Complex, degradable polyester materials via ketoxime ether-based functionalization: Amphiphilic, multifunctional graft copolymers and their resulting solution-state aggregates

Article abstract of DOI:10.1002/pola.24132

Degradable, amphiphilic graft copolymers of poly(ε-caprolactone)- grarf-poly(ethylene oxide), PCL-g-PEO, were synthesized via a grafting onto strategy taking advantage of the ketones presented along the backbone of the statistical copolymer poly(ε-caprolactone)-co-(2-oxepane-1, 5-dione), (PCLco-OPD). Through the formation of stable ketoxime ether linkages, 3 kDa PEO grafts and p-methoxybenzyl side chains were incorporated onto the polyester backbone with a high degree of fidelity and efficiency, as verified by NMR spectroscopies and GPC analysis (90% grafting efficiency in some cases). The resulting block graft copolymers displayed significant thermal differences, specifically a depression in the observed melting transition temperature, T _m, in comparison with the parent PCL and PEO polymers. These amphophilic block graft copolymers undergo self-assembly in aqueous solution with the P(CL-coOPD-co-(OPD-g-PEO)) polymer forming spherical micelles and a P(CL-co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)) forming cylindrical or rod-like micelles, as observed by transmission electron microscopy and atomic force microscopy.

Full text of DOI:10.1002/pola.24132

Complex, Degradable Polyester Materials via Ketoxime Ether-Based
Functionalization: Amphiphilic, Multifunctional Graft Copolymers and
Their Resulting Solution-State Aggregates
1
2
3
RHIANNON K. IHA, BROOKE A. VAN HORN, KAREN L. WOOLEY
1
Department of Chemistry, Washington University in Saint Louis, Saint Louis, Missouri 63130-4899
Department of Chemistry and Biochemistry, The College of Charleston, Charleston, South Carolina 29424
Department of Chemistry, Texas A&M University, College Station, Texas 77842
2
3
Received 25 January 2010; accepted 15 May 2010
DOI: 10.1002/pola.24132
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Degradable, amphiphilic graft copolymers of poly-
and PEO polymers. These amphiphilic block graft copolymers
undergo self-assembly in aqueous solution with the P(CL-co-
OPD-co-(OPD-g-PEO)) polymer forming spherical micelles and
(
e-caprolactone)-graft-poly(ethylene oxide), PCL-g-PEO, were
synthesized via a grafting onto strategy taking advantage of
the ketones presented along the backbone of the statistical co-
polymer poly(e-caprolactone)-co-(2-oxepane-1,5-dione), (PCL-
co-OPD). Through the formation of stable ketoxime ether link-
ages, 3 kDa PEO grafts and p-methoxybenzyl side chains were
incorporated onto the polyester backbone with a high degree
of fidelity and efficiency, as verified by NMR spectroscopies
and GPC analysis (90% grafting efficiency in some cases). The
resulting block graft copolymers displayed significant thermal
differences, specifically a depression in the observed melting
a
P(CL-co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)) forming
cylindrical or rod-like micelles, as observed by transmission
electron microscopy and atomic force microscopy. VC 2010
Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48:
3553–3563, 2010
KEYWORDS: aminooxy; amphiphiles; amphiphilic copolymer;
block copolymers; block graft copolymer; graft copolymers;
heterograft copolymer; ketoxime ether; poly(e-caprolactone);
poly(ethylene oxide)
m
transition temperature, T , in comparison with the parent PCL
INTRODUCTION When investigating chemistries for the func-
tionalization of polymeric materials, it is critical to consider
reactions that are quantitative, chemoselective, and func-
tional group tolerant, especially when performing chemistry
in the presence of biological molecules or macromolecules
that may contain sensitive or reactive groups. Consequently,
synthetic strategies used in the creation or modification of
well-defined structurally and compositionally complex mate-
rials must, by necessity, employ reactions that exhibit a high
degree of fidelity and that proceed under mild reaction con-
ness in the modification and fabrication of biocompatible
polymer systems.
1
0–12
Aliphatic polyesters are one class of polymers that offer an
attractive platform for biomedical, drug delivery, and tissue
engineering applications, due to the ability to synthesize
13
14
well-defined polymers and oligomers as well as a variety
15–17
of architectures
that produce benign degradation prod-
Despite this advantageous attribute, their lack of
18–20
ucts.
chemical handles for further derivatization and inherent
hydrophobicity necessitate the development of strategies for
the incorporation of functional ligands and hydrophilic seg-
ments to construct polyester systems that are better suited
for in vivo applications. Recent literature documents the
1
–3
ditions.
In terms of transformations that are efficient yet
orthogonal to a multiplicity of chemical centers, those involv-
ing carbonyls demonstrate great breadth, due to the unique-
ness and high reactivity of aldehydes and ketones. Hydrazide,
2
1
incorporation of functional molecules including folic acid,
2
2
23
(
thio)semicarbizide, and aminooxy compounds are all nitro-
RGD peptide, and sugars into aliphatic polyester systems
to make the polymers more effective as therapeutic or diag-
nostic agents. In addition to ligands and targeting moieties,
amino groups have been grafted onto the backbone to gener-
gen-containing nucleophiles that are capable of specific reac-
tion with ketones and aldehydes, and have been used in the
4
,5
construction of complex bioconjugates.
Recent literature
2
4
indicates that this same set of nucleophiles and their utility
in polymer synthesis and postpolymerization modification
are being investigated for the preparation of functional mate-
ate cationic, water-soluble polyesters. Another strategy for
making aliphatic polyesters water-dispersible involves the
synthesis of polyesters bearing hydophilic polymer grafts to
6
–9
25,26
rials,
with special attention being given to their effective-
generate amphipilic block graft copolymers. Poly(L-lysine)
Correspondence to: K. L. Wooley (E-mail: wooley@chem.tamu.edu)
Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 48, 3553–3563 (2010) V
C
2010 Wiley Periodicals, Inc.
COMPLEX, DEGRADABLE POLYESTER MATERIALS, IHA, VAN HORN, AND WOOLEY
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
and PEO grafts have been the primary polymer systems for
study as hydrophilic grafts. A variety of chemistries including
2
7
28
anionic modification, atom transfer radical addition, and
2
9–31
‘‘click’’ cycloaddition
have been used for attachment of
the grafts onto polyester backbones with varying degrees of
grafting efficiency.
