A convenient synthesis of α,α′- homo- and α,α′-hetero-bifunctionalized poly(ε-caprolactone)s by ring opening polymerization: The potentially valuable precursors for miktoarm star copolymers

Article abstract of DOI:10.1002/pola.27924

Two new ring opening polymerization (ROP) initiators, namely, (3-allyl-2-(allyloxy)phenyl)methanol and (3-allyl-2-(prop-2-yn-1-yloxy)phenyl)methanol each containing two reactive functionalities viz. allyl, allyloxy and allyl, propargyloxy, respectively, were synthesized from 3-allylsalicyaldehyde as a starting material. Well defined α-allyl, α′-allyloxy and α-allyl, α′-propargyloxy bifunctionalized poly(ε-caprolactone)s with molecular weights in the range 4200-9500 and 3600-10,900 g/mol and molecular weight distributions in the range 1.16-1.18 and 1.15-1.16, respectively, were synthesized by ROP of ε-caprolactone employing these initiators. The presence of α-allyl, α′-allyloxy and α-allyl, α′-propargyloxy functionalities on poly(ε-caprolactone)s was confirmed by FT-IR, ¹H, ¹³C NMR spectroscopy, and MALDI-TOF analysis. The kinetic study of ROP of ε-caprolactone with both the initiators revealed the pseudo first order kinetics with respect to ε-caprolactone consumption and controlled behavior of polymerization reactions. The usefulness of α-allyl, α′-allyloxy functionalities on poly(ε-caprolactone) was demonstrated by performing the thiol-ene reaction with poly(ethylene glycol) thiol to obtain (mPEG)₂-PCL miktoarm star copolymer. α-Allyl, α′-propargyloxy functionalities on poly(ε-caprolactone) were utilized in orthogonal reactions i.e copper catalyzed alkyne-azide click (CuAAC) with azido functionalized poly(N-isopropylacrylamide) followed by thiol-ene reaction with poly(ethylene glycol) thiol to synthesize PCL-PNIPAAm-mPEG miktoarm star terpolymer. The preliminary characterization of A₂B and ABC miktoarm star copolymers was carried out by ¹H NMR spectroscopy and gel permeation chromatography (GPC).

Full text of DOI:10.1002/pola.27924

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A Convenient Synthesis of a,a0- Homo- and a,a0-Hetero-Bifunctionalized
Poly(e-caprolactone)s by Ring Opening Polymerization: The Potentially
Valuable Precursors for Miktoarm Star Copolymers
Sachin S. Patil, Bhausaheb V. Tawade, Prakash P. Wadgaonkar
Polymer Science and Engineering Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune,
Maharashtra 411008, India
Correspondence to: P. P. Wadgaonkar (E-mail: pp.wadgaonkar@ncl.res.in)
Received 24 May 2015; accepted 9 September 2015; published online 15 October 2015
DOI: 10.1002/pola.27924
ABSTRACT: Two new ring opening polymerization (ROP) initia-
tors, namely, (3-allyl-2-(allyloxy)phenyl)methanol and (3-allyl-2-
(prop-2-yn-1-yloxy)phenyl)methanol each containing two reac-
tive functionalities viz. allyl, allyloxy and allyl, propargyloxy,
respectively, were synthesized from 3-allylsalicyaldehyde as a
starting material. Well defined a-allyl, a0-allyloxy and a-allyl, a0-
propargyloxy bifunctionalized poly(e-caprolactone)s with
molecular weights in the range 4200–9500 and 3600–10,900 g/
mol and molecular weight distributions in the range 1.16–1.18
and 1.15–1.16, respectively, were synthesized by ROP of e-
caprolactone employing these initiators. The presence of a-
allyl, a0-allyloxy and a-allyl, a0-propargyloxy functionalities on
poly(e-caprolactone)s was confirmed by FT-IR, 1H, 13C NMR
spectroscopy, and MALDI-TOF analysis. The kinetic study of
ROP of e-caprolactone with both the initiators revealed the
pseudo first order kinetics with respect to e-caprolactone con-
sumption and controlled behavior of polymerization reactions.
The usefulness of a-allyl, a0-allyloxy functionalities on poly(e-
caprolactone) was demonstrated by performing the thiol-ene
reaction with poly(ethylene glycol) thiol to obtain (mPEG)2-PCL
miktoarm star copolymer. a-Allyl, a0-propargyloxy functional-
ities on poly(e-caprolactone) were utilized in orthogonal reac-
tions i.e copper catalyzed alkyne-azide click (CuAAC) with azido
functionalized poly(N-isopropylacrylamide) followed by thiol-
ene reaction with poly(ethylene glycol) thiol to synthesize PCL-
PNIPAAm-mPEG miktoarm star terpolymer. The preliminary
characterization of A2B and ABC miktoarm star copolymers
was carried out by 1H NMR spectroscopy and gel permeation
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Sci., Part A: Polym. Chem. 2016, 54, 844–860
KEYWORDS: 3-allylsalicyaldehyde; a-allyl; a0-allyloxy and a-allyl;
a0-propargyloxy bifunctionalized poly(e-caprolactone)s; atom
transfer radical polymerization; orthogonal reactions; ring-
opening polymerization; star copolymers
miktoarm star copolymers can be tailored by varying the
nature and arm lengths of copolymer.18 Recent advances in
polymer synthesis have made possible the development of
sophisticated and efficient synthetic strategies to obtain
functional materials and different macromolecular architec-
tures. There are four widely used approaches for precise
synthesis of star/miktoarm star copolymers: (A) “Core First”
approach- multifunctional initiator core is designed first and
polymers are grown outwards by controlled polymerization
techniques such as atom transfer radical polymerization
(ATRP),19 ring opening polymerization (ROP),20 nitroxide-
mediated radical polymerization (NMP)21 or reversible
addition-fragmentation chain transfer (RAFT)22 to synthesize
star copolymers with different arms.23–25 The number of
arms in the star copolymer depends on the number of differ-
ent orthogonal initiating sites in the multifunctional initiator
INTRODUCTION Amphiphilic macromolecular architectures
such as star copolymers are considered as versatile materials
and have attracted the significant attention for applications
as rheology modifiers,1 emulsifiers,2 compatibilizers in
blends,3,4 controlled and targeted drug delivery systems5–8
and stimuli responsive materials9–12 in biomedical, pharma-
ceutical, tissue engineering, and surface sciences.13 Miktoarm
star copolymers are interesting class of synthetic polymer
architectures as they form unique self assemblies due to dif-
ferent phase separation behaviors of various arms attached
at a common junction point and their nanostructures possess
higher drug loading capacities compared with their linear
counterparts.14,15 Biodegradable synthetic miktoarm star
copolymers mimic the structures of natural polymers and
their assembled structures are widely used as potential gene
and drug delivery vehicles.16,17 The chemical properties of
Additional Supporting Information may be found in the online version of this article.
