Figure 2. Structures of azido-substituted compounds C1ꢀ7 and terminal azido functionalized polymers P1ꢀ4 employed for click functionalization of
alkyne star CCS 2.
anthrancene-9-carboxylate C2 and 3-azidopropyl 4-oxo-4-(pyren-
4-yl) butanoate C3; (ii) saccharides, including β-galactopyranosyl
azide C5 and mono-6-deoxy-6-azido-β-cyclodextrin C6; (iii) small
hydrophobic molecules with linear structures, including 3-azido-
propyl furan-2-ylmethylcarbamate C4 and 1-azidodecane C7, and;
(iv) macromolecules, including PEG with various molecular
weights (P1ꢀ3) and poly(t-butyl acrylate) (PtBA) P4. The
successful synthesis of C1ꢀ7 was confirmed by NMR spectro-
scopic analysis, GC-MS and MALDI ToF MS (C6 only). Azido
terminated PEG with various molecular weights (Mn = 440, 1070,
and 1800 kDa) were prepared by mesylation of poly(ethylene
glycol) monomethyl ether followed by azide substitution and
characterized via GPC, 1H NMR spectroscopic analysis and
MALDI ToF MS. Quantification of the degree of azide substitution
was achieved using 1H NMR spectroscopic analysis and MALDI
ToF MS (Figures S2ꢀS4, Supporting Information), which re-
vealed a high degree of azide functionalization (>85%) for all PEG
samples. Terminal azido PtBA P4 was prepared first via ATRP of
tert-butyl acrylate using methyl 2-bromopropionate as the initiator
followed by substitution of the ω-bromo group with azide. The
polymer P4 was analyzed via GPC, 1H NMR spectroscopic analysis
and MALDI ToF MS, with the latter revealing quantitative azide
substitution (Figure S5, Supporting Information) in agreement
with the literature.46
Functionalization of Alkyne CCS Polymer Scaffold via
CuAAC. Functionalization of the alkyne CCS polymer scaffold
CCS 2 was achieved by grafting the azido substituted compounds
C1ꢀ7 and P1ꢀ4 via CuAAC chemistry using Cu(I)/PMDETA
as the catalyst (Scheme 1, route (v)) to afford CCS C1ꢀ7 and
CCS P1ꢀ4, respectively (Table 1). The reactions were per-
formed by adding an excess of the azido substituted compounds
to a 0.037 mM (16.8 mM pendent alkyne groups) solution of
CCS 2. This solution was subjected to several freezeꢀpumpꢀ
thaw cycles prior to the addition of a degassed Cu(I)/PMDETA
catalyst stock solution (20 mol % relative to alkyne) to prevent
oxidation of the catalyst and possible side reactions. All reactions
were conducted under argon at room temperature for 48 h. Low
reaction temperatures and catalyst loadings were employed to
suppress potential side reactions, and long reaction times were
used to compensate for the retarded rate of CuAAC chemistry
resulting from steric congestion of the pendent alkyne groups. At
the end of the reactions, the Cu/PMDETA catalyst was isolated
via the addition of excess dodecanthiol,47 which forms an
insoluble copper complex that can be removed by filtration.
Incomplete removal of copper complex was found to lead to
gel formation as the result of starꢀstar coupling upon iso-
lation of the functionalized stars (Scheme 2). All click-functio-
nalized CCS polymers (except CCS P4) were isolated from the
crude reaction solution via precipitation or dialysis and char-
1
acterized by GPC, H NMR spectroscopic analysis and DLS
(Table 1).