Our strategy for the transformation of degradable aliphatic
polyesters into functional materials for biomedical applica-
tions centers on their outfitting with multiple moieties,
including hydrophilic polymer grafts, to afford amphiphilic
block graft copolymers that are capable of assembly into
well-defined, multifunctional nanostructures. Our efforts in
this area focus on poly(e-caprolactone-co-2-oxepane-1,5-
SCHEME 1 Synthesis of a-methoxy-x-aminooxy-poly(ethylene
oxide), 1.
types of chemistries employed and reaction conditions uti-
lized. For example, the reaction environment should be suffi-
ciently mild to avoid premature degradation of the polymer,
while still allowing for the economical incorporation of
numerous polymer and small molecule ligands onto the poly-
mer backbone. It is often difficult to remove free polymer
remaining in the desired graft polymeric material; the choice
of a highly efficient grafting chemistry would improve the
consumption of the polymer reagents and would produce a
more pure product. Additionally, when working with a
hydrolytically degradable polymer system, the ability to
incorporate both hydrophilic polymer grafts and other units
in a single step to afford a functional amphiphilic copolymer
is beneficial, as it minimizes the premature degradation of
the polyester backbone that may result from sequential func-
tionalization reactions. Consequently, the modification of
P(CL-co-OPD) with aminooxy-functionalized PEO was studied
independently and with a small molecule ligand, p-methoxy-
O-benzylhydroxylamine, to obtain a high degree of grafting
density and multifunctionality efficiently, under mild reaction
conditions.
3
2
dione) (P(CL-co-OPD)), an aliphatic polyester with reactive
ketones presented along the polyester backbone. The chemi-
cal approach exploits the inherent electrophilicity of the ke-
tone carbonyls to achieve economical and orthogonal incor-
poration of multiple functionalities through ketoxime ether
formation, while minimizing exposure to reaction conditions
that could lead to premature degradation. Aminooxy chemis-
try affords a convenient and efficient method for the con-
struction of functional and crosslinked polyester materials
3
3,34
using P(CL-co-OPD).
Analogously, using a ‘‘grafting onto’’
approach, hydrophilic polymers with an aminooxy-terminus
can be employed as nucleophiles to obtain amphiphilic graft
copolymers via reaction with the ketones on the hydrophobic
P(CL-co-OPD) backbone. Mayes and coworkers employed
ketoxime ether formation for the chemoselective incorpora-
3
5
tion of PEO grafts ranging from 150 Da to 2 kDa, and have
used these graft copolymers to create functional biocompati-
3
6
ble surfaces. Although the approach yielded the desired
graft copolymers, the method of conjugation employed
required long reaction times (days), high stoichiometry (up
to 25 equivalents of hydroxylamine to ketone) and heat to
maximize the number of PEO grafts.
Synthesis of PCL-g-PEO Ketoxime Ether Conjugates
A a-methoxy-x-aminooxy-poly(ethylene oxide), 1, was syn-
thesized by a two-step process, adapting a procedure
3
7
reported by Gajewiak et al. (Scheme 1). The first step
involved a Mitsunobu displacement of the hydroxyl chain
end on a 3 kDa a-methoxy-poly(ethylene oxide) to give the
x-phthalimido compound, 2. Removal of the phthalimide
group was accomplished through hydrazinolysis to yield the
Because of the versatility of the ketone moiety and the
potential indicated by previous research, we are interested
in further developing and optimizing the P(CL-co-OPD) sys-
tem for use in the creation of functional, water-soluble,
nanoscale particles through the combined incorporation of
various chemical handles and hydrophilic PEO grafts. Herein,
we report a highly efficient method for the addition of 3 kDa
PEO-grafts and small molecule probes onto the P(CL-co-OPD)
backbone via acid-catalyzed ketoxime ether formation at
room temperature using low stoichiometric equivalents of
PEO. The resulting amphiphilic graft block copolymers dis-
play unique thermal characteristcs relative to their parent
copolymers, and were found to self-assemble in aqueous so-
lution yielding aggregates of varying morphology.
1
desired aminooxy-terminated poly(ethylene oxide), 1. H nu-
clear magnetic resonance (NMR) spectra were collected for 2
and 1, in both CDCl and acetone-d (Fig. 1), to confirm their
3
6
structures, spectroscopically and chemically. As expected,
there was almost no difference for the spectra of 2 in the
two solvents, whereas 1 underwent reaction with acetone to
afford a ketoxime product that allowed for further differen-
tiation of the proton signals adjacent to the x-terminal func-
1
tional group. The H NMR spectrum of 2, taken in CDCl
3
,
had signals at 7.80 ppm and 4.38 ppm, corresponding to the
aromatic protons on the phthalimide (Phth) group and the
RESULTS AND DISCUSSION
methylene protons of the ACH AO-Phth group, respectively;
2
To create multifunctional amphiphilic copolymers, having a
high degree of versatility in their structure and composition,
and involving the coupling of small molecules to hydrolyti-
cally degradable macromolecules and/or of macromolecules
to each other (i.e., grafting of poly(ethylene oxide) (PEO) and
a PCL backbone), a few criteria must be met regarding the
the proton signal arising from the methoxy chain end was
observed as a singlet at 3.38 ppm [Fig. 1(a)]. Integration of
the resonances belonging to the methoxy terminus and the
multiplet corresponding to the ACH AO-Phth methylene
2
protons indicated quantitative conversion of the hydroxyl
group to the phthalimide. On transformation to the aminooxy
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1
FIGURE 1 (a) H NMR (300 MHz) spectra of a-methoxy-x-phthalimido-PEO, 2, and a-methoxy-x-aminooxy-PEO, 1, in CDCl
3
, and (b)
of a-methoxy-x-phthalimido-PEO, 2, and a ketoxime ether derivative, 1 , of a-methoxy-x-
aminooxy-PEO, 1, formed through a reaction between the aminooxy chain end and acetone-d
1
0
H NMR (300 MHz) spectra in acetone-d
6
6
.
group of 1, the signal for the methylene protons at 4.38 ppm
disappeared, however, direct confirmation of their resonance
frequency could not be made. As it was difficult to discern
the signal corresponding to the chain end ACH AOANH
6
with acetone-d chemically confirmed the presence of the
terminal aminooxy functionality.
A P(CL-co-OPD) polymer, 3, containing an average of 45 re-
active OPD repeat units per polymer chain was used as the
parent polymer substrate for the conjugation of a-methoxy-
x-aminooxy-PEO, 1, to yield the PCL-g-PEO block graft co-
polymer, 4 (Scheme 2). Additionally, as part of a strategy to
work toward the synthesis of multifunctional, water-dispersi-
ble PCL materials, the a-methoxy-x-aminooxy-PEO, 1, and
2
2
1
protons, a H NMR spectrum of 1 was obtained in acetone-
d [Fig. 1(b)]. In this case, the acetone-d acted not only as
6
6
the NMR solvent, but also as a derivatizing agent, used to
produce the corresponding ketoxime ether conjugate.
Through the formation of the oxime, the methylene protons
shifted upfield from 4.35 ppm when adjacent to the phthal-
p-methoxy-O-benzylhydroxylamine,
a small molecule de-
imide of 2 to 4.10 ppm when adjacent to the ketoxime of
signed to act as an analog for a chromophore or other imag-
ing agent, were allowed to undergo reaction in a single-step,
one-pot reaction with P(CL-co-OPD) to produce the graft
block copolymer, 5, containing both hydrophilic PEO grafts
and functional small molecule side chains (Scheme 2). In
both cases, the reactions were conducted in THF for 24 h
using a catalytic amount of p-toluenesulfonic acid; the result-
ing grafting efficiencies of the aminooxy-terminated PEO and
the p-methoxy-O-benzylhydroxylamine were found to be
remarkably high.