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core.26 (B) “Arm First” approach- macroinitiators synthesized
by different controlled radical polymerization (CRP) techni-
ques are tied at a common junction point.27,28 (C) “Coupling
Onto” approach- multifunctional core is designed first and
different functional polymers synthesized by CRP techniques
are coupled onto the multifunctional core by some efficient,
high yielding reactions such as “click reaction”. These effi-
cient reactions should be orthogonal to each other so as to
get high yields of the final star copolymer.29,30 Yagci et al.
demonstrated the success of this approach by synthesizing
ABC miktoarm star terpolymer by orthogonal triple click
chemistry.31(D) “Core First-Coupling Onto” approach- multi-
functional initiator core containing polymerization initiating
sites and efficient reactive groups is designed. Polymers are
grown outwards first and then on the multifunctional poly-
mer the different orthogonal efficient reactions are per-
formed to couple the functional polymers or vice-versa.32,33
Of these approaches, “Core first-Coupling Onto” approach
has been considered as reliable and is widely used to con-
struct miktoarm star copolymers due to its exceptional toler-
ance towards a variety of functional groups present on the
core and different reaction conditions.34 The combinations of
controlled polymerization methods viz. ATRP, ROP, NMP or
RAFT and consecutive reactions such as, copper catalyzed
alkyne-azide reaction, Diels-Alder reaction, thiol-ene reaction,
etc. have been exploited for the precise and modular synthe-
sis of various macromolecular architectures by taking advan-
tages offered by these techniques.34–40
thiol-ene and CuAAC double click reaction strategy to syn-
thesize PS-PCL-PEG miktoarm star terpolymer.55 Diels-Alder
and CuAAC are widely used orthogonal click reactions for
the synthesis of miktoarm star copolymers.56 However, thiol-
ene and CuAAC orthogonal reactions are scarcely used for
this purpose. We previously reported the synthesis of a, a0-
hetero-bifunctionalized
poly(e-caprolactone)s
containing
clickable aldehyde and allyloxy groups.57 In continuation of
our work on functional polymers by ROP, we report herein
the synthesis of a-allyl, a0-allyloxy and a-allyl, a0-propargyloxy
bifunctionalized poly(e-caprolactone)s and their potential
utility for preparation of miktoarm star copolymers using
orthogonal chemistry approach.
Toward this end, two new ROP initiators, namely, (3-allyl-2-
(allyloxy)phenyl)methanol and (3-allyl-2-(prop-2-yn-1-yloxy)-
phenyl)methanol containing allyl, allyloxy and allyl, propar-
gyloxy functional groups, respectively, were synthesized from
commercially available 3-allylsalicyaldehyde as a starting
material. Well defined a-allyl, a0-allyloxy and a-allyl, a0-prop-
argyloxy bifunctionalized poly(e-caprolactone)s were synthe-
sized with controlled molecular weights in the range 4200–
9500 and 3600–10,900 g/mol, respectively, and molecular
weight distributions in the range 1.16–1.18 and 1.15–1.16,
respectively, by varying the monomer to initiator feed ratios
employing these ROP initiators. The presence of these reac-
tive functionalities on the polymers was confirmed by FT-IR,
NMR spectroscopy and MALDI-TOF analysis. Furthermore,
the usefulness of diallyl functionalities in 5a was demon-
strated by thiol-ene reaction with poly(ethylene glycol) thiol
(mPEG-SH) to synthesize (mPEG)2-PCL star copolymer. a-
Allyl, a0-propargyloxy functionalities in 5b were utilized in
orthogonal reactions i.e sequential CuAAC with azido func-
tionalized poly(NIPAAm) followed by thiol-ene reaction with
mPEG-SH, respectively, to synthesize PCL-PNIPAAm-mPEG
miktoarm star terpolymer. The preliminary characterization
of (mPEG)2-PCL and PCL-PNIPAAm-mPEG star copolymers
was performed by NMR spectroscopy and GPC. The issues
encountered with utility of thiol-ene chemistry for polymer-
polymer conjugation reactions have been highlighted.
Star copolymers bearing poly(e-caprolactone) arms are
mostly focused because of their different phase separation
behaviors41 and special attention has been given to the
assemblies obtained from thermoresponsive star copolymers
containing PCL which makes them the suitable candidates
for biomedical applications such as drug delivery, sensors,
gene delivery and stimuli responsive materials.42,43 The
introduction of poly(ethylene glycol) and thermoresponsive
poly(N-isopropylacrylamide) blocks on PCL preserves the
biocompatibility and biodegradability of PCL and also these
polymers are less cytotoxic hence the star copolymers
obtained from these systems are considered as suitable for
biological applications.5,18,44 PCL-PNIPAAm2 and PEG2-PCL
star copolymers have already been reported in the literature
and their cell study showed less cytotoxicity and these poly-
mers are found to be biocompatible.14 Junkers and
coworkers have reported the synthesis of biodegradable star
copolymers via RAFT copolymerization of methyl methacry-
late with cyclic ketene acetal.45
EXPERIMENTAL
Materials
3-Allylsalicyaldehyde (97%), propargyl bromide (80 wt. % in
toluene), and tin(II) 2-ethylhexanoate (95%) were purchased
from Sigma Aldrich (St. Louis, Missmouri) and were used as
received. e-Caprolactone (99%, Sigma Aldrich, St. Louis, Mis-
smouri) was stirred over calcium hydride overnight and dis-
tilled prior to use and stored over Linde type (4 A8)
molecular sieves. Allyl bromide (98%, Loba Chemie, Mumbai,
India) was used as received. Acetone was stirred over
potassium carbonate and distilled before use. Potassium car-
bonate (99%, Fischer Scientific, Mumbai, India) and potas-
sium iodide (99.8%, Thomas Baker, Mumbai, India) were
dried before use. Sodium borohydride (99%, Thomas Baker,
Mumbai, India) and 18-crown-6 (99%, Alfa Aesar, Heysham,
England) were used as received. N, N-dimethylformamide
Polymers with reactive groups such as allyl,46 propargyl,47
azido,48,49 maleimide,50 anthracene,51 or 4-dibenzocycloocty-
nol52 at the terminal position were synthesized using appro-
priate functional initiator and their consecutive click
reactions were exploited to obtain different macromolecular
architectures. The post-polymerization modification of poly-
mers with multiple functionalities requires the chemistry
that is orthogonal which does not interfere with each other
during transformations.53,54 Yagci et al. reported the use of
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(DMF) was stirred over calcium hydride and distilled under
reduced pressure. N-Isopropylacrylamide (99%, Sigma
Aldrich) was recrystallized from n-hexane and dried prior to
use. a-Bromoisobutyryl bromide (98%, Steinheim, Germany)
and 2, 2-dimethoxy-2-phenyl-acetophenone (DMPA) (99%,
Sigma Aldrich) were used as received. Triethylamine (99%,
Spectrochem, Mumbai, India) was stirred over potassium
hydroxide overnight and distilled before use. Copper bro-
mide (99.99%, Missmouri) was stirred in acetic acid, filtered,
washed with ethanol and dried at 70 8C for 6 h. 4-Amino
phenol (98%, Avra, Hyderabad, India) was purified by subli-
mation under reduced pressure. Sodium azide (99.5%,
Thomas Baker, Mumbai, India), 2-chloroethanol (99%, Spec-
trochem, Mumbai, India), methane sulphonyl chloride (98%,
Spectrochem, Mumbai, India), sodium hydrosulfide hydrate
(Sigma Aldrich, Missmouri) and DL-dithiothreitol (99%,
Himedia, Mumbai, India) were used as received. Thiol func-
tional poly(ethylene glycol) was synthesized as per the
reported procedure with some modifications (Supporting
determine the end functionalities by spotting the mixture of
4 lL polymer sample (1 mg/mL) with 20 lL of dithranol
(10 mg/mL) as matrix and 1 lL of sodium iodide as an ion-
izing agent (0.2 g/mL) on a metal target plate. Mass range
was selected between 2000-5000 g/mol during MALDI-TOF
acquisitions on the basis of molecular weights previously
determined from 1H-NMR spectroscopy. Molecular weights
and molecular weight distributions were also determined
from MALDI-TOF analysis. To get accurate results, average
peak difference of all the peaks were considered and all the
calculations were performed by considering four digits after
the decimal point. MALDI-TOF MS analysis of initiator (4)
was performed by spotting the mixture of 4 lL of sample
(1 mg/mL) with 20 lL of HABA (10 mg/mL) as a matrix
and 1 lL of sodium iodide as an ionizing agent (0.2 g/mL)
in THF as a solvent.
