A chemoselective approach to grafting biodegradable polyesters

Article abstract of DOI:10.1021/ma0487554

The process of chemoselective coupling applied to side chains of poly(ethylene oxide) (PEO) grafted to ketone-bearing polyetsers yielding biodegradable polyesters, was investigated. Chemoselective coupling was performed by mixing the ketone-bearing PCL an

Full text of DOI:10.1021/ma0487554

216
Macromolecules 2005, 38, 216-219
Scheme 1. Synthetic Pathway for PCL-graft-PEO
A Chemoselective Approach to Grafting
Biodegradable Polyesters
Ikuo Taniguchi† and Anne M. Mayes*
Department of Materials Science and Engineering,
Massachusetts Institute of Technology, 77 Massachusetts
Avenue, Cambridge, Massachusetts 02139
Eugene W. L. Chan†
Biological Engineering Division, Massachusetts Institute of
Technology, 77 Massachusetts Avenue,
Cambridge, Massachusetts 02139
bearing PCL 1 as a demonstration of our approach
(Scheme 1). Je´roˆme and co-workers first described the
chemical synthesis of 1 in which the authors reported
that reduction of the ketone to the corresponding alcohol
gave a functional polyester in high yield.18-20 Our
attempts in the chemical reduction, however, invariably
led to degradation of the polymer backbone. This result
prompted us to consider an alternate route for func-
tionalizing the ketone-bearing polyester of Je´roˆme using
the chemoselective reaction of ketones with the ami-
nooxy terminal groups of modified PEO. We chose PEO
for our model reaction because its terminal OH group
provides opportunity for further functionalization, while
PEO itself is known to inhibit protein adsorption,
reducing inflammatory response. The combination of
these two properties can extend the spectrum of ap-
plications of biodegradable polyesters and enhance their
performance in therapeutic devices.
Aminooxy-terminated PEOs21 of lengths ranging from
3 to 45 ethylene glycol units were prepared following
the reaction shown in Scheme 2.22 The PCL backbone,
a ketone-bearing PCL, was synthesized following meth-
ods published by Je´roˆme and co-workers,18-20 except
using tin 2-ethylhexanoate as a catalyst in ROP of ꢀ-CL
and 1,4,8-trioxaspiro[4,6]-9-undecanone to achieve a
high molecular weight PCL derivative (>100 kg/mol).23
The incorporation ratio of 1,4,8-trioxaspiro[4,6]-9-un-
decanone to ꢀ-CL in the resulting polymer and weight-
average molecular weight (Mw) of the polymer were well
controlled from 6.7 to 31.2 mol % and from 30 to 230
kg/mol, respectively. Molecular weight was determined
by size exclusion chromatography (SEC) based on
polystyrene standards.
Linda G. Griffith
Biological Engineering Division, Mechanical Engineering
Department, and Biotechnology Process Engineering Center,
Massachusetts Institute of Technology, 77 Massachusetts
Avenue, Cambridge, Massachusetts 02139
Received June 22, 2004
Revised Manuscript Received December 9, 2004
Aliphatic polyesters, such as poly(ꢀ-caprolactone)
(PCL), poly(L-lactide) (PLLA), and polyglycolide (PGA),
are of great interest as biomaterials due to their
excellent biodegradability, bioresorbability, and me-
chanical properties.1,2 The potential applications of these
polymers are further broadened when functional pen-
dant groups are incorporated into the polymer back-
bones. Various chemical approaches have been devel-
oped to present amino,3,4 carboxyl,5,6 hydroxyl,7-9 and
sulfhydryl groups10,11 onto such polyesters via ring-
opening polymerization (ROP) of lactones or lactides
with the appropriate functional monomer. While useful,
these methods generally require a complex multistep
synthesis of the protected monomer before polymeriza-
tion and removal of the protective groups prior to
further chemical manipulation, which can result in
degradation of the polymer. The extent of copolymeri-
zation obtained by ROP of lactones and lactides can also
be low due to large differences in monomer reactiv-
ity.6,9,12-17
Alternatively, the direct coupling of unprotected
functional groups to the polymer backbone under mild
reaction conditions would circumvent these shortcom-
ings. In this communication, we report a new approach
to graft unprotected functional groups onto the back-
bones of aliphatic polyesters. This approach is based on
the selective reaction between a ketone-bearing ali-
phatic polyester and aminooxy-terminated functional
groups. Our interest in using chemoselective coupling
to graft functional groups onto aliphatic polyesters is
motivated by several considerations: (1) The reactive
partners are highly selective and therefore can tolerate
the presence of diverse functional groups without using
protection chemistries. (2) The reaction occurs rapidly
and efficiently under mild reaction conditions, minimiz-
ing chemical degradation of the polymer. (3) The two
partners react covalently to form a chemically stable
linkage.
Chemoselective coupling was performed by simply
mixing the ketone-bearing PCL and aminooxy-termi-
nated PEO in chloroform at various stoichiometries and
temperatures. After a predetermined time, the product
was recovered by reprecipitation in cold methanol,
which efficiently removed any unreacted PEO. Figure
1
1 shows the H NMR spectra of ketone-bearing PCL
(Mw: 30 kg/mol; Mw/Mn: 1.3; ketone: 30 mol %)23 before
and after reaction with monoaminooxy-terminated hexa-
ethylene glycol (MW: 297 g/mol).22 In this case, the
stoichiometry of aminooxy groups to ketone was 3:1, and
the coupling was carried out at 25 °C for 3 days. PCL-
graft-PEO comb copolymer with 43.9 wt % PEO was
obtained. The peaks of ꢀ-methylene protons of ketone-
bearing ꢀ-CL units and methylene protons adjacent to
the aminooxy terminus of PEO shift from 4.35 to 4.25
ppm and 3.82 to 4.15 ppm, respectively. However, since
the peaks of ꢀ-methylene protons of the PCL chain end
ꢀ-CL units (4.1-4.3 ppm) overlap with those peaks, the
For this work, we grafted aminooxy-terminated poly-
(ethylene oxide) (PEO) onto the backbone of ketone-
† Contributed equally to this work.
* To whom correspondence should be addressed. E-mail
amayes@mit.edu.
10.1021/ma0487554 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/24/2004