0
1
, well resolved from the broad AOCH CH A signal of the
2 2
1
PEO chain. Examination of the H NMR spectrum of the
aminooxy compound in acetone-d6 indicated complete re-
moval of the phthalimide through comparison of the inte-
gration of the singlet corresponding to the methoxy end
group at 3.29 ppm to the multiplet at 4.10 ppm, which is
the resonance attributed to the ACH AOAN ¼¼ C(CD )
2
3 2
methylene protons [Fig. 1(b)]. In addition to providing bet-
ter resolution of the chain end protons, the reaction of 1
SCHEME 2 Synthesis of PCL-g-PEO graft block copolymers, 4 and 5.
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
1
FIGURE 2 (a) H NMR spectra (300 MHz, CDCl
3
) of the parent P(CL-co-OPD) polymer, 3 (red), P(CL-co-OPD-co-(OPD-g-PEO)), 4
blue), a fully functionalized P(CL-co-OPD-co-(ODP-g-pMeOBn)) (purple), and P(CL-co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)), 5
green). (b) An overlay of GPC RI traces of the parent P(CL-co-OPD) polymer, 3 (red), P(CL-co-OPD-co-(OPD-g-PEO)), 4 (blue), P(CL-
(
(
co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)), 5 (green), and 3 kDa PEO (black).
1
H NMR spectra were collected for 4 and 5 in CDCl
3
to con-
are relative to the P(CL-co-OPD) (20 mol:1 mol, 1:3), not rel-
ative to the ketone stoichiometry (0.4 mol:1 mol, 1:ketones
on 3). The grafting efficiency for the conjugation of
a-methoxy-x-aminooxy-PEO, 1, and p-methoxy-O-benzylhy-
droxylamine to the PCL backbone in a single step, though
slightly lower, was also highly efficient at 75 and 80% graft-
ing efficiency for the PEO and the p-methoxybenzyl com-
pounds, respectively.
firm their structures and to determine the number of grafts
incorporated onto the P(CL-co-OPD) backbone (Fig. 2). The
1
H NMR spectrum of the PCL-g-PEO graft block copolymer,
4
, had proton signals indicating the conversion of a portion
of the ketones to ketoxime ethers [blue spectrum in Fig.
(a)]. The resonance at 4.25 ppm corresponds to protons on
2
the methylene adjacent to the oxygens of the ester groups in
functionalized OPD repeat units [blue f in Fig. 2(a)]. In addi-
0
GPC analysis of the resulting PCL-g-PEO block graft copoly-
mers 4 and 5, showed a marked increase in the molecular
weight of the graft copolymer relative to the parent P(CL-co-
OPD) polymer. There was not a substantial increase in the
polydispersity of the graft copolymer products, suggesting
that little to no degradation of the polyester backbone
occurred during the coupling reaction [Fig. 2(b)]. Interest-
ingly, in the case of both graft copolymers, a small amount of
free PEO remained present in the isolated precipitate, as
observed in the GPC traces. This free PEO could not be
removed with subsequent precipitations or fractional precip-
itation techniques, and dialysis was found to be an unsuit-
able method for removal of excess PEO due to the resulting
degradation of the graft copolymer backbone.
tion, an intense signal from the PEO chain at 3.6–3.7 ppm,
the protons on the methoxy end group at 3.39 ppm, and the
appearance of a quartet at 4.15 ppm corresponding to the
0
ACH
2
AON ¼¼ C methylene [blue g in Fig. 2(a)], each sup-
ported the covalent attachment of PEO chains onto the PCL
backbone. The H NMR spectrum of the bi-functionalized
1
graft block copolymer, 5, had diagnostic signals associated
with the conversion of ketones to ketoxime ether linkages at
0
0
4
.25 ppm [purple f Fig. 2(a)]; the presence of PEO-grafts
was confirmed by the strong signal for the PEO chain at 3.6–
.7 ppm and a multiplet corresponding to ACH
3
2
AON ¼¼ C
protons at 4.15 ppm [green spectrum, Fig. 2(a)]. The incor-
poration of p-methoxybenzyl (p-MeOBn) grafts was con-
firmed by the appearance of aromatic resonances at 6.85
ppm, two signals indicative of the benzylic protons at 4.96
ppm, and a singlet corresponding to the methoxy protons at
Thermal Characterization of PCL-g-PEO Ketoxime Ether
Conjugates
3.75 ppm [purple and green spectra, Fig. 2(a)]. To assist
Differential scanning calorimetry (DSC) experiments were
performed to compare the thermal characteristics of the
PCL-g-PEO ketoxime ether conjugates to the parent P(CL-co-
OPD) and PEO polymers. Substantial differences in the melt-
ing transition temperatures of 4 and 5 relative to the peak
melting temperature transition of the P(CL-co-OPD) parent
copolymer and the 3 kDa PEO were observed, and are illus-
trated in Figure 3(a) as DSC traces of the third heating cycle
so that each sample had undergone similar thermal anneal-
ing. The grafting of 3 kDa a-methoxy-x-aminooxy-PEO onto
the PCL backbone via ketoxime ether formation resulted in a
polymeric material diplaying a single melting transition—
with the confirmation of the assignments of the proton sig-
nals responsible for the p-MeOBn functionalities, a sample
that resulted from reaction only between P(CL-co-OPD) and
p-methoxy-O-benzylhydroxylamine was prepared and ana-
lyzed [purple spectrum of Fig. 2(a)].
The reaction between P(CL-co-OPD), 3, and 20 equivalents of
a-methoxy-x-aminooxy-PEO, 1, resulted in the grafting of 18
PEO chains, giving a grafting efficiency of 90%, based on the
integration of signals representing the remaining OPD repeat
units relative to those signals associated with the CL repeat
units. It is important to note that the equivalents used here
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ARTICLE
FIGURE 3 (a) DSC thermograms from the third heating cycle of the melting transition region of the parent P(CL-co-OPD) polymer,
3
(red); 3 kDa PEO (black); a physical mixture of the parent P(CL-co-OPD) polymer, 3, and 3 kDa PEO (orange); P(CL-co-OPD-co-
(
OPD-g-PEO)), 4 (blue); and P(CL-co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)), 5 (green), and (b) DSC thermograms from the first
heating cycle of the melting transition region of the parent P(CL-co-OPD) polymer, 3 (red); 3 kDa PEO (black); a physical mixture of
the parent P(CL-co-OPD) polymer, 3, and 3 kDa PEO (orange); P(CL-co-OPD-co-(OPD-g-PEO)), 4 (blue); and P(CL-co-OPD-co-(OPD-g-
PEO)-co-(OPD-g-pMeOBn)), 5 (green).