Synthesis
Synthesis of 3-Allyl-2-(allyloxy)benzaldehyde (1)
Into a 100 mL two necked round bottom flask equipped
with a mechanical stirrer, a gas inlet and a reflux condenser
were charged 3-allylsalicyaldehyde (2.0 g, 12.33 mmol),
potassium carbonate (3.41 g, 24.66 mmol), potassium iodide
(0.20 g, 1.23 mmol), 18-crown-6 (0.33 g, 1.23 mmol) and
acetone (50 mL). The solution of allyl bromide (2.98 g, 24.66
mmol) in acetone (10 mL) was added at room temperature
and the reaction mixture was refluxed for 3 h, filtered
through a small bed of celite and solvent was removed. The
residue was dissolved in chloroform and washed with water
(3 3 100 mL), the combined organic layer was evaporated.
The crude product was purified by column chromatography
using petroleum ether: ethyl acetate (96:04, v/v) as an elu-
ent to afford 2.3 g, (92%) of 3-allyl-2-(allyloxy)benzaldehyde
as a colorless liquid.
Information).58
N,N,N0,N00,N00,N00-Hexamethyl-[tris(aminoe-
thyl)amine] (Me6TREN) was synthesized by methylation of
tris(2-aminoethyl)amine (TREN) as reported in the
literature.59
Characterization and Measurements
FT-IR spectra were recorded on Perkin Elmer Spectrum GX
spectrophotometer using chloroform as a solvent. NMR spec-
tra were recorded on Bruker- 400 or 500 MHz frequency
spectrometers in CDCl3 as a solvent and TMS as an internal
reference. Melting points of solid compounds were deter-
mined on electrothermal MEL-TEMP apparatus at 230 volt
potential. Photochemical thiol-ene reaction on the polymers
was performed inside the photochemical reactor equipped
with a Hanovia made mercury lamp at 365 nm wavelength
and 450 Watt power equipped with a water circulation
pump.
IR (CHCl3, cm21): 3081 (@CAH), 1688 (AC@O of aldehyde)
and 1638 (AC@CA of allyl).
Polymer Characterization
Gel Permeation Chromatography
1H-NMR (400 MHz, CDCl3, d/ppm): 10.36 (s, 1H aldehyde),
7.73 (d, 1H), 7.47 (d, 1H), 7.19 (t, 1H), 6.14–6.03 (m, 1H),
6.03–5.92 (m, 1H), 5.46-5.28 (m, 2H), 5.15–5.05 (m, 2H),
4.46 (d, 2H), 3.47 (d, 2H).
Molecular weight and molecular weight distribution of
poly(e-caprolactone)s were determined by gel permeation
chromatography (GPC) equipped with Viscotek VE-3580 RI
and Viscotek VE-3210 UV/VIS detectors and Viscotek VE-
1122 pump using 1 mg/mL of polymer sample in tetrahy-
drofuran (Merck, Lichrosolv) as an eluent at flow rate of
1 mL/min and narrow molecular weight polystyrenes as cali-
bration standards with detector and column temperatures at
35 8C. Sample injection volume for GPC analysis was fixed at
100 lL.
13C-NMR (125 MHz, CDCl3, d/ppm): 190.33, 160.0, 136.84,
136.31, 134.43, 132.59, 129.64, 126.99, 124.57, 118.58,
116.56, 77.50, 33.33.
Synthesis of 3-Allyl-2-(prop-2-yn-1-yloxy)benzaldehyde (2)
Into a 100 mL two necked round bottom flask equipped
with a mechanical stirrer, a gas inlet and a reflux condenser
were charged 3-allylsalicyaldehyde (2.0 g, 12.33 mmol),
potassium carbonate (3.41 g, 24.66 mmol), potassium iodide
(0.20 g, 1.23 mmol), 18-crown-6 (0.33 g, 1.23 mmol) and
acetone (50 mL). The solution of propargyl bromide (2.93 g,
3.6 mL, 24.66 mmol) in acetone (10 mL) was added at room
temperature and the reaction mixture was refluxed for 2 h,
filtered through a small bed of celite and solvent was
removed. The residue was dissolved in chloroform and
washed with water (3 3 100 mL), the combined organic
MALDI-TOF Analysis
Matrix assisted laser desorption ionization – time of flight
(MALDI-TOF) spectrum acquisition was recorded on AB-
SCIEX TOF/TOF 5800 instrument with 4500 laser intensity
and reflector positive operating method in tetrahydrofuran
as a solvent using dithranol (5 volume equivalent with poly-
mer) as a matrix and 1 mg/mL concentration of poly(e-cap-
rolactone) at 20 8C. Polymer samples were characterized to
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layer was evaporated. The crude product was purified by
column chromatography using petroleum ether: ethyl acetate
(94:06, v/v) as an eluent to afford 2.2 g, (89%) of 3-allyl-2-
(prop-2-yn-1-yloxy)benzaldehyde as a colorless liquid.
eluent to afford 1.9 g (94%) of (3-allyl-2-(prop-2-yn-1-yloxy)
phenyl)methanol as a colorless liquid.
IR (CHCl3, cm21): 3416 (OAH broad), 3304 (BCAH), 2127
(ACBCA) and 1638 (AC@CA of allyl).
IR (CHCl3, cm21): 3295 (ꢀCAH), 3081 (@CAH), 2127
(ACꢀCA), 1688 (AC@O of aldehyde) and 1638 (AC@CA of
allyl).
1H-NMR (500 MHz, CDCl3, d/ppm): 7.26 (d, 1H), 7.17 (d,
1H), 7.11 (t, 1H), 5.90–6.10 (m, 1H), 5.0–5.15 (m, 2H), 4.77
(d, 2H), 4.60 (d, 2H), 3.47 (d, 2H), 2.56 (t, 1H), 2.14 (broad
t, 1H).
1H-NMR (400 MHz, CDCl3, d/ppm): 10.42 (s, 1H), 7.75 (d,
1H), 7.49 (d, 1H), 7.24 (t, 1H), 6.04–5.92 (m, 1H), 5.16–5.06
(m, 2H), 4.69 (d, 2H), 3.50 (d, 2H), 2.55 (t, 1H).
13C-NMR (125 MHz, CDCl3, d/ppm): 154.75, 137.09, 134.71,
133.51, 130.70, 127.89, 125.30, 116.42, 79.25, 75.93, 61.97,
61.62, 34.22.
13C-NMR (100 MHz, CDCl3, d/ppm): 190.40, 158.48, 136.88,
136.18, 134.43, 130.31, 127.21, 125.17, 116.76, 77.79, 77.32,
63.14, 33.39.
General Procedure for Synthesis of a,a0-Homo and a,a0-
Hetero-Bifunctionalized Poly(e-caprolactone)s by ROP
Into a flame dried 100 mL Schlenk tube fitted with rubber
septum, an argon inlet and a mechanical stirrer bar were
charged e-caprolactone (20 g, 175.22 mmol), tin(II) 2-
ethylhexanoate (1.18 g, 2.92 mmol) and (3-allyl-2-(allyloxy)-
phenyl)methanol (3)/(3-allyl-2-(prop-2-yn-1-yloxy)phenyl)-
methanol (4) (5.84 mmol). The reaction mixture was purged
with argon for 10 min and the Schlenk tube was immersed
in the oil bath preheated at 95 8C and quenched after appro-
priate time by sudden cooling in the liquid nitrogen. The
percentage conversion of the polymerization reaction was
determined from 1H-NMR spectroscopy by analyzing the
reaction mixture directly after quenching. The resultant
poly(e-caprolactone)s (5a and 5b) were precipitated into the
cold acidified methanol and filtered to afford white solid.