As a result of the unique architecture of the click-functiona-
lized stars (Scheme 1), GPC systems (using THF or DMF as the
mobile phase) equipped with MALLS detectors were employed
to calculate the molecular weight characteristics of the CCS
polymers based upon the assumption of 100% mass recovery,48
since this allows the absolute molecular weights to be determined
1
independent of the polymers’ architectures. H NMR spectro-
scopic analysis was predominately used to quantify the grafting
efficiency of azido substituted compounds, since GPC might give
erroneous results due to possible intermolecular coupling of star
polymers. Furthermore, dynamic light scattering (DLS) was
employed to investigate the variation in hydrodynamic volume
of the CCS polymers upon click-functionalization. The Mn of the
functionalized CCS polymers calculated via GPC (Table 1)
revealed an increase from 267 (CCS 2) to 320ꢀ885 kDa
depending on the clicked compound. DLS results revealed
an increase of the hydrodynamic volumes of the functionalized
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Table 1. Characterization of Corona-Functionalized CCS Polymers
polymer
massa (g mol-1)
CEb (%)
errorc ( (%)
functional units no.d
Mntheo (kDa)
MnNMR (kDa)e
MnGPC (kDa)f
PDI
Dhg (nm)
CCS 1h
CCS 2
-
-
-
-
-
-
-
-
265
358
413
448
377
368
798
358
450
726
1176
-
-
-
300
267/(257i)
1.25
1.30
1.35
1.60
1.14
1.08
1.31
1.29
1.25
1.75
1.54
1.56
-
29.6
18.0(25.5j)
18.6
-
CCS C1
CCS C2
CCS C3
CCS C4
CCS C5
CCS C6
CCS C7
CCS P1
CCS P2
CCS P3
CCS P4
183.2
305.3
383.1
224.1
205.1
1160.0
183.3
440k
99þ
86
76
99
18
43
99þ
93
64
43
10
10
9
450
388
344
445
82
358
395
408
376
293
499
358
437
562
662
-
330
427
30.8
8
449
28.0
10
2
424
32.1
320i
520i
345
455i
618i
885i
-
33.8j
31.6j
22.6
4
192
450
418
286
193
45
11
10
7
30.1
1070k
1800k
6840l
70.2
4
145.8
-
-
a Molecular weight for corresponding azido substituted compound. b Click efficiency determined by 1H NMR spectroscopic analysis. c Error of click
efficiency calculation based upon 1H NMR spectroscopic analysis resonance integrations. d Number of azido substituted compounds attached per star.
e Number average molecular weight of functionalized stars determined by H NMR spectroscopic analysis. Number average molecular weight of
1
f
functionalized stars determined by GPC (THF) and based upon the assumption of 100% mass recovery. g Hydrodynamic diameter of functionalized
stars determined by DLS at 25 ( 0.1 °C. h Protected alkyne star polymer prepared using macroinitiator 3 (Table S1, Entry 4). Molecular weight
i
measurement determined by GPC (DMF) and based upon the assumption of 100% mass recovery.48 j DLS measurement using DMF as solvent at 25 (
0.1 °C. k Number average molecular weight calculated using MALDI ToF MS. l Number average molecular weight measured by GPC (THF) based upon
the assumption of 100% mass recovery.
Scheme 2. Side Reactions That Could Potentially Cause StarꢀStar Coupling During CuAAC Reactions, Including (a)
Sonogashira-Type Coupling, (b) Radical dimerization, and (c) Glaser Coupling
stars after click modification, with hydrodynamic diameters
suffer from increased polydispersities (>1.30) and Mn values
calculated via GPC are generally higher than those determined by
1H NMR spectroscopic analysis, which indicates possible starꢀ
star coupling as a result of side reactions. Three possible side
reactions that might lead to starꢀstar coupling are illustrated in
Scheme 2.
1
(Dh) increasing from 18 to 18.6ꢀ145.8 nm. From H NMR
spectroscopic analysis the number of functional compounds
attached to each CCS polymer ranged from 45 to 450 and was
highly dependent on their structure and functionality. Interest-
ingly, it was noted that some of the functionalized CCS polymers
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(i) Sonogashira-type coupling of terminal R-carbon on CCS
polymer arms with pendent alkyne groups along the arms of the
other CCS polymer (after elimination of the terminal bromide
groups) can be catalyzed by Cu(I) and tertiary bases (e.g.,
PMDETA) leading to the formation of starꢀstar coupled
products (Scheme 2a). (ii) In absence of oxygen (or other
radical scavengers) Cu(I)/PMDETA abstracts bromine atoms
from the CCS polymers to form terminal radical sites that can
undergo intermolecular dimerization, resulting in starꢀstar
coupling (Scheme 2b). (iii) In the presence of oxygen or a base
(e.g., PMDETA), Cu(I) can catalyze the Glaser coupling of
terminal alkynes (Scheme 2c).49 Thus, intermolecular coupling
of pendent terminal alkynes on CCS polymers could lead to
starꢀstar coupling. Intermolecular couplings can not be detected
using characterization techniques such as 1H NMR spectroscopic
analysis since characteristic resonances resulting from side-reac-
tions are insignificant compared to resonances from the polymer.