rather than two transitions corresponding to the melting
In both cases, neat P(CL-co-OPD) and 3 kDa PEO present a
well-defined transition, with the peak Tm of the PEO appear-
temperatures of the PEO and the P(CL-co-OPD)—with a peak
ꢀ
ꢀ
melting temperature of 48 C for the P(CL-co-OPD-co-(OPD-
ing at 61 C and the peak Tm of the parent polyester, 3,
ꢀ
g-PEO)) copolymer, 4 [Fig. 3(a), blue]. In the case of the mul-
tifunctional, amphiphilic graft copolymer, 5, the incorporation
of 3 kDa PEO and p-methoxy-benzyl ketoxime ether grafts
also yielded a material with a single transition having a peak
occuring at 66 C [Fig. 3 (b), red and black]. In the first heat-
ing cycle, a two-stage melt was observed for the physical
mixture of the P(CL-co-OPD) copolymer, 3, and 3 kDa PEO
ꢀ
[Fig. 3(b), orange], with one stage having a peak Tm at 60 C,
ꢀ
melting point of 49 C [Fig. 3(a), green]. In both cases, the
which matches the Tm for PEO, and a second less intense
ꢀ
addition of grafts onto the polymer backbone resulted in a
melting transition that was significantly lower than the tem-
perature observed for the parent PCL copolymer and the
PEO composing the grafts. This result is consistent with pre-
viously reported melting transitions observed in PCL materi-
als with small molecule ketoxime ether grafts that disrupted
transition appearing at 64 C, corresponding to a slightly
m
depressed T for P(CL-co-OPD). Observation of two melting
transitions for physical mixtures containing two crystalline
polymers is not uncommon, and has been previously
observed in investigations studying the melting transitions of
3
9
PCL and PEO blends. Similarly, the thermogram from the
3
8
the crystallinity. To demonstrate that the depression in
melting temperature was caused by both compositional and
structural changes resulting from the covalent attachment of
PEO to the PCL backbone, the melting transition tempera-
first heating cycle for the P(CL-co-OPD-co-(OPD-g-PEO)) co-
ꢀ
polymer, 4 [Fig. 3(b), blue], exhibits a peak Tm at 52 C asso-
ciated with the melting transition of the PEO grafts and a
ꢀ
slight shoulder at 55 C, likely corresponding to the Tm of
tures, T ’s, of the PCL-g-PEO ketoxime ether conjugates were
the P(CL-co-OPD) backbone. The multifunctional, amphiphilic
graft copolymer, 5 [Fig. 3(b), green] has a peak Tm at 55 C,
but does not clearly display two obvious stages or a
shoulder that would suggest two unique melting points.
m
ꢀ
compared with a physical mixture, 1:1 by mass of the parent
P(CL-co-OPD) polymer, 3, and 3 kDa PEO, which is a compa-
rable mass ratio to that found in both graft copolymers. The
resulting T
m
for the physical blend was a single peak at 59
The differences observed in the first and third heating cycles
are due to the different thermal histories of the polymer
samples; the first heating cycle was heated from room tem-
perature with no annealing, but in the case of the third heat-
ing cycle the polymer samples had been crystallized noniso-
ꢀ
ꢀ
C [Fig. 3(a), orange]. This temperature is ꢁ10 higher than
the melting transitions observed for 4 and 5, and is compa-
rable with the peak melting transition temperatures of 61
ꢀ
and 60 C obtained for P(CL-co-OPD) and 3 kDa PEO, respec-
tively [Fig. 3(a), red and black].
ꢀ
thermally twice at a rate of 10 C/min. Despite the
Although all of the melting transitions observed in the third
heating cycle display a single peak, suggesting a single melt-
ing transition for each of the polymer samples characterized,
thermograms from the first heating cycles provide additional
insight into the unique behavior of the PCL-g-PEO ketoxime
ether conjugates relative to their parent polymers [Fig. 3(b)].
differences in thermal history, in both the first and third
heating cycles, the PCL-g-PEO ketoxime ether conjugates, 4
and 5, exhibited significantly lower melting temperatures
than the parent polymers and the mixture of P(CL-co-OPD)
with 3 kDa PEO. These results suggest that the covalent
attachment of PEO grafts onto the polyester backbone
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
the shape of the aggregates formed by P(CL-co-OPD-co-(OPD-
g-PEO)) copolymer 4, with the heights being determined by
AFM and the diameters by TEM, each after deposition of the
aqueous solutions onto solid substrates. The aggregates
visualized by tapping-mode AFM appear globular in shape
with a fairly broad height distribution [Fig. 5(a)]. Calculation
2
of the particle sizes over a 5 ꢂ 5 lm area gave an average
height of 2 6 1 nm, with the height of the observed aggre-
gates ranging from 1 to 7 nm. The TEM image obtained from
a 0.3 mg/mL solution of 4 in 9:1 water/THF (v/v) showed
circular, particle-like aggregates with an average diameter of
116 6 35 nm [Fig. 5(b)]. There is clearly a broad distribu-
tion of particle diameters in the micrograph, which is compa-
rable with the broad size distributions observed by DLS and
AFM. The low height value observed through AFM, relative
to the large diameter, suggests a reorganization of the aggre-
gates to cause flattening on adsorption onto the solid sub-
strates (mica (AFM) or carbon-coated copper grid (TEM)).
Furthermore, the large, unusual aggregates observed in the
TEM image suggest significant reorganization events. As
opposed to our past experience with hydrophilic
FIGURE 4 (a) Intensity-averaged DLS histogram showing the
bimodal size distribution of the aggregates, (b) volume-aver-
aged DLS histogram, and (c) the number-averaged DLS histo-
gram of the aggregates present in a 0.3 mg/mL solution of
P(CL-co-OPD-co-(OPD-g-PEO)), 4, a block graft copolymer con-
taining 55 wt % PEO.
disrupts the crystallinity present in both polymer species,
and that the thermal profiles of the of the PCL-g-PEO ketox-
ime ether conjugates can be correlated to chemical and
structural changes in the polymer architecture.
Self-Assembly of PCL-g-PEO Ketoxime Ether Conjugates
in Aqueous Solution
The amphiphilic block graft copolymers, when transitioned
from organic solvent (tetrahydrofuran, THF) to water,
undergo multimolecular aggregation to afford nanostructures
having interesting morphologies. The P(CL-co-OPD-co-(OPD-
g-PEO)) copolymer, 4, having a 55 wt % of PEO was allowed
to undergo assembly in an aqueous solution. This particular
block graft copolymer formed micellar aggregates with an in-
tensity-averaged hydrodynamic diameter, D , of 225 6 21
h
h
nm, a volume-averaged D of 29 6 4 nm, and a number-
averaged Dh of 16 6 1 nm, as measured by dynamic light
scattering (DLS). DLS analysis reveals that the aggregates
exhibited a bimodal distribution with population size max-
ima at approximately 19 nm and 285 nm, which can both be
observed in the intensity-averaged DLS histogram of Figure
4. Such bimodal distributions of aggregates have been
observed previously for block graft copolymers where PEO
has been grafted onto PCL backbones via other chemical
coupling methods.