Synthesis of (3-Allyl-2-(allyloxy)phenyl)methanol (3)
Into a 250 mL round bottom flask equipped with a mechani-
cal stirrer were charged 3-allyl-2-(allyloxy)benzaldehyde
(2 g, 9.89 mmol), methanol (80 mL) and water (20 mL). The
reaction mixture was cooled to 0 8C and sodium borohydride
(0.45 g, 11.87 mmol) was added portionwise over a period
of 20 min. The reaction mixture was stirred for additional
2 h. Methanol was removed and the pH of suspension was
adjusted to 4 by addition of dilute hydrochloric acid and the
product was extracted into chloroform (3 3 50 mL). The
combined organic layer was evaporated and the crude prod-
uct was purified by column chromatography using petroleum
ether: ethyl acetate (90:10, v/v) as an eluent to afford 1.9 g
(94%) of (3-allyl-2-(allyloxy)phenyl)methanol as a colorless
liquid.
Synthesis of a-Allyl, a0-Allyloxy Bifunctionalized
Poly(e-caprolactone) (5a)
IR (CHCl3, cm21): 3382 (OAH broad), 3081 (@CAH) and
1638 (AC@CA of allyl).
IR (CHCl3, cm21): 3442 (AOAH broad) and 1730 (AC@O of
ester).
1H-NMR (500 MHz, CDCl3, d/ppm): 7.23 (d, 1H), 7.16 (d,
1H), 7.09 (t, 1H), 6.05–6.15 (m, 1H), 5.92–6.04 (m, 1H),
5.15–5.50 (m, 2H), 5.0–5.15 (m, 2H), 4.72 (s, 2H), 4.39 (d,
2H), 3.44 (d, 2H), 2.25 (broad s, 1H, alcoholic OH)
1H-NMR (400 MHz, CDCl3, d/ppm): 7.22 (d, 1H), 7.19 (d,
1H), 7.08 (t, 1H), 5.90–6.02 (m, 1H), 6.02–6.15 (m, 1H),
5.23–5.46 (m, 2H), 5.18 (s, 2H), 5.02–5.12 (m, 2H), 4.36 (d,
2H), 4.06 (t, ACH2AO from poly(e-caprolactone) backbone),
3.64 (t, 2H), 3.43 (d, 2H), 2.30 (t, ACH2ACO from poly(e-cap-
rolactone) backbone), 1.53–1.73 (m, ACH2ACH2 from poly
(e-caprolactone) backbone), 1.31–1.45 (m, ACH2ACH2 from
poly(e-caprolactone) backbone).
13C-NMR (100 MHz, CDCl3, d/ppm): 154.99, 136.94, 134.14,
133.60, 133.14, 130.13, 127.22, 124.43, 117.45, 115.95,
74.92, 61.31, 33.75.
Synthesis of (3-Allyl-2-(prop-2-yn-1-yloxy)phenyl)
methanol (4)
Into a 250 mL round bottom flask equipped with a mechani-
cal stirrer were charged 3-allyl-2-(prop-2-yn-1-yloxy)benzal-
dehyde (2 g, 9.99 mmol), methanol (80 mL) and water
(20 mL). The reaction mixture was cooled to 0 8C and
sodium borohydride (0.45 g, 11.99 mmol) was added por-
tionwise over a period of 20 min. The reaction mixture was
stirred for additional 2 h. Methanol was removed and the pH
of suspension was adjusted to 4 by addition of dilute hydro-
chloric acid and the product was extracted into chloroform
(3 3 50 mL). The combined organic layer was evaporated
and the crude product was purified by column chromatogra-
phy using petroleum ether: ethyl acetate (92:08, v/v) as an
Synthesis of a-Allyl, a0-Propargyloxy Bifunctionalized
Poly(e-caprolactone) (5b)
IR (CHCl3, cm21): 3442 (AOAH broad) and 1730 (AC@O of
ester)
1H-NMR (500 MHz, CDCl3, d/ppm): 7.23 (d, 1H), 7.19 (d, 1H),
7.10 (t, 1H), 5.91-6.10 (m, 1H), 5.22 (s, 2H), 5.05–5.12 (m,
2H), 4.55 (d, 2H), 4.05 (t, ACH2AO from poly(e-caprolactone)
backbone), 3.63 (t, 2H), 3.47 (d, 2H), 2.54 (t, 1H), 2.30 (t,
ACH2ACO from poly(e-caprolactone) backbone), 1.59–1.68
(m, ACH2ACH2 from poly(e-caprolactone) backbone), 1.33–
1.42 (m, ACH2ACH2 from poly(e-caprolactone) backbone).
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Thiol-Ene Reaction of a-Allyl, a0-Allyloxy Bifunctionalized
Poly(e-caprolactone) (5a) with mPEG-SH
1H-NMR (400 MHz, CDCl3, d/ppm): 8.07 (s, 1H), 7.67 (d,
2H), 7.23 (d, 1H), 7.13 (t, 1H), 7.07 (d, 2H), 6.55 (broad
peak from NAH of PNIPAAm), 5.92–6.03 (m, 1H), 5.23 (s,
2H), 5.05–5.12 (m, 2H), 5.09 (s, 2H), 4.42 (broad peak, 2H),
4.24 (broad peak, 2H), 4.05 (t, ACH2AO from poly(e-capro-
lactone) backbone), 3.98 (s, CAH from PNIPAAm), 3.63 (t,
2H), 3.51 (d, 2H), 2.29 (t, ACH2ACO from poly(e-caprolac-
tone) backbone), 1.2–2.5 (m, ACH2 and ACH from PNIPAAm
backbone), 1.58–1.70 (m, ACH2ACH2 from poly(e-caprolac-
tone), 1.3–1.42 (m, ACH2ACH2 from poly(e-caprolactone)
backbone), 1.12 (broad s, ACH3 from PNIPAAm).
A flame dried 20 mL pyrex tube fitted with a rubber septum
and equipped with a magnetic stirrer bar was evacuated and
refilled with argon and to the tube were charged 5a
(500 mg, 0.119 mmol), DMPA (12.2 mg, 0.4 eq.), mPEG-SH
(5 g, 2.38 mmol) and DMF (10 mL). The reaction mixture
was again purged for 30 min and sealed under argon and
irradiated for 4 h inside the photochemical reactor at
365 nm wavelength. DMF was removed under reduced pres-
sure. The reaction product was dissolved in THF (10 mL)
and to the solution was added water (30 mL) dropwise. The
solution was treated with dithiothreitol (500 mg) to cleave
disulfide linkage present in mPEG-S-S-mPEG formed as unde-
sired product during thiol-ene reaction. The solution was
dialyzed against water using 2 KD dialysis bag to remove
mPEG-SH. This procedure was repeated nine times to ensure
complete cleavage of mPEG-S-S-mPEG to mPEG-SH and
removal of mPEG-SH. The polymer solution was lyophilized
to obtain (mPEG)2-PCL miktoarm star copolymer (Yield –
88%, Mn,NMR29100 g/mol, PDI-1.19).
Thiol-Ene Reaction of Allyl Mid-Functional PCL-b-PNIPAAm
Copolymer with mPEG-SH
Into a flame dried 10 mL pyrex tube fitted with a rubber sep-
tum and equipped with a magnetic stirrer bar was thoroughly
purged with argon and to the tube were charged PCL-b-PNI-
PAAm copolymer (500 mg, 0.030 mmol), DMPA (1.56 mg, 0.2
eq.), mPEG-SH (640 mg, 0.30 mmol) and DMF (2 mL). The
reaction mixture was again purged for 30 min and sealed
under argon and irradiated for 4 h inside the photochemical
reactor at 365 nm wavelength. DMF was removed under
reduced pressure. The reaction product was dissolved in THF
(2 mL) and to the solution was added water (6 mL) dropwise.