It is evident that even small proportions of coupling reactions can
lead to detrimental effects on the molecular weight characteristics
of the functionalized star polymers, and given the high functional
density of the corona the chance of coupling reactions is
amplified.
Synthesis of Fluorescent CCS Polymers. Fluorescent stars
CCS C1ꢀ3 carrying a high number of polycyclic aromatic
hydrocarbons were prepared through grafting of azido substi-
tuted naphthalene, anthracene and pyrene (C1ꢀ3, respectively)
derivatives onto CCS 2 via CuAAC chemistry. 1H NMR spectro-
scopic analysis (vide infra) revealed that the grafting was success-
ful in all cases with the click efficiency decreasing as the number
of aromatic units increased. For stars CCS C1ꢀ3 GPC-MALLS
provided increases in molecular weight (Table 1), although
interestingly the RI chromatograms (Figure 3) revealed slight
shifts to higher elution time. This unexpected shift may originate
from an increase in structure rigidity of the functionalized stars
causing delayed elution similar to that reported in linear polymer
cyclization.50 Furthermore, the high density of aromatic groups
on the stars corona may interact with the column material (cross-
linked polystyrene) through πꢀπ stacking, thus causing a delay
in their elution.
Closer examination of the GPC RI chromatogram for the
anthracene corona-functionalized star CCS C2 revealed a bimo-
dal distribution (Figure 3b) with broad polydispersity and higher
than theoretically predicted Mn. These results indicate the
occurrence of starꢀstar coupling, which might result from the
previously described click side-reactions, but more likely, anthra-
cene dimerization in the presence of light.51ꢀ53 As a result of the
chromophoric nature of the polycyclic aromatic hydrocarbon
derivatives used it was possible to quantify their loading via
UVꢀvis spectroscopic analysis, as demonstrated for the pyrene
corona-functionalized star CCS C3 (Figure 4).
UVꢀvis spectra of pyrene derivative C3 were recorded at
known concentrations and the absorption measured at 354 nm to
generate a calibration curve from which the excitation coefficient
was determined to be 60000 Mꢀ1cmꢀ1 (Figure 4). Utilizing this
Figure 3. GPC (THF) RI chromatograms for (a) naphthalene, (b)
anthracene and (c) pyrene corona-functionalized stars CCS C1ꢀ3,
respectively, and (d) alkyne CCS polymer scaffold CCS 2.
Figure 4. (a) UVꢀvis spectra (THF) for pyrene corona-functionalized star CCS C3 and azido pyrene C3. (b) Calibration curve for C3 and
determination of CCS C3 pyrene loading. Inset: THF solution of CCS C3 under (i) white light and (ii) UV irradiation (λ = 254 nm).
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Figure 6. GPC (THF) RI chromatograms for quantitatively grafted
CCS polymers: (a) naphthalene corona-functionalized star CCS C1, (b)
furan corona-functionalized star CCS C4, (c) decane corona-functio-
nalized star CCS C7, and (d) alkyne CCS polymer scaffold CCS 2.
structural rigidity as previously discussed. The successful
click-functionalization of CCS 2 with saccharide-based com-
pounds C5 and C6 was also confirmed by 1H NMR spectro-
scopic analysis (Figure S6, Supporting Information) and DLS
(Table 1).
Amphiphilic stars CCS P1ꢀ3 were prepared by grafting
various molecular weight azido substituted PEGs P1ꢀ3, respec-
tively, allowing the effect of PEG degree of polymerization to be
studied. In contrast to the saccharide functionalized stars, GPC
RI analysis revealed a decrease in elution time for the PEG
functionalized stars as a result of a large increase in molecular size,
which was confirmed by DLS (Table 1). It is proposed that the
long and flexible grafted PEG chains are capable of extending past
the stars original alkyne corona, resulting in an increased
molecular size without significantly increasing the overall struc-
tural rigidity. This would also be aided by any incompatibility
between the inner shell PCL chains and grafted PEG.