2
8
FIGURE 5 (a) Height image of tapping mode AFM image of
P(CL-co-OPD-co-(OPD-g-PEO)), 4 (concentration 0.3 mg/mL). (b)
TEM image of the micellar aggregates formed by P(CL-co-OPD-
co-(OPD-g-PEO)), 4 (0.3 mg/mL solution).
Atomic force microscopy (AFM) and transmission electron
microscopy (TEM) were used to analyze the size and also
3558
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
4
0,42,43
reduced.
At this time, it is unclear whether the forma-
tion of the cylindrical aggregates in this graft copolymer sys-
tem results from a diminished density of PEO grafts in 5 rel-
ative to 4, or if the self-assembly process and the rod-like
aggregates are a consequence of having pMeOBn side chains
covalently attached to the PCL backbone. To better under-
stand this system and the self-assembly of PCL-g-PEO
copolymers in general, further investigation pertaining to the
self-assembly of these rod-like aggregates and the character-
istics that influence aggregate shape is ongoing.
EXPERIMENTAL
Materials
The synthesis of 1,4,8-trioxaspiro-9-undecanone (TOSUO)
3
2,44–48
has been described elsewhere.
Aldrich Chemical Company) was distilled from CaH2 and
e-Caprolactone (CL)
(
stored under argon. Toluene (Aldrich Chemical Company)
was dried by heating at reflux over sodium and distilled
FIGURE 6 TEM image of the cylindrical aggregates formed
by P(CL-co-OPD-co-(OPD-g-PEO)-co-(OPD-g-pMeOBn)), 5, at
ꢂ50,000 magnification (0.3 mg/mL solution).
under argon before use. Aluminum triisopropoxide Al(OiPr)
Aldrich Chemical Company) was purified by sublimation
and dissolved in dry toluene before use. Polyethylene oxide
3 kDa PEO) was purchased from Nektar and was dried by
3
(
(
nanoparticles, these new materials presented difficulties in
the preparation of samples for AFM and TEM imaging. In
many cases, cooling was necessary and deposition conditions
required optimization (see ‘‘Experimental’’ section for
details). Each of these results illustrates the unique charac-
teristics of these amphiphilic and crystalline block graft
copolymers in water as well as the challenges in working
with these systems.
azeotropic distillation of toluene (3ꢂ) to dryness to remove
residual water. All other reagents (solvents, p-toluenesulfonic
acid (p-TsOH), diethyl azodicarboxylate (DEAD), triphenyl-
phosphene, etc.) were purchased from Aldrich and used as
received.
Instrumentation
H NMR (300 MHz) and C NMR (75 MHz) spectra were
1
13
The PCL-PEO graft block copolymer with pendant p-
methoxybenzyl groups, 5, having 49 wt % PEO, showed
unique self-assembly behavior on being dispersed in aque-
ous solution. Unlike the graft copolymer 4, which has only
PEO grafts, TEM images obtained after drop deposition of a
solution of 5 onto a carbon-coated copper grid, indicated
that the copolymer having both PEO grafts and dangling
pMeOBn side chains forms cylindrical or rod-like aggregates
having an average diameter of 12 6 2 nm and an average
length of 190 6 37 nm when dispersed in aqueous solution
at the same block graft copolymer concentrations as used for
acquired in CDCl3 unless otherwise noted on a Varian Mer-
cury 300 spectrometer using the residual solvent signal as
the internal reference. Infrared spectra were recorded on a
Perkin-Elmer Spectrum RX FTIR system by film deposition
onto NaCl salt plates. DSC was performed under nitrogen
atmosphere using 40 lL aluminum pans on a Mettler Toledo
ꢀ
DSC822 with heating and cooling at 10 C/min from ꢃ100
ꢀ
ꢀ
C to 100 C. Tm values were obtained from the third heating
scan as the peak values from the thermogram. Gel permea-
tion chromatography was performed on a Waters Chroma-
tography, 1515 isocratic HPLC pump equipped with an inline
ꢀ
ꢀ
4
(Fig. 6). The reason for the observed differences in the so-
degasser, a model PD2020 dual-angle (15 and 90 ) light
scattering detector (Precision Detectors), a model 2414 dif-
ferential refractometer (Waters), and four PLgel polystyrene-
co-divinylbenzene gel columns (Polymer Laboratories) con-
lution-state aggregates formed by 4 and 5 is not obvious at
this time and warrants additional study. One potential char-
acteristic that may generate differences in the observed
aggregates is the change in the overall weight percent of
PEO present in the block graft copolymer samples; specifi-
cally the reduced number of PEO grafts present on 5 relative
to 4, may be influencing the morphology of the solution state
aggregates. Previous research on PCL-b-PEO copolymer sys-
tems indicates that these block copolymer systems form cy-
lindrical and wire-like aggregates with certain ratios of PCL
2
nected in series: 5 lm Guard (50 ꢂ 7.5 mm ), 5 lm Mixed C
2
4
2
(300 ꢂ 7.5 mm ), 5 lm 10 (300 ꢂ 7.5 mm ), and 5 lm
2
500 Å (300 ꢂ 7.5 mm ) using the Breeze (version 3.30,
ꢀ
Waters) software. The instrument was operated at 35
C
with THF as eluent. Data collection was performed with Pre-
cision Acquire 32 Acquisition program (Precision Detectors)
and analyses were carried out using Discovery32 software
(Precision Detectors) with a system calibration curve gener-
ated from plotting molecular weight as a function of reten-
tion time for a series of broad polydispersity poly(styrene)
4
0,41
to PEO and block copolymer concentrations.
A prefer-
ence for cylindrical or worm-like micelles was noted to occur
when the hydrophobic PCL block was longer, while a prefer-
ence for spherical aggregates was observed when the
standards. The height measurements (H ) for the aggregates
av
4
1
amount of PEO was increased, or if the block length of
PEO was held constant while the PCL block length was
formed by the PCL-g-PEO ketoxime ether conjugates were
determined by tapping-mode AFM under ambient conditions
COMPLEX, DEGRADABLE POLYESTER MATERIALS, IHA, VAN HORN, AND WOOLEY
3559

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
in air. The AFM instrumentation consisted of a Nanoscope III
BioScope system (Digital Instruments, Veeco Metrology
Group, Santa Barbara, CA) and standard silicon tips (type,
OTESPA-70; L, 160 lm; normal spring constant, 50 N/m; res-
onance frequency, 246–282 kHz). The sample solutions were
drop cast (50–100 lL) onto freshly cleaved mica and
allowed to settle freely for 60 s, after which the excess solu-
tion was removed by wicking with filter paper and the mica
surface was allowed to dry in air. Hydrodynamic diameters
4H, aromatic of phthalimide), 7.45 (dt, J ¼ 9, 2 Hz, 2H, aro-
matic of p-MeO-Bn), 6.9 (dt, J ¼ 9, 2 Hz, 2H, aromatic of p-
MeO-Bn), 5.15 (s, 2H, AOCH A), 3.8 (s, 3H, AOCH ) ppm.