The solution was treated with dithiothreitol (64 mg) in order
to cleave disulfide linkage present in mPEG-S-S-mPEG formed
as undesired product during thiol-ene reaction. The solution
was dialyzed against water using 2 KD dialysis bag to remove
mPEG-SH. This procedure was repeated nine times to ensure
complete cleavage of mPEG-S-S-mPEG to mPEG-SH and
removal of mPEG-SH. The polymer solution was lyophilized to
obtain PCL-PNIPAAm-mPEG miktoarm star terpolymer (Yield-
89%, Mn,NMR218400 g/mol, PDI-1.23).
IR (CHCl3, cm21): 1731 (AC@O of ester) and 1112
(ACAOA).
1H-NMR (400 MHz, CDCl3, d/ppm): 7.22 (d, 1H), 7.19 (d,
1H), 7.08 (t, 1H), 5.16 (s, 2H), 4.05 (t, CH2AO from poly(e-
caprolactone) backbone), 3.81 (t, 4H), 3.63 (s, OACH2 from
PEG backbone), 3.55 (t, 4H), 3.37 (s, 6H, O-CH3), 2.73 (t,
2H), 2.30 (t, CH2ACO from poly(e-caprolactone) backbone),
1.58-1.70 (m, ACH2ACH2 from poly(e-caprolactone) back-
bone), 1.31-1.44 (m, ACH2ACH2 from poly(e-caprolactone)
backbone).
IR (CHCl3, cm21): 1731 (AC@O of ester), 1640 (AC@O of
amide) and 1112 (ACAO–).
Orthogonal Reactions of a-Allyl, a0-Propargyloxy
Bifunctionalized Poly(e-caprolactone) (5b) with
PNIPAAm-N3 and mPEG-SH
1H-NMR (500 MHz, CDCl3, d/ppm): 8.06 (s, 1H), 7.67 (broad
peak, 2H), 7.23 (d, 1H), 7.13 (t, 1H), 7.08 (broad d, 2H), 7.07
(broad peak, 2H), 6.42 (broad peak from NAH of PNIPAAm),
5.23 (s, 2H), 5.10 (s, 2H), 4.42 (broad peak, 2H), 4.26 (broad
peak, 2H), 4.05 (t, ACH2AO from poly(e-caprolactone) back-
bone), 3.99 (s, CAH from PNIPAAm), 3.77 (t, 2H), 3.63 (s,
OACH2 from PEG backbone), 3.54 (broad t, 2H), 3.50 (broad
t, 2H), 3.37 (s, 3H, OACH3), 2.73 (t, 2H), 2.30 (t, CH2ACO
from poly(e-caprolactone) backbone), 1.2-2.5 (m, ACH2 and
ACH from PNIPAAm backbone), 1.54-1.72 (m, ACH2ACH2
from poly(e-caprolactone) backbone), 1.3-1.48 (m, ACH2
ACH2 from poly(e-caprolactone) backbone), 1.13 (broad s,
ACH3 from PNIPAAm).
Alkyne-Azide Click Reaction of a-Allyl, a0-Propargyloxy
Bifunctionalized Poly(e-caprolactone) (5b) with
PNIPAAm-N3
A flame dried 10 mL Schlenk tube fitted with a rubber sep-
tum and equipped with a magnetic stirrer bar was evacuated
and refilled with argon and to the tube were charged 5b
(500 mg, 0.138 mmol), PNIPAAm-N3 (2.06 g, 0.166 mmol),
PMDETA (24 mg, 0.138 mmol) and tetrahydrofuran (5 mL).
The reaction mixture was degassed twice by vacuum-freeze-
pump thaw cycles. Copper bromide (19.9 mg, 0.138 mmol)
was then added under the positive pressure of argon and
stirred for 24 h at room temperature. The reaction mixture
was passed through a small bed of alumina column to
remove the copper residues, concentrated and dialyzed
against water using 12 KD dialysis bag to remove excess of
PNIPAAm-N3. The polymer solution was lyophilized to obtain
allyl mid-functional PCL-b-PNIPAAm copolymer (Yield- 95%,
RESULTS AND DISCUSSION
Synthesis of New ROP Initiators viz. (3-Allyl-2-(allyloxy)
phenyl)methanol (3) and (3-Allyl-2-(prop-2-yn-1-yloxy)
phenyl)methanol (4)
Mn,NMR216400 g/mol, PDI-1.21).
Two new ROP initiators, viz. (3-allyl-2-(allyloxy)phenyl)methanol
(3) and (3-allyl-2-(prop-2-yn-1-yloxy)phenyl)methanol (4) were
synthesized from commercially available 3-allylsalicyaldehyde
IR (CHCl3, cm21): 1731 (AC@O of ester) and 1636 (AC@O
of amide).
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SCHEME 1 Synthesis of (3-allyl-2-(allyloxy)phenyl)methanol (3) and (3-allyl-2-(prop-2-yn-1-yloxy)phenyl)methanol (4).
as
a
starting material (Scheme 1). The reaction of 3-
ness of these reactive functionalities during polymerization
reactions (Fig. 2). FT-IR spectra of 5a and 5b showed the
peak at 1730 cm21 due to carbonyl stretching frequency of
ester in the poly(e-caprolactone) backbone. Well defined a-
allyl, a0-allyloxy and a-allyl, a0-propargyloxy bifunctionalized
poly(e-caprolactone)s were synthesized with molecular
weights in the range 4200–9500 and 3600–10900 g/mol
and molecular weight distributions in the range 1.16–1.18
and 1.15–1.16, respectively, by varying the monomer to ini-
tiator feed ratios and keeping catalyst to initiator ratio con-
stant (Tables 1 and 2). In both the cases, the percentage
conversions were calculated by considering the integral ratio
of methylene protons (adjacent to oxygen) of poly(e-capro-
lactone) to the total integration of methylene protons of e-
caprolactone and poly(e-caprolactone) i.e monomer and
polymer.
allylsalicyaldehyde with allyl bromide or propargyl bromide in
the presence of potassium carbonate resulted into formation of
3-allyl-2-(allyloxy)benzaldehyde (1) and 3-allyl-2-(prop-2-yn-1-
yloxy)benzaldehyde (2), respectively. The appearance of peaks at
1638 and 3081 cm21 corresponding to allyl and allyloxy groups
in 1 and at 1638, 3081 and at 2127 and 3295 cm21 correspond-
ing to allyl and propargyloxy groups, respectively, in 2 revealed
the presence of corresponding functionalities. The presence of a
peak at 1688 cm21 in FT-IR spectra showed aldehyde functional-
ity in 1 and 2.
The reduction of aldehyde functional group present in 1 and
2 using sodium borohydride afforded 3 and 4. The disap-
pearance of a peak at 1688 cm21 in FT-IR spectrum (Fig. S1
Supporting Information) corresponding to carbonyl stretch-
ing frequency of aldehyde and appearance of peaks at
3382 cm21 and 3416 cm21 corresponding to hydroxyl group
% Conversion 5 ½Iꢁ4:03 or 4:02=½Iꢁ4:21 1 4:03 or 4:19 1 4:02
1
revealed the formation of alcohols. H NMR spectra of 3 and
Degree of polymerization (DPn) in 5a and 5b was calculated
by 1H NMR spectroscopy considering the integration ratios
of methylene protons adjacent to oxygen in poly(e-caprolac-
tone) backbone at 4.06/4.05 ppm to the triplet at 7.08/7.10
ppm originating from initiator fragment, respectively.