Figure 5. GPC (DMF) RI chromatograms of (a) β-galactose corona-
functionalized star CCS C5, (b) β-CD corona-functionalized star CCS
C6, (c) PEG400, (d) PEG1000 and (e) PEG2000 corona-functionalized
stars CCS P1-3, respectively, and (f) alkyne CCS polymer scaffold
CCS 2.
excitation coefficient the loading of pyrene molecules at the
corona of star CCS C3 was calculated to be 370, which is similar
to that determined via 1H NMR spectroscopic analysis (Table 1).
Furthermore, the fluorescent nature of CCS C3 was demon-
strated upon UV irradiation (λ = 254 nm) (Figure 4), which
provides additional evidence for the successful incorporation of
pyrene.
Synthesis of Amphiphilic CCS Polymers. Amphiphilic CCS
polymers with hydrophobic polyester-based cores and inner
shells, and hydrophilic coronas were prepared through grafting
CCS C2 with hydrophilic azido substituted saccharides C5 and
C6, and PEGs P1ꢀ3; GPC RI chromatograms for the resulting
amphiphilic stars, CCS C5ꢀ6 and CCS P1ꢀ3, respectively, are
provided in Figure 5. Saccharide-based amphiphilic star polymers
CCS C5 and CCS C6 were prepared through ‘click’ attachment
of monoazide functionalized β-galactopyranose and β-cyclodex-
trin onto CCS 2, with GPC-MALLS (DMF) revealing increases
in Mn from 267 kDa to 320 and 520 kDa, repectively. GPC RI
chromatograms once again revealed peak shifts toward lower
elution times (Figure 5a-b), possibly indicating an increase in the
Synthesis of quantitatively grafted CCS polymers. Out of
all the CCS polymers functionalized via CuAAC chemistry, three
displayed quantitative grafting efficiency, CCS C1, CCS C4 and
CCS C7. Whereas GPC RI chromatograms for these stars
(Figure 6) revealed very slight peak shifts toward lower elution
times, the Mns closely resemble the theoretical molecular weights
(100% grafting efficiency) (Table 1) within the determined
1
margin of error. H NMR spectroscopic analysis (Table 1 and
Figure S7, Supporting Information) also implied that quantita-
tive click efficiency was achieved in agreement with GPC results.
The high grafting efficiency can be accounted for by the small
molecular size of compounds C1, C4, and C7, which minimizes
steric hindrance and improves their ability to penetrate readily
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Figure 7. 1H NMR spectra of (a) naphthalene, (b) anthracene and (c) pyrene functionalized stars CCS C1, CCS C2, and CCS C3, respectively. The
asterisk denotes solvent resonances.
into the corona of the star and access complementary reactive
sites.
spectroscopic analysis for determination of the click efficiency in
the case of the PtBA functionalized star CCS P4. However, even
without a good separation, the extent of click functionalization
could be calculated from GPC, via integration and comparison of
RI peak areas of the star and the unreacted PtBA-N3 before and
after reaction (Figure S8, Supporting Information).
GPC RI chromatograms of CCS C4 and CCS C7 (Figure 6, b)
displayed small shoulder peaks at low elution time (t = 15ꢀ17
min), which are attributed to intermolecular coupling (i.e.,
starꢀstar coupling) resulting from the previously discussed click
side-reactions.
The results obtained from click functionalization of the alkyne
star CCS 2 imply that the molecular size of the azido substituted
compounds is a major factor affecting the click efficiency; the
larger the molecular size of the azido substituted compounds, the
lower the click efficiency. For example, NMR spectroscopic
analysis of stars functionalized with C1, C2, and C3, revealed a
decrease from 15.9 to 12.7 in the integrated area of the
characteristic methylene resonance (δH = 5.05 ppm, 2b,
Figure 7), which indicates a decrease in the number of triazoles
formed across these three reactions. This decrease in click
efficiency can be explained by the increasing number of aromatic
rings in going from C1 to C3, which hinders the ability for the
azido compounds to penetrate the stars’ corona and reach the
complementary alkyne functionalities. Therefore, the resultant
CCS polymers are less functionalized when larger azido sub-
stituted compounds are employed. This is also supported by the
series of PEG functionalized stars CCS P1ꢀ3, with the click
efficiency decreasing as the degree of polymerization of the PEG-
N3 P1ꢀ3 increased (Figure S9).