2
3
1
3
C NMR (75 MHz, CDCl ) d 163.7, 160.6, 134.6, 131.8,
3
129.1, 126.0, 114.1, 79.7, 55.4 ppm.
O-(p-Methoxybenzyl)hydroxylamine
O-(p-methoxybenzyl)-N-hydroxyphthalimide (0.985 g, 3.48
mmol, 1.0 eq) was dissolved in 35 mL of dry THF. Hydrazine
monohydrate (0.5 mL, 10 mmol, 3 eq) was added and the
reaction was allowed to proceed at room temperature for 18
(Dh) and distributions for the PCL-g-PEO ketoxime ether
aggregates in aqueous solution were determined by DLS. The
DLS instrumentation consisted of a Brookhaven Instruments
Limited (Worcestershire, UK) system, including a model BI-
1
h, monitored by H NMR spectroscopy. The reaction mixture;
a clear solution containing a white solid, was dissolved into
1
00 mL CH Cl , extracted with 1.0 M KOH (2 ꢂ 50 mL) and
2
2
200SM goniometer, a model BI-9000AT digital correlator, a
H O (2 ꢂ 50 mL), dried over Na SO , and concentrated in
2
2
4
model EMI-9865 photomultiplier, and a model 95-2 Ar ion
laser (Lexel, Farmindale, NY) operated at 514.5 nm. Measure-
vacuo to afford the product, O-(p-methoxybenzyl)hydroxyl-
amine, as a clear, colorless oil. Yield: 0.55 g, >98%.
ꢀ
ments were made at 25 6 1 C. Scattered light was collected
ꢀ
at a fixed angle of 90 . The digital correlator was operated
IR (NaCl) 3314, 3235, 3100–3000, 2950–2840, 1611, 1585,
ꢃ1
1
with 522 ratio spaced channels and initial delay of 2.4 ls, a
final delay of 250 ms, and a duration of 2 min. A photomulit-
plier aperture of 400 lm was used, and the incident laser in-
tensity was adjusted to obtain a photon counting greater
than 75 kcps. Only measurements in which the measured
and calculated baselines of the intensity autocorrelation
function agreed to within 0.3% were used to calculate parti-
cle size. Particle size distributions were performed with the
ISDA software package (Brookhaven Instruments Company),
which employed single-exponential fitting, cumulant analysis,
and nonnegatively constrained least-squares particle size dis-
tribution analysis routines. Samples for TEM measurements
1
512, 1464, 1362, 1301, 1247, 1174, 1032, 814 cm . H
NMR (300 MHz, CDCl ) d 7.3 (dt, J ¼ 9, 2 Hz, 2H, aromatic
3
of p-MeO-Bn), 6.9 (dt, J ¼ 9, 2 Hz, 2H, aromatic of p-MeO-
Bn), 5.3 (s, 2H ACH AONH ), 4.6 (s, 2H, ACH AONH ) ppm,
2
2
2
2
1
3
3
.8 (s, 3H, AOCH ) ppm. C NMR (75 MHz, CDCl ) d 159.5,
3
3
130.5, 130.1, 129.5, 113.9, 77.6, 71.5, 55.3 ppm.
P(CL-co-OPD) Copolymer Synthesis
Random copolymers of e-caprolactone (CL) and 2-oxepane-
,5-dione (OPD) were prepared by ring opening polymeriza-
tion of CL and the synthetic monomer TOSUO by initiation
1
with Al(OiPr) , and the resulting P(CL-co-TOSUO) was subse-
3
ꢀ
quently deprotected using triphenylcarbenium tetrafluorobo-
were precooled (ca. 5 C) and drop deposited onto prechilled
3
2,44,45
ꢀ
rate as previously reported.
(
ca. 0 C) carbon coated-copper grids, were diluted with
with a 1% phosphotungstic acid (PTA) stain (v/v, 1:1), and
then the excess solution was removed by wicking with filter
paper. The samples were allowed to dry under ambient con-
ditions and then were imaged on a Hitachi H-600 TEM
instrument. The number average particle diameters (Dav)
and standard deviations were generated from the analysis of
P(CL327-co-OPD ) (3). GPC: M
¼ 38700 Da, M
¼
49
n, PS
w, PS
1
5
0400 Da, PDIPS ¼ 1.3. M
n
( H NMR) ¼ 43600 Da. T ¼ 61
m
ꢀ
C. IR (NaCl) 3600–3000, 2940–2860, 1732 (str, multiple
modes), 1595, 1470, 1437, 1420, 1397, 1367, 1295, 1244,
ꢃ1
1
1191, 1108, 1065, 1046, 962, 933, 903, 841 cm . H NMR
(
300 MHz, CDCl ) d 5.0 (septet, J ¼ 6.3 Hz, 1 H of initiated
3
40 particles.
chain end, (CH )CHO), 4.25 (t, J ¼ 7.2 Hz, 2 H of OPD units,
3
CH
2
OCO), 4.05 (t, J ¼ 6.6 Hz, 2 H of CL units, CH
2
OCO), 3.65
Synthesis
(
t, J ¼ 6.3 Hz, 2 H of terminated chain end, CH OH), 2.82 (t,
2
O-(p-Methoxybenzyl)-N-hydroxyphthalimide
J ¼ 7.2 Hz, 2 H of OPD units, C(O)CH CH CO), 2.75 (t, J ¼
2
2
N-Hydroxyphthalimide (5.71 g, 35.0 mmol, 1.41 eq) was dis-
solved in 100 mL of dry THF followed by addition of trie-
thylamine (5.0 mL, 36 mmol, 1.4 eq) to yield a deep red so-
lution. p-Methoxybenzylbromide (5.00 g, 24.9 mmol, 1.0 eq
Br) was added to the reaction mixture dropwise. The reac-
tion was allowed to proceed at reflux for 18 h and moni-
7
2
.2 Hz, 2 H of OPD units, C(O)CH2CH2), 2.62 (t, J ¼ 7.5 Hz,
H of OPD units, C(O)CH CH OCO), 2.30(t, J ¼ 7.5 Hz, 2 H
2
2
of CL units, CH COOCH ), 1.65 (m, 4 H of CL units, OCH CH ,
2
2
2
2
and CH CH COO), 1.45 (m, 2 H of CL units, CH CH CH COO),
2
2
2
2
2
1
.25 (d, J ¼ 6.3 Hz, 6 H of initiated chain end, (CH
3
)
2
CHO)
ppm. C NMR (75 MHz, CDCl3) d 205.9, 173.4, 172.7, 64.6,
4.2, 59.2, 41.6, 37.5, 34.2, 34.0, 28.4, 27.9, 25.6, 24.7, 24.5
1
3
1
tored by TLC and H NMR spectroscopy. CH Cl was added
2
2
6
and the solution was washed with H O (3ꢂ), dried over
2
ppm.
Na SO , and concentrated in vacuo to afford the crude prod-
2
4
1
uct (91% conversion by H NMR spectroscopy). Flash col-
umn chromatography of the crude product yielded O-(p-
methoxybenzyl)-N-hydroxyphthalimide as white crystals.