4 (Fig. 1) showed the disappearance of peaks at 10.36 and
10.42 corresponding to protons of aldehyde functionality,
respectively and appearance of peaks at 4.72 and 4.77 ppm
and at 2.25 and 2.14 ppm corresponding to benzylic methyl-
ene and alcoholic protons revealed the formation of 3 and 4,
respectively. The presence of peaks corresponding to allyl
and propargyloxy groups in the 1H NMR spectra of 3 and 4
showed the inertness of these functional groups during
reduction of aldehyde. 13C NMR spectra of 3 and 4 showed
the disappearance of peaks corresponding to carbonyl car-
bon of aldehyde at 190.33 and 190.40 ppm which gives an
additional support for the complete conversion of aldehydes
to the corresponding alcohols.
DPn5 ½Iꢁ4:06 or 4:05=2=½Iꢁ7:08 or 7:10=1
Molecular weight (Mn,NMR) of poly(e-caprolactone)s were cal-
culated from degree of polymerization (DPn) as follows,
M
n;NMR5½DPn3 Molecular weight of e-caprolactoneꢁ
1 Molecular weight of initiator:
Molecular weights and molecular weight distributions of PCL
synthesized by varying monomer to initiator feed ratios
were determined from GPC. Typical GPC chromatograms of
5a and 5b are shown in Figure 3. GPC chromatograms of 5a
and 5b appeared symmetric and showed monomodal distri-
butions which support the controlled polymerization
behavior.
Synthesis of a-Allyl, a0-Allyloxy (5a) and a-Allyl, a0-
Propargyloxy Bifunctionalized Poly(e-caprolactone) (5b)
The new functional ROP initiators 3 and 4 were employed
for synthesis of poly(e-caprolactone)s 5a and 5b. In a typical
experiment, polymerization reaction was carried out at 95 8C
in the presence of Sn(Oct)2 as a catalyst under inert atmos-
phere (Scheme 2).
MALDI-TOF spectrum of 5a (Table 1, Entry 1) (Fig. 4) and
5b (Table 2, Entry 1) (Fig. 5) showed a mass series I corre-
sponding to a-allyl, a0-allyloxy and a-allyl, a0-propargyloxy
bifunctionalized poly(e-caprolactone)s, respectively, with
1H NMR spectra of 5a and 5b showed the peaks correspond-
ing to allyl and propargyl groups at their respective positions
as they appeared in the initiators, which revealed the intact-
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FIGURE 1 1H NMR spectrum (in CDCl3) of (A) (3-allyl-2-(allyloxy)phenyl)methanol (3) (bottom) and (B) (3-allyl-2-(prop-2-yn-1-yloxy)-
phenyl)methanol (4) (top).
SCHEME 2 Synthesis of a-allyl, a0-allyloxy (5a) and a-allyl, a0-propargyloxy bifunctionalized poly(e-caprolactone) (5b).
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1
FIGURE 2 H NMR spectrum (in CDCl3) of (A) a-allyl, a0-allyloxy (5a) (bottom) and (B) a-allyl, a0-propargyloxy bifunctionalized
poly(e-caprolactone) (5b) (top).
peak difference equal to the molecular weight of e-
caprolactone monomer repeating unit. The presence of a-
allyl, a0-allyloxy and a-allyl, a0-propargyloxy end groups was
determined from MALDI-TOF analysis by calculating the
molecular weight of initiator fragment and monomer repeat-
ing units including the sodium ion. Theoretical molecular
weight calculated from MALDI-TOF spectrum considering the
initiator fragment for a-allyl, a0-allyloxy and a-allyl, a0-
TABLE 1 Reaction Parameters and Results of Synthesis of a-Allyl, a0-Allyloxy Bifunctionalized Poly(e-caprolactone) (5a)
Conversion (%)b
Mn,theo
Mn,NMR
Mn,GPC
Mw/Mn
a
c
d
e
Sr. No.
[M]0/[I]0
Time (min)
1
2
3
30
100
165
210
98
80
81
3600
4800
9400
4200
4900
9500
5700
5200
6700
1.18
1.16
1.16
50
100
d
e
Temperature: 95 8C (In bulk), Sn(Oct)25 50 mol % of initiator.
M
M
n,NMR 5 Determined by 1H NMR spectroscopy.
n,GPC 5 Determined by GPC; polystyrene standard; tetrahydrofuran
a
[M]0/[I]0: [Monomer]0/[Initiator]0 feed ratio.
Conversions were determined by 1H NMR spectroscopy.
b
as an eluent.
c
M
n,theo 5 {[M]0/[I]0 3 (% conv.)/100 3 mol. weight of monomer} 1 mol.
weight of initiator.
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TABLE 2 Reaction Parameters and Results of Synthesis of a-Allyl, a0-Propargyloxy Bifunctionalized Poly(e-caprolactone) (5b)
Conversion (%)b
Mn,theo
Mn,NMR
Mn,GPC
Mw/Mn
a
c
d
e
Sr. No.
[M]0/[I]0
Time (min)
1
2
3
30
60
88
93
89
3200
5500
10400
3600
6300
10900
5600
6900
8000
1.15
1.15
1.16
50
180
250
100
d
e
Temperature: 95 8C (In bulk), Sn(Oct)25 50 mol % of initiator.
M
M
n,NMR 5 Determined by 1H NMR spectroscopy.
n,GPC 5 Determined by GPC; polystyrene standard; tetrahydrofuran
a
[M]0/[I]0: [Monomer]0/[Initiator]0 feed ratio.
Conversions were determined by 1H NMR spectroscopy.
b
as an eluent.
c
M
n,theo 5 {[M]0/[I]0 3 (% conv.)/100 3 mol. weight of monomer} 1 mol.
weight of initiator.
propargyloxy bifunctionalized poly(e-caprolactone) was in
good agreement with observed molecular weight which
revealed the presence of the corresponding functionalities. In
addition to the mass series I, MALDI-TOF spectrum of 5a
and 5b showed two additional mass series II and III, respec-
tively, corresponding to the acid and its sodium salt function-
alized poly(e-caprolactone)s (Figs. 4 and 5). The appearance
of acid functionalized poly(e-caprolactone)s prompted us to
perform 13C-NMR analysis to detect the resonance for car-
bonyl carbon of acid. However, 13C-NMR spectra of 5a and
5b showed the absence of resonance corresponding to the
carbonyl carbon of acid (Fig. S2 Supporting Information).
Thus, the origin of the acid functionalized poly(e-caprolac-
tone)s in MALDI-TOF spectra could likely be ascribed to the
fragmentation at benzylic site of initiator during the MALDI-
TOF acquisition, as exo-cleavage from a-benzyloxy group has
been considered as a potential site for fragmentation.60
exo-cleavage indeed occurs. MALDI-TOF MS/MS acquisition
of a selected line at M/Z 2393.5 for series I was performed
to confirm the fragmentation pattern of a-allyl a0-propargy-
loxy bifunctionalized poly(e-caprolactone) (5b) (Fig. S4 Sup-
porting Information). The appearance of peaks at M/Z 2209,
185 and 23 corresponding to acid functional PCL, benzylic
cation and sodium ion, respectively, confirmed the exo-
cleavage from a-benzyloxy group and presence of sodium ion
in series I. Additionally, MALDI-TOF MS spectrum of PCL
(5b) was recorded using HABA as a matrix and potassium
iodide as an ion source (Fig. S5 Supporting Information).
The spectrum indicated the line series corresponding to
potassium salt of PCL and the potassium salt of correspond-
ing fragmentation products which further supported the
occurence of exo-cleavage from a-benzyloxy group.