Click Efficiency of High Density Functionalization of CCS
Polymers. Upon isolation, the click efficiency of the grafted CCS
1
polymer was determined by H NMR spectroscopic analysis,
using the integration of characteristic resonances (Figure 7,
signals 1 and 2b). For example, resonance 1 (δH = 4.05 ppm)
corresponds to methylene protons adjacent to ester groups
present along the backbone of the PCL arms, whereas resonance
2b (δH = 5.05 ppm) results from methylene protons adjacent to
triazoles formed through click reactions. For all click efficiency
calculations resonance 1 was normalized to a value of 43, which
corresponds to the average number of CL repeat units per arm.
As such, the click efficiency can be calculated using the ratio of
the area under resonance 2b (A2b) over the calculated alkyne
repeated units (NCtC) per arm using eq 1, where NCtC = 18
(Table S1, Supporting Information, entry 4). All calculated click
efficiencies of various CCS polymers are summarized in Table 1.
A2b
CE ¼
ð1Þ
NC tC
In order to gain a better understanding on the molecular size
effect on the click efficiency of various azido compounds, the
click efficiency versus estimated molecular size was plotted
In contrast, the low click functionalization and difficulties in the
separation of unreacted PtBA-N3 precluded the use of 1H NMR
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Figure 8. “Click” functionalization efficiency of azido substituted
compounds onto the alkyne star CCS 2 versus the estimated molecular
size of those compounds.62
Figure 9. Bar chart comparing click functionalization efficiency of azido
substituted compounds onto the alkyne star CCS 2 and the linear
macroinitiator LP.
(Figure 8). This graph clearly indicates there is a relationship
between the click efficiency and the estimated size of the azido
substituted compounds; a linear trend line with negative slope is
included to illustrate this relationship. Evidently, terminal azido
polymers with higher degrees of polymerization and larger
molecular sizes (P2ꢀ4) displayed lower grafting efficiencies
than azido substituted compounds (C1ꢀ4, C6, and C7) as a
result of steric effects and entropic penalties.54ꢀ57 Among the
terminal azido polymers, PtBA-N3 possessed the lowest click
efficiency due to its bulky pendent tertiary butyl groups along the
polymer chain and secondary azide, resulting in a high degree of
steric hindrance. Interestingly, the β-galactopyranosyl azide C5
revealed a large deviation from the proposed trend line. With an
estimated molecular size of less than 1 nm, the low click efficiency
(18%) of C5 indicates that other factors in addition to the
proposed size-efficiency relationship are responsible for its low
click efficiency. For example, the hydrophilic nature of C5 could
lead to incompatibility issues with the hydrophobic alkyne CCS
polymer, making it difficult for C5 to approach and diffuse
through the hydrophobic corona and react with the pendent
alkynes, as has been reported for compounds with similar
structures.58 In addition, the secondary azide of C5 attached directly
to the sugar without any alkyl spacer between the azide group and the
sugar ring would experience more steric restrictions than its primary
azide counterparts resulting in decreased click efficiencies.
Contradictory to the proposed theory is the relatively high
click efficiency of the monoazido β-CD C6, which is also
comprised of hydrophilic sugars like C5 and has a significantly
larger molecular size. This unexpected result is believed to result
from the hydrophobic internal cavity of C6 and slightly lower
hydrophilicity than C5, which allows C6 to penetrate the corona
of the hydrophobic star more readily. In addition, β-CDs can
form unstable inclusion complexes59ꢀ61 with hydrophobic moi-
eties, such as the poly(propargyl methacrylate) repeat units of
star CCS 2. This potential unstable inclusion complex formation
would provide an additional synergistic driving force for C6 to
pass through and interact with the corona of the star to access the
alkyne functionalities. Furthermore, the primary azide of C6
makes it more reactive toward CuAAC chemistry, as opposed to
the secondary azide of C5. So it is reasonable for C6 to possess
higher click efficiency than C5. On the other hand, comparing C6
to the similarly sized azido pyrene C3 reveals that the click
efficiency of C6 is still lower owing to its lower hydrophilicity-
related incompatibility with the hydrophobic alkyne CCS polymer.