Yield: 6.11 g, 87%.
a-Methoxy-x-phthalimidoxy-poly(ethylene oxide), 2
A solution of triphenyl phosphine (4.4 g, 17 mmol) in THF
ꢀ
(
70 mL) was cooled to ꢃ78 C under argon. A 40 wt % solu-
tion of diethyl azodicarboxylate in toluene (7.5 mL, 17
mmol) was added to the reaction dropwise via syringe, and
the reaction was stirred under argon and allowed to warm
to room temperature over 1 h. The reaction mixture was
IR (NaCl) 3037, 2960–2840, 2037, 2962, 2839, 1783, 1726,
1
612, 1516, 1463, 1387, 1253, 1174, 1142, 1027, 972, 877,
ꢃ1
1
822, 697 cm . H NMR (300 MHz, CDCl ) d 7.7–7.9 (two m,
3
3560
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
ꢀ
again cooled to ꢃ78 C under argon, a solution of 3 kDa a-
173.4, 172.8, 156.4, 155.7, 77.4, 72.1, 70.7, 69.7, 64.7, 64.3,
59.2, 41.6, 37.7, 34.3, 34.2, 33.9, 30.4, 30.3, 30.2, 28.5, 28.0,
25.7, 24.7, 24.5, 24.4 ppm.
methoxy-poly(ethylene oxide) (5.0 g, 1.7 mmol) in THF (50
mL) was added dropwise by syringe, and the reaction was
allowed to warm to room temperature over 30 min. A solu-
tion of N-hydroxy phthalimide (2.8 g, 17 mmol) in THF (50
mL) was added to the reaction by syringe over a 30-min pe-
riod, and the reaction was allowed to stir at room tempera-
ture under argon for 18 h. The resulting phthalimidoxy-ter-
minated PEO was isolated and purified by two precipitations
into diethyl ether (3.9 g, 75% yield).
P(CL327-co-OPD -co-(OPD-g-PEO) -co-(OPD-g-MeOBn) ), 5
27
15
8
A solution of a-methoxy-x-aminooxy(poly(ethylene oxide)), 1,
128 mg, 0.042 mmol ) in THF (1.2 g) was added to a solution
(
of P(CL327-co-OPD ) (66 mg, 0.0017 mmol) in THF(0.5 g).
45
The reaction mixture was stirred at RT for 1 min. to ensure
the dissolution of both polymer species. A solution of O-(4-
methoxybenzyl)hydroxylamine (2.6 mg, 0.017 mmol) in THF
IR (NaCl) 2950–2690, 1789, 1734, 1466, 1359, 1342, 1280,
241, 1147, 1113, 1060, 962, 842 cm . H NMR (300 MHz,
CDCl ) d 7.7–7.9 (m, 4H of phthalimido chain end), 4.39 (dd,
(0.5 g) was added to the reaction mixture, and then four drops
ꢃ1
1
1
of a solution of p-TsOH (7.5 mg) in THF (20 mL) was added.
The reaction was stirred at RT for 24 h and the polymer was
purified by precipitation into hexanes. The stringy white solid
was isolated via vacuum filtration with a coarse glass frit, and
3
J ¼ 4, 5 Hz, 2H, CH AO-Phth chain end), 3.65 (bs, 4H of PEO
2
1
3
repeat unit), 3.39 (s, 3H of AOCH chain end). C NMR (75
3
3
MHz, CDCl ) d 163.5, 134.5, 129.1, 123.6, 70.7, 59.1 ppm.
was dried in vacuo for 12 h (180 mg, 89% yield). GPC: M
n, PS
1
¼
74900 Da, Mw, PS ¼ 97600 Da, PDI ¼ 1.3. M ( H NMR)
PS
n
a-Methoxy-x-aminooxy-poly(ethylene oxide), 1
ꢀ
¼
89700 Da. T
m
¼ 49 C.
Hydrazine monohydrate (1.0 mL, 20 mmol) was added in a
single portion to a solution of a-methoxy-x-phthalimidoxy-
poly(ethylene oxide) (2.1 g, 0.67 mmol) in THF (50 mL). The
reaction was capped and stirred at room temperature for 96
h. The resulting polymer was isolated by precipitation into
diethyl ether (1.55 g, 76% yield). T
IR (NaCl) 2950–2800, 1733, 1466, 1456, 1360, 1342, 1280,
ꢃ1
1
1
240, 1149, 1110, 1061, 963, 842 cm . H NMR (300 MHz,
CDCl ) d 6.86 (d, J ¼ 8.8 Hz, 4H, aromatic), 4.94–4.96 (two
3
singlets, 2H, Ph-CH ), 4.33 (t, J ¼ 6.2 Hz, 2H of OPD units,
2
ꢀ
CH OCO), 4.3–4.1(pair of multiplets, 2H of ketoxime ether
¼ 60 C.
2
m
isomers of OPD-g-PEO units, CH OCO, and pair of multiplets,
2
IR (NaCl) 2950–2800, 1466, 1359, 1342, 1280, 1240, 1148,
109, 1060, 962, 842 cm
.85 (m, 2H of ACH AONH chain end), 3.65 (bs, 4H of PEO
repeat unit), 3.39 (s, 3H of AOCH chain end). C NMR (75
2H of ketoxime ether isomers of OPD-g-pMeOBn units), 4.05
ꢃ1
1
1
3
. H NMR (300 MHz, CDCl ) d
(
t, J ¼ 6.7 Hz, 2H of CL units, CH
2
OCO), 3.80 (s, 3H, CH O-
3
3
2
2
Ph) 3.64 (bs, 4H of PEO repeat unit), 3.37 (s, 3H of OCH3
PEO end group), 2.79 (t, J ¼ 6.3 Hz, 2H of OPD units,
1
3
3
MHz, CDCl ) d 74.7, 70.5, 59.0 ppm.
3
C(O)CH2 CH COO), 2.74 (t, J ¼ 6.6 Hz, 2H of OPD units,
2
C(O)CH CH OCO), 2.62–2.50 (t, J ¼ 6.6 Hz, 2H OPD,
2
2
P(CL327-co-OPD27-co-(OPD-g-PEO) ), 4
A solution of a-methoxy-x-aminooxy(poly(ethylene oxide)),
, (118 mg, 0.39 mmol) in THF (1.0 g) was added to a solu-
tion of P(CL327-co-OPD ), 3, (73 mg, 0.0015 mmol) in THF
18
CH COOCH ; m, 6H of OPD-g-PEO; m, 6H of OPD-g-pMeOBn),
2
2
2
.30 (t, J ¼ 7.5 Hz, 2H of CL units, CH
2 2
COOCH ), 1.64 (m, 4H
1
of CL units, OCH CH and CH CH COO), 1.37 (m, 2H of CL
2
2
2
2
45
units, CH CH CH COO), 1.22 (d, J ¼ 6.3 Hz, 6H of initiated
2
2
2
(
0.5 g). The reaction mixture was allowed to stir at RT for 1
1
3
chain end (CH )CHO) ppm. C NMR (75 MHz, CDCl ) d
3
3
min, after which four drops of a solution of p-TsOH (7.5 mg)
in THF (20 mL) was added. The reaction was stirred at RT
for 24 h. The polymer was purified by precipitation into hex-
anes, the stringy white solid was isolated via vacuum filtra-
tion with a coarse glass frit, and was dried in vacuo for 12 h
2
7
3
05.9, 173.7, 173.4, 172.8, 157.8, 156.2, 129.5, 113.8, 77.4,
2.2, 71.0, 70.7, 69.5, 64.7, 64.5, 64.3, 59.1, 41.6, 37.6, 34.3,
4.1, 28.5, 27.9, 25.7, 24.6, 24.5 ppm.