MALDI-TOF analysis at higher laser intensity (6000) showed
the complete reversal of series I and II which confirmed the
origin of acid functionalized poly(e-caprolactone)s during the
acquisition (Fig. S6, Supporting Information). Furthermore,
MALDI-TOF spectra of 5a and 5b were symmetric and
molecular weight distributions obtained from MALDI-TOF
analysis were below 1.09 which attested the controlled poly-
merization behavior.
In order to support the hypothesis that exo-cleavage from a-
benzyloxy group occurs, MALDI-TOF MS spectrum of (3-allyl-
2-(prop-2-yn-1-yloxy)phenyl)methanol (4) was recorded
(Fig. S3 Supporting Information). The appearance of peak at
M/Z 185.26 corresponding to the benzylic cation formed by
exo-cleavage from a-benzyloxy group supports the fact that
FIGURE 3 Typical GPC trace for (A) a-allyl, a0-allyloxy (5a) and (B) a-allyl, a0-propargyloxy bifunctionalized poly(e-caprolactone) (5b).
[Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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FIGURE 4 MALDI-TOF spectrum of a-allyl, a0-allyloxy bifunctionalized poly(e-caprolactone) (5a) (top) and a portion from M/Z 2375-
2612 (bottom). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Kinetics of ROP of e-Caprolactone Using 3 and 4
tion with respect to e-caprolactone monomer. This suggests the
constant rate of consumption of e-caprolactone monomer and
absence of chain terminations, if any, throughout the polymer-
ization. Furthermore, the linear increase of molecular weight
with percentage conversions and almost constant polydisper-
sities below 1.2 revealed the controlled polymerization behav-
ior with constant number of growing polymer chains and
absence of significant side reactions (Figs. 6 and 7).
The kinetics of e-caprolactone polymerization was performed
using ROP initiators 3 and 4 by keeping monomer to initiator
feed ratio at 100. The kinetic studies were performed at 95 8C by
taking the aliquots from the reaction mixtures at different time
intervals and analyzing directly by 1H NMR spectroscopy to
determine the percentage conversion. All the samples were fur-
ther purified by precipitating into cold acidified methanol and
molecular weights were determined by 1H NMR spectroscopy.
The linear dependence of ln[M]0/[M]t with polymerization time
passing through the origin (Figs. 6 and 7) in both the systems
revealed the pseudo first order kinetic behavior of polymeriza-
Thus, the initiators 3 and 4 were found to be efficient for
ROP of e-caprolactone affording well defined a-allyl, a0-
allyloxy and a-allyl, a0-propargyloxy bifunctionalized poly(e-
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FIGURE 5 MALDI-TOF spectrum of a-allyl, a0-propargyloxy bifunctionalized poly(e-caprolactone) (5b) (top) and a portion from M/Z
2470-2726 (bottom). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
caprolactone)s. The in-built allyl functionality in 3-
allylsalicyaldehyde offers the flexibility in terms of choice of
other functional groups for orthogonal chemistries and hence
can be considered as a versatile precursor for synthesis of
multifunctional ROP initiator cores for designing homo- and
hetero-bifunctionalized polymers. Such functional initiators
with noninterferable functionalities offer the reactive sites for
orthogonal reactions and post modifications of the polymers.
sors for synthesis of star copolymers by exploitation of the
reactivity of allyl and propargyl groups with appropriate
reagents/prepolymers.
The literature reports indicate that thiol-ene reactions are
sensitive to reaction conditions and are accompanied by the
formation of side products. Insightful discussion of thiol-ene
reaction for polymer-polymer conjugation has been provided
in the reported studies.46,61–64 It is now accepted that the
thiol-ene reaction is far from being satisfactory to be consid-
ered as a click reaction. Based on several intricate studies
reported in the literature, reaction conditions for thiol-ene
reaction have been suggested under which the reaction is
Thiol-Ene Reaction of a-Allyl, a0-Allyloxy Bifunctionalized
Poly(e-caprolactone) with mPEG-SH
a-Allyl, a0-allyloxy and a-allyl, a0-propargyloxy bifunctional-
ized poly(e-caprolactone)s were considered as useful precur-
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FIGURE 6 Kinetics of ROP of e-caprolactone using (3-allyl-2-(allyloxy)phenyl)methanol (3). [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
1
likely to proceed with maximum conversion and minimum
formation of undesired side products. The favorable thiol-
ene reaction conditions recommended are: (1) Thiol:ene
molar stoichiometry of 10:1 (2) Use of polar solvents such
as N-methyl-2-pyrrolidone (NMP) or DMF (3) Minimum
quantity of solvent (4) Photoinitiator whose generated radi-
cals are capable of only abstracting proton from thiol (5)
Higher ratio of thiol to photoinitiator and (6) Longer reac-
tion time. In the present work, thiol-ene reactions were car-
ried out taking into consideration the above mentioned
published information.
(Scheme 3). H NMR spectrum of the reaction mixture at the
end of reaction time was recorded after removal of solvent.
1H NMR spectrum (Fig. S12 Supporting Information) showed
a triplet at 2.88 ppm which could be ascribed to methylene
protons adjacent to disulfide linkage.65 This is an indication
of formation of mPEG-S-S-mPEG because of thiyl–thiyl radical
coupling reaction which is a prevalent side reaction in thiol-
ene coupling reaction. The reaction product was dissolved in
a minimum quantity of THF and to the solution was added
excess of water dropwise. The solution was treated with
dithiothreitol in order to cleave disulfide linkage present in
mPEG-S-S-mPEG and form mPEG-SH. The solution was dia-
lyzed against water using 2 KD dialysis bag to remove
mPEG-SH. This procedure was repeated nine times to ensure
complete cleavage of mPEG-S-S-mPEG to mPEG-SH and
removal of mPEG-SH. It is to be noted that both mPEG-SH
and mPEG-S-S-mPEG are soluble in water which allows their
a-Allyl, a0-allyloxy bifunctionalized poly(e-caprolactone)
(Mn,NMR5 4200 g/mol, DPn235) was reacted with 10 equiv-
alents (w.r.t. alkene) of mPEG-SH (Mn,NMR52100 g/mol,
DPn245) in DMF as a solvent using DMPA (0.2 eq. w.r.t.
alkene) as a photoinitiator by irradiating with light of
365 nm wavelength in a photochemical reactor for 4 h
1
separation from the product polymer by dialysis process. H
FIGURE 7 Kinetics of ROP of e-caprolactone using (3-allyl-2-(prop-2-yn-1-yloxy)phenyl)methanol (4). [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
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SCHEME 3 Thiol-ene reaction of a-allyl, a0-allyloxy bifunctionalized poly(e-caprolactone) (5a) with mPEG-SH.
NMR spectrum (Fig. 8) of the purified product polymer indi-
cated the disappearance of peaks in the region 5.8–6.2 ppm
corresponding to allyl functionalities indicating the success
of thiol-ene reaction. The peak at 2.88 ppm corresponding to
the methylene protons adjacent to disulfide linkage observed
in the product polymer before purification was completely
absent in the purified product. The relative integration of the
peak at 3.63 ppm corresponding to methylene protons adja-
cent to oxygen in PEG chain with that of the peak at 4.05
ppm corresponding to the methylene protons adjacent to
oxygen in PCL chain indicated higher content of PEG units
(by 16 mol %) than the theoretical value. The results of 1H
NMR spectroscopy studies indicated that the target polymer
viz. (mPEG)2-PCL was formed albeit contaminated with
unidentified products. Due to the experimental difficulties
involved in isolation of the side products, no efforts were
made to establish their identity. Molecular weight and molec-
ular weight distribution of (mPEG)2-PCL miktoarm star
copolymer was determined by GPC analysis. The shift of GPC
curve corresponding to (mPEG)2-PCL miktoarm copolymer
to the higher molecular weight side (lower retention vol-
ume) revealed the formation of star copolymer (Fig. 9). Star
copolymers exhibit lower hydrodynamic volume due to their
compact structure as compared with their linear counter-
parts with same molecular parameters.66 The observed mag-
nitude of shift of GPC curve corresponding to (mPEG)2-PCL
FIGURE 8 1H NMR spectrum (in CDCl3) of (mPEG)2-PCL miktoarm star copolymer. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
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(mPEG)2-PCL star copolymer showed the peak series corre-
sponding to (mPEG)2 benzylic cation in addition to the peak
series corresponding to acid functionalized PCL which con-
firmed the formation of the desired star copolymer (Fig. S13
Supporting Information).