Macromolecules, Vol. 38, No. 2, 2005
Communications to the Editor 217
Scheme 2. Synthetic Pathways for (a) Aminooxy-Terminated Methoxy-PEO and (b) Monoaminooxy-Terminated
Hexaethylene Glycol
coupling was characterized by monitoring the chemical
shifts for the protons corresponding to the two methyl-
ene groups adjacent to the ketone before (2.7-2.9 ppm)
and after (2.5-2.7 ppm) chemoselective coupling. The
coupling reaction was further confirmed by 13C NMR
(Supporting Information). The peak of the ketone carbon
at 206 ppm decreases while two peaks at 155 ppm
emerge, which can be assigned to the oxime carbon, split
due to the two geometric isomers of the CdN-O group.
Fourier transfer infrared spectroscopy (FT-IR) also
revealed the formation of oxime by the coupling reaction
(Supporting Information). The ketone stretching peak
at 1716 cm-1 shifted to 1640 cm-1, consistent with the
stretching of the CdN bond. Ketone groups in the PCL
backbone react exclusively with the oxyamine even in
the presence of unprotected hydroxyl groups, allowing
the preparation of functionalizable PEO-grafted PCL.
The coupling efficiency was investigated in various
ONH2:CdO molar ratios from 1 to 25 at 25 or 40 °C.
The polymer concentration in chloroform was kept at
5.0 wt %. As expected, the coupling efficiency is affected
by both the stoichiometry and temperature of the
reaction, as shown in Figure 2. The coupling rate
increased with increase in the reaction temperature.
With excess of aminooxy-terminated PEO, the coupling
was completed in a day. The results obtained show that
the coupling proceeds efficiently even at room temper-
ature.
chain end methyl group at 1.24 ppm and other protons
of the polymer backbone did not change during the
coupling reaction.
Thermal stability of the comb copolymer was inves-
1
tigated by H NMR and thermal gravimetric analysis
(TGA). Heat treatment in air at 100 °C for 10 min
1
resulted in no changes to the H NMR spectrum. TGA
also revealed higher thermal stability of PCL-g-PEO
than the pregrafted polymer (Supporting Information),
showing 0.6% weight loss at 200 °C, and 5% at 290 °C,
compared to 5% at 260 °C for the parent polyester.
Several methods to tether PEO side chains onto
biodegradable polyesters have been published.9,24-27
However, the molecular weights of the obtained graft
copolymers were usually low.9,24,25,27 Because of severe
reaction conditions, chain cleavage of the backbone
might be expected.26 In addition, such synthetic strate-
gies typically exclude the possibility for further modi-
fication of the free PEO end. By using this chemoselec-
tive technique, PCL-g-PEO biodegradable comb copoly-
mers with controlled PEO content can be prepared. In
addition, the molecular weights of both side chains and
backbone are simultaneously well controlled with suit-
able combinations of PCL backbone and aminooxy-
terminated PEO. PCL-g-PEO copolymers containing up
to 70 wt % PEO have been synthesized. When the PEO
content exceeds 50 wt %, however, the resulting mater-
ial becomes soluble in both water and methanol, and
thus separation of excess PEO is difficult.
SEC results suggest that no degradation of the
polymer backbone occurs during the coupling reaction.
The values of Mw and polydispersity index (Mw/Mn) of
the polymer fraction monitored by refractive index
before (233 kg/mol and 1.9) and after (237 kg/mol and
1.8) the coupling were nearly identical (Supporting
Information). This conclusion is further supported by
the 1H NMR spectrum of a 30 kg/mol PCL-g-PEO
prepared with Al(OiPr)3.11-13,23 The peak ratio of the
In conclusion, PEO side chains have been grafted to
ketone-bearing polyesters through a chemoselective
reaction, yielding biodegradable amphiphilic comb poly-
esters of well-defined chemical structure under mild
synthetic conditions. The chemoselective approach pre-
sented here illustrates a general route to chemically
introducing functional pendant groups onto ketone-
bearing polyesters obtained by ROP. The selectivity for