Self-Assembly Procedure
(
7
ꢀ
166 mg, 91% yield). GPC: M
¼ 60000 Da, M
¼
Approximately 15 mg of polymer was massed into a 5 mL
volumetric flask, and THF was added to the flask until a final
volume of 5 mL was achieved. A 1 mL aliquot of the polymer
solution was transferred to a small vial, and nanopure water
(pH 6, 18 MX cm) was added to the polymer solution at a
rate of 10 mL/h until a total volume of 10 mL was obtained.
The resulting solutions were used subsequently in DLS, TEM,
and AFM studies without further purification, as dialysis
against nanopure water was found to result in degradation
of the graft copolymers.
n, PS
w, PS
1
8500 Da, PDIPS ¼ 1.3. M ( H NMR) ¼ 97800 Da. T ¼ 48
n
m
C.
IR (NaCl) 2950–2800, 1733, 1726, 1465, 1456, 1384, 1357,
ꢃ1
1
342, 1278, 1239, 1193, 1145, 1109, 1064, 961, 842 cm
.
1
H NMR (300 MHz, CDCl ) d 4.33 (t, J ¼ 6.2 Hz, 2H of OPD
3
units, CH
2
OCO), 4.3–4.1 (pair of multiplets, 2H of ketoxime
ether isomers of OPD-g-PEO units, CH
Hz, 2H of CL units, CH OCO), 3.64 (bs, 4H of PEO repeat
2
OCO), 4.05 (t, J ¼ 6.7
2
unit), 3.37 (s, 3H of OCH PEO end group), 2.79 (t, J ¼ 6.6
3
Hz, 2H of OPD units, C(O)CH CH COO), 2.74 (t, J ¼ 6.6 Hz,
2
2
CONCLUSIONS
2
H of OPD units, C(O)CH CH OCO), 2.62–2.50 (2H OPD,
2 2
CH COOCH ; m, 6H of OPD-g-PEO), 2.30 (t, J ¼ 7.4 Hz, 2H of
An efficient strategy for the functionalization of a ketone-
containing polyester, taking advantage of stable ketoxime
ethers with enhanced reaction conditions for their formation,
was employed to yield a functional amphiphilic graft copoly-
mer system, with up to 90% grafting efficiencies. Specifically,
2
2
CL units, CH
2 2 2 2
COOCH ), 1.64 (m, 4H of CL units, OCH CH
and CH CH COO), 1.37 (m, 2H of CL units, CH CH2
2
2
2
CH COO), 1.22 (d, J ¼ 6.3 Hz, 6H of initiated chain end
2
1
3 3
3
(
CH )CHO) ppm. C NMR (75 MHz, CDCl ) d 205.9, 173.7,
COMPLEX, DEGRADABLE POLYESTER MATERIALS, IHA, VAN HORN, AND WOOLEY
3561

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
this methodology was used for the incorporation of both
hydrophilic poly(ethylene oxide) grafts and p-methoxybenzyl
side chains onto the backbone of poly((e-caprolactone)-co-(2-
oxepane-1,5-dione)) allowing for the creation of functional
PCL-g-PEO ketoxime ether conjugates that were shown to be
capable of undergoing self-assembly in aqueous solution.
The graft block copolymer system containing only PEO grafts
formed spherical aggregates in aqueous solution, whereas
the copolymer system with both PEO and p-MeOBn grafts
was found to form rod-like aggregates.
7 Hwang, J.; Li, R. C.; Maynard, H. D. J Controlled Release
2007, 122, 279–286.
8
9
Fulton, D. A. Org Lett 2008, 10, 3291–3294.
Yang, S. K.; Weck, M. Macromolecules 2008, 41, 346–351.
1
0 Barrett, D. G.; Yousaf, M. N. Biomacromolecules 2008, 9,
2
029–2035.
11 Barrett, D. G.; Yousaf, M. N. Macromolecules 2008, 41,
6347–6352.
1
2 Timbart, L.; Amsden, B. G. J Polym Sci Part A: Polym Chem
2
008, 46, 8191–8199.
The ability to form a variety of self-assembled architectures
based on the degree of PEO grafting or the incorporation of
small molecule side chains onto a PCL backbone is a power-
ful tool for the efficient synthesis of well-defined multifunc-
tional degradable materials. Consequently, it is of great im-
portance to continue to explore the chemistries involving the
grafting of polymer chains and small molecule ligands onto
P(CL-co-OPD) copolymers since this system provides a mod-
ular platform for the creation of a variety of complex hydro-
lytically degradable nanostructures. Efforts to better under-
stand the way in which the density of PEO grafts and the
incorporation of small, hydrophobic side chains affects the
self-assembly process are also currently under investigation.
Because of the potential of this copolymer system, we con-
tinue to extend this work through the incorporation of other
functional grafts—including chromophores for imaging and
ligands for tissue-selective targeting—for the creation of
more complex polyester nanoobjects.
1
3 J e´ r oˆ me, C.; Lecomte, P. Adv Drug Delivery Rev 2008, 60,
1056–1076.
4 Takizawa, K.; Nulwala, H.; Hu, J.; Yoshinaga, K.;
Hawker, C. J. Polym Sci Part A: Polym Chem 2008,
1
J
4
6, 5977–5990.
1
5 Odelius, K.; Albertsson, A.-C. J Polym Sci Part A: Polym
Chem 2008, 46, 1249–1264.
16 H o¨ glund, A.; Albertsson, A.-C. J Polym Sci Part A: Polym
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This material is based on work supported, in part, by the
National Science Foundation under Grant Nos. DMR-0451490
and DMR-0906815, by the Department of Energy under
Grant No. DE-FG02-08ER64671, and by the National Heart
Lung and Blood Institute of the National Institutes of Health
as a Program of Excellence in Nanotechnology (HL080729).
Transmission electron microscopy images were obtained, in
part, using the equipment and facilities at Washington Uni-
versity in St. Louis, Department of Otolaryngology, Research
Center for Auditory and Visual Studies funded by NIH P30
DC004665. The authors thank G. Veith (Washington Univer-
sity Electron Microscopy Laboratory) and Yun (Lily) Lin for
assistance with TEM, and Nam S. Lee for assistance with
DLS.
4
617–4629.
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