Orthogonal Reactions of a-Allyl, a0-Propargyloxy
Bifunctionalized Poly(e-caprolactone) (5b) with
PNIPAAm-N3 and mPEG-SH
a-Allyl, a0-propargyloxy bifunctionalized poly(e-caprolactone)
was reacted with azido terminated poly(N-isopropylacryla-
mide) (PNIPAAm-N3) followed by reaction with poly(ethyl-
ene glycol) thiol with an objective to synthesize PCL-
PNIPAAm-mPEG miktoarm star terpolymer. The exploitation
of alkyne-azide click reaction for synthesis of various macro-
molecular architectures such as block, star and dendritic
structures has been successfully demonstrated previously by
several research groups.67,68 The requisite azido terminated
PNIPAAm-N3 was synthesized by ATRP of N-isopropylacryla-
mide employing a new ATRP initiator, namely, 2-(4-azidophe-
noxy)ethyl 2-bromo-2-methylpropanoate at 25 8C in the
presence of CuBr/Me6TREN as a catalytic system under
argon (Scheme S3, Supporting Information). The percentage
conversion of ATRP reaction was determined by 1H NMR
spectroscopy. The presence of clickable azido functionality in
PNIPAAm was confirmed by FT-IR (Supporting Information).
Molecular weight and molecular weight distribution of
FIGURE 9 GPC trace of (A) a-allyl, a0-allyloxy bifunctionalized
poly(e-caprolactone) (5a) and (B) (mPEG)2-PCL miktoarm star
copolymer. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
miktoarm star copolymer was not very significant as com-
pared to allyl, allyloxy bifunctionalized poly(e-caprolactone)
possibly because of the low molecular weight of mPEG-SH
used for thiol-ene reaction and lower hydrodynamic volume
of (mPEG)2-PCL miktoarm star copolymer due to the star
architecture (Fig. 9). MALDI-TOF MS spectrum of purified
SCHEME 4 Orthogonal reactions of a-allyl, a0-propargyloxy bifunctionalized poly(e-caprolactone) (5b) with PNIPAAm-N3 and mPEG-SH.
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FIGURE 10 1H NMR spectrum (in CDCl3) of allyl mid-functional PCL-b-PNIPAAm block copolymer. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
FIGURE 11 1H NMR spectrum (in CDCl3) of PCL-PNIPAAm-mPEG miktoarm star terpolymer. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
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toarm star terpolymer (Fig. 12). The incorporation of poly
(ethylene glycol) arm shifts the retention volume of PCL-
PNIPAAm-mPEG miktoarm star terpolymer to the higher side
due to the greater dipolar interaction of PEG block with the
stationary phase of GPC column.31,69 The combined results
of 1H NMR spectroscopy and GPC measurements indicated
that the target polymer viz. PCL-PNIPAAm-mPEG was formed.
Thus, the utility of a-allyl, a0-allyloxy and a-allyl, a0-propargy-
loxy bifunctionalized poly(e-caprolactone)s for the synthesis
of miktoarm star copolymer was demonstrated. However, con-
sidering the need to use high molar excess of thiol-terminated
polymer in thiol-ene polymer-polymer conjugation reaction
and laborious and extensive purification steps involved, the
approach presented herein for synthesizing star copolymers
using thiol-ene reaction is of limited scope and utility.
FIGURE 12 GPC trace of (A) a-allyl, a0-propargyloxy bifunction-
alized poly(e-caprolactone) (5b), (B) allyl mid functional PCL-b-
PNIPAAm block copolymer, and (C) PCL-PNIPAAm-mPEG mik-
toarm star terpolymer. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
CONCLUSIONS
Two new ROP initiators, namely, (3-allyl-2-(allyloxy)phenyl)me-
thanol and (3-allyl-2-(prop-2-yn-1-yloxy)phenyl)methanol con-
taining reactive functionalities such as allyl, allyloxy and allyl,
propargyloxy, respectively, were synthesized starting from a
common precursor- 3-allylsalicyaldehyde. Well defined a, a0-
homo- and a, a0-hetero-bifunctionalized poly(e-caprolactone)s
were conveniently synthesized by controlled polymerization of
e-caprolactone employing these ROP initiators. Thiol-ene reac-
tion and orthogonal alkyne-azide and thiol-ene reactions,
respectively, of a-allyl, a0-allyloxy and a-allyl, a0-propargyloxy
bifunctionalized poly(e-caprolactone)s were studied to synthe-
size (mPEG)2-PCL and PCL-PNIPAAm-mPEG star copolymer.
The preliminary characterization of star copolymers was per-
formed by 1H NMR spectroscopy and GPC. The limitations of
thiol-ene polymer-polymer conjugation reaction for the synthe-
sis of miktoarm star copolymers were highlighted.
PNIPAAm-N3 was determined by GPC analysis and was found
to be well controlled and with narrow polydispersity index
(1.19). Allyl mid functional PCL-b-PNIPAAm copolymer was
synthesized by CuAAC reaction of 5b with PNIPAAm-N3
(Scheme 4). The complete disappearance of protons corre-
sponding to propargyl group and appearance of triazole pro-
ton resonance at 8.07 ppm in 1H NMR spectrum revealed
the formation of PCL-b-PNIPAAm copolymer with allyl func-
tionality at the midpoint (Fig. 10). The relative integration of
the triplet at 4.05 ppm attributed to methylene protons adja-
cent to oxygen in PCL with that of a broad singlet at 3.98
ppm assignable to methine protons in PNIPAAm chain indi-
cated the formation of desired allyl mid-functional PCL-b-
PNIPAAm. The corresponding shift of GPC chromatogram of
PCL-b-PNIPAAm to the lower retention volume due to larger
hydrodynamic volume compared to 5b also revealed the for-
mation of PCL-b-PNIPAAm.
ACKNOWLEDGEMENTS
SSP and BVT are grateful for research fellowship and financial
support from University Grants Commission (UGC) and Council
of Scientific and Industrial Research (CSIR), New Delhi, India.
Allyl mid-functional PCL-b-PNIPAAm copolymer (Mn,NMR5
16400 g/mol) was reacted with 10 equivalents of mPEG-SH
(Mn,NMR5 2100 g/mol, DPn245) in DMF as a solvent using
DMPA (0.2 eq.) as a photoinitiator by irradiating a reaction
mixture with light of 365 nm wavelength in a photochemical
reactor for 4 h (Scheme 4). The reaction product was purified
as described for preparation of (mPEG)2-PCL miktoarm star
copolymer. 1H NMR spectrum (Fig. 11) of the purified polymer
indicated the disappearance of peaks in the region 5.8–6.1
ppm corresponding to allyl functionality indicating the com-
pletion of thiol-ene reaction. The relative integration of the
peak at 3.63 ppm due to methylene protons adjacent to oxy-
gen in PEG chain with that of the triplet at 4.05 ppm attributed
to methylene protons adjacent to oxygen in PCL was in reason-
ably good agreement, thus, indicating the formation of target
miktoarm copolymer namely PCL-PNIPAAm-mPEG.
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