For CCS polymers, the arms are constrained within a compact
sphere and assume a semidilute and random coil conformation at
the inner and outer corona, respectively.63 Limited space be-
tween adjacent arm polymers would hinder the diffusion of azido
substituted compounds into the alkyne corona of the CCS
polymer during click functionalization. In addition surrounding
arms could shield the pendent alkyne groups away from the
approaching azido compounds. Therefore, the click functionali-
zation efficiency on the uncross-linked linear macroinitiator (arm
precursor) would be expected to be higher than for the alkyne
CCS polymer.
To demonstrate the effect of CCS architecture on click
efficiency, the linear HO-P(CL-b-TMS-PgMA)-Br (Table S1,
Supporting Information, entry 6) was deprotected and subse-
quently grafted with selected azide substituted compounds C2,
C6, and C7. The click efficiency on the deprotected macro-
1
initiator LP was calculated via H NMR spectroscopic analysis
(Figures S10 and S11, Supporting Information) and compared
with the click efficiency on CCS 2 (Figure 9). The linear
macroinitiator LP 1 click efficiency was found to be ∼13, 13
and 34% higher than for the alkyne star CCS 2 for compounds
C2, C6, and C7, respectively. It is noteworthy that the click
efficiency difference is less significant for polycyclic aromatic
hydrocarbon C2 and cyclic saccharide C6 compared to the PEG-
N3 P2. The results reveal that the steric congestion generated by
the arm conformation in the CCS polymer has less impact on the
diffusion of small sized molecules (e.g., C2 and C6) than
macromolecules (e.g., C7).
’ CONCLUSION
In this report, an improved synthetic approach toward the
clickable alkyne CCS polymer scaffold was reported utilizing the
robust stannous triflate (Sn(OTf)2) catalyst for ring-opening
polymerization. The reported approach provides high macro-
initiator-to-star conversions and negligible starꢀstar coupling,
therefore increasing the yield of the alkyne CCS polymer. We
have demonstrated that a library of highly corona-functionalized
CCS polymers can be rapidly prepared by grafting the alkyne
CCS polymer scaffold with various azido substituted compounds
and polymers via CuAAC chemistry. For example, fluorescently
tagged, saccharide-based and amphiphilic CCS polymers could
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be readily prepared via the reported approach. However, in some
cases the resulting functionalized CCS polymers suffer from an
increase in molecular weight distribution due to starꢀstar
coupling caused by possible side-reactions of CuAAC chemistry.
Through NMR spectroscopic analysis the number of click
grafted compounds was quantified and ranged from 45 to 450
depending on their molecular size and functionality. The grafting
efficiency (i.e., click efficiency) was studied for various azido
substituted compounds and in general, it was found that small
molecules with primary azide groups can be quantitatively
grafted onto the alkyne CCS polymer via CuAAC chemistry.
As the molecular size of the azide substituted compounds
increase the click efficiency decreases. Terminal azido functio-
nalized polymers can also be grafted onto the alkyne CCS
polymer scaffold to afford stars with brush-like arms, although
lower grafting efficiencies are observed due to steric hindrance
and entropic penalties. An inversely related molecular size to
click efficiency relationship was established, even though devia-
tions from this proposed relationship still exist for some azido
substituted compounds. These deviations can be explained by
the hydrophilicity-related compatibility of functional compounds
with the alkyne CCS scaffold, steric hindrance around the azide,
and other synergic effects, such as the formation of potential
inclusion complexes. Moreover, the steric congestion generated
by the arm conformation within the CCS polymer results in
lower click efficiency as compared to uncross-linked linear
polymer (arm precursor). Therefore, this investigation has
demonstrated that the high density functionalization of 3D
nanostructures via the grafting-to approach is dependent on a
number of factors and not just the molecular size of the
functional compounds.
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’ ASSOCIATED CONTENT
S
Supporting Information. Summary of macroinitiator
b
“arm” synthesis, characterization results of macroinitiator 2 and
3, “arm” number calculation of CCS 1, 1H NMR spectra of CCS
polymer CCS 1, 2, C4ꢀ7 and P1ꢀ3, and grafted linear polymer
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gregghq@unimelb.edu.au.
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’ ACKNOWLEDGMENT
The authors wish to acknowledge the Australian Research
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