218 Communications to the Editor
Macromolecules, Vol. 38, No. 2, 2005
Figure 1. 1H NMR spectra of PCL backbone (upper) and PCL backbone reacted with monoaminooxy-terminated hexaethylene
glycol (bottom).
the coupling between ketones and aminooxy groups,
even in the presence of other potentially reactive groups
such as hydroxyls, is highly useful for the syntheses of
biodegradable combs with bioinert side chains that can
be further functionalized with cell-signaling peptides for
a desired biological response.28-30
Therics, Inc. I. Taniguchi acknowledges the financial
support of the Japanese Ministry of Education, Culture,
Sports, Science and Technology.
Supporting Information Available: SEC traces, 13C
NMR spectra, FT-IR spectra, and TGA traces of parent PCL
and PCL-g-PEO. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by
NIH Awards GM59870 and 5U54GM064346-03 and by

Macromolecules, Vol. 38, No. 2, 2005
Communications to the Editor 219
nooxy-terminated PEO circumvents these shortcomings by
forming a chemically stable oxime bond with the ketone
without the use of a base.
(22) Representative synthetic procedures: 3 g of methoxy-PEO
(MW: 750, 4.0 mmol) was reacted with 1.14 g of p-
toluenesulfonyl chloride (tosyl chloride) (6.0 mmol) and 0.84
mL of triethylamine (6.0 mmol) in dichloromethane for 5 h
at 0 °C. The product was purified by filtration followed by
reprecipitation in diethyl ether. 1H NMR (400 MHz in
CDCl3), δ (ppm): 2.32 (s, 3H, Ar-CH3), 3.35 (s, 3H, CH3),
3.5-3.8 (m, 62H, CH2CH2O), 4.14 (t, 2H, CH2OSO2Ar), 7.12
(d, 2H, Ar), 7.76 (d, 2H, Ar). Tosylated PEO derivative (2.0
g, 2.2 mmol) was reacted with N-hydroxyphthalimide (0.54
g, 3.3 mmol) and triethylamine (0.46 mL, 3.3 mmol) in THF
at 65 °C for 24 h. The product was purified by the same
methods as described above. 1H NMR (400 MHz in CDCl3),
δ (ppm): 3.35 (s, 3H, CH3), 3.5-3.8 (m, 62H, CH2CH2O),
4.36 (t, 2H, CH2ON), 7.71 (d, 2H, Ar), 7.83 (d, 2H, Ar). The
obtained PEO derivative (2.0 g, 2.2 mmol) was then treated
with hydrazine (0.11 mL, 3.3 mmol) in dichloromethane at
25 °C for 8 h. The product was collected by reprecipitation
in diethyl ether. 1H NMR (400 MHz in CDCl3), δ (ppm): 3.35
(s, 3H, CH3), 3.5-3.8 (m, 62H, CH2CH2O), 3.82 (t, 2H, CH2-
ON). When the molecular weight of methoxy-PEO was less
than 750, its derivative was purified by column chromatog-
raphy. In the case of monoaminooxy-terminated hexaeth-
ylene glycol, PEO (MW: 282) was at first reacted with 3,4-
dihydro-2H-pyran, and monoprotected PEO was isolated by
column chromatography. The protecting group was removed
by adding pyridinium p-toluenesulfonate after tosylation of
the hydroxyl group (Scheme 2b).
(23) Lower molecular weight (<100 kg/mol) PCL derivatives were
prepared with aluminum isopropoxide.11-13 For higher
molecular weight PCL derivatives, typical synthetic proce-
dures were as follows. The ring-opening copolymerization
of ꢀ-CL (9.3 g, 81.6 mmol) and 1,4,8-trioxaspiro[4,6]-9-
undecanone (1.0 g, 5.8 mmol) was carried out with tin
octoate (40 mg, 100 µmol) at 110 °C in 5 mL of toluene for
24 h. After polymerization, an excess of 1 N HCl was added
to terminate polymerization, and the copolymer was col-
lected by reprecipitation in methanol. The Mw and Mw/Mn
of the resulting polymer were determined to be 233 kg/mol
and 1.9, respectively, by size exclusion chromatography.
Finally, PCL incorporating 6.6 mol % of ketone group was
obtained after deacetalization with triphenylcarbenium
tetrafluoroborate.
Figure 2. Effect of stoichiometry and temperature on ami-
nooxy-terminated PEO (MW: 750) coupling as a function of
time at 25 °C (open symbols) and 40 °C (filled symbols).
Stoichiometry: aminooxy group/ketone ) 1 (circles), 3 (squares),
and 25 (triangles).
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MA0487554