Functional aliphatic polyesters and nanoparticles prepared by organocatalysis and orthogonal grafting chemistry

Article abstract of DOI:10.1002/pola.26114

We describe the use of organic catalysis for the ring-opening polymerization of functionalized lactones and conversion of the resulting aliphatic polyesters into crosslinked nanoparticles that carry additional functional groups amenable to further modific

Full text of DOI:10.1002/pola.26114

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Functional Aliphatic Polyesters and Nanoparticles Prepared by
Organocatalysis and Orthogonal Grafting Chemistry
Angela L. Silvers, Chia-Chih Chang, Todd Emrick
Department of Polymer Science and Engineering, University of Massachusetts, Conte Center for Polymer Research,
120 Governors Drive, Amherst, Massachusetts 01003
Correspondence to: T. Emrick (E-mail: tsemrick@mail.pse.umass.edu)
Received 29 January 2012; accepted 8 April 2012; published online
DOI: 10.1002/pola.26114
ABSTRACT: We describe the use of organic catalysis for the
ring-opening polymerization of functionalized lactones and
conversion of the resulting aliphatic polyesters into crosslinked
nanoparticles that carry additional functional groups amenable
to further modification. Specifically, highly functional aliphatic
polyester homopolymers, as well as random and block copoly-
mers, were prepared by 1,5,7-triazabicyclo[4.4.0]dec-5-ene ca-
talysis, giving polyesters with pendent alkene and alkyne
groups. Azide-alkyne click and thiol-ene chemistries were used
for postpolymerization modification of diblock copolymers pos-
sessing alkene groups on one block and alkyne groups on the
other block. The polyesters were crosslinked using azide/alkyne
cycloaddition, by reaction of a,x-diazides with the pendent
alkynes on the polyester backbone. This gave polyester nano-
particles possessing alkene functionality, which were subjected
to further modification using thiol-ene reactions to introduce
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additional functionality. 2012 Wiley Periodicals, Inc. J Polym
Sci Part A: Polym Chem 000: 000–000, 2012
KEYWORDS: click chemistry; CuAAC; diblock copolymers; functional
polyesters; nanoparticles; organocatalyst; polyesters; ring-opening
polymerization; thiol-ene; 1,5,7-triazabicyclo[4.4.0]dec-5-ene
INTRODUCTION Aliphatic polyesters are recognized for their
useful combination of biocompatibility and biodegradability
and, therefore, present new opportunities in applications
ranging from drug delivery to implant materials to degrad-
able plastics. In recent years, aliphatic polyesters have
become especially interesting when chemical functionality is
introduced that distinguishes novel structures from conven-
tional forms. For example, functionalization of aliphatic poly-
esters can afford hydrophilic and water soluble derivatives
of conventional poly(lactide) and poly(e-caprolactone). When
pendent functionality is introduced in a controlled manner,
synthetic handles become available for subsequent attach-
ment of solubilizing groups, drugs, targeting groups, and flu-
orophores. However, as aliphatic polyesters are subject to
ester bond degradation during chemical transformations,
there is a pressing need for efficient reactions that proceed
effectively but do not cause significant backbone
degradation.
and used copper(I)-catalyzed azide-alkyne cycloaddition
(CuAAC; ‘‘click chemistry’’) on the resulting alkyne-substi-
tuted polyesters, giving access to efficient attachment of
phosphorylcholine (PC) groups,5 poly(ethylene glycol) (PEG)
and oligopeptides,6 and the oncology drug camptothecin.7
Hawker and coworkers8 recognized the utility of thiol-ene
coupling for postpolymerization reactions on alkene-func-
tionalized polyesters, whereas Harth and coworkers9
recently described the conversion of functionalized aliphatic
polyesters into crosslinked polyester nanoparticles.
Traditionally, aliphatic polyesters have been prepared by
ring-opening polymerization (ROP) of cyclic esters using
metal catalysts, such as tin and aluminum salts. However,
recent success in catalyst development has uncovered small
organic molecules as appealing alternatives to metallic cata-
lysts, including, for example, 4-(dimethylamino)pyridine
(DMAP),10 N-heterocyclic carbenes,11 and 1,5,7-triazabicy-
clo[4.4.0]dec-5-ene (TBD).12 These compounds catalyze the
ROP of lactones and lactides, offering the benefits of fast po-
lymerization kinetics and low polydispersity index (PDI)
products in a metal-free environment at ambient temperature.
However, to date we are not aware of reports using organic
catalysts, such as TBD which we have chosen for this study, to
polymerize functional lactones, though we note they have
been recently used to polymerize functional lactides.13
A number of elegant methodologies have been reported to
give functional aliphatic polyesters. Early on, Jerome,1
Hedrick,2 and others3 prepared several examples, such as
through Baeyer–Villager oxidation of 2-allyl-cyclohexanone to
give an allyl-functionalized e-caprolactone,4 from which
numerous polyester derivatives were prepared. We later pre-
pared and polymerized a-propargyl-d-valerolactone (PgVL),
Additional Supporting Information may be found in the online version of this article.
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FIGURE 1 Structures of functional lactones 1–4 (AVL 1, PgVL 2, TMS-PgVL 3, and PgCL 4) used in TBD-catalyzed ROP, and diblock
polyesters 5 and 6 formed from their polymerization.
We previously demonstrated the preparation of aliphatic
polyester diblock copolymers that differentiated click cyclo-
addition between the two blocks by placing alkyne groups
on one block and trimethylsilyl-protected alkyne groups on
the other block.14 A click-deprotection-click sequence gave a
novel set of diblock structures, bearing different pendent
groups on each block. Here, we report a simple route to
highly functional polyester-based diblock copolymers, with
alkyne groups on one block and alkene groups on the other.
These structures are amenable to orthogonal azide-alkyne
and thiol-ene coupling, without the need for protection/
deprotection steps. Although prior work has explored end-
group orthogonality of azide-alkyne and thiol-ene click reac-
tions8 and orthogonal surface-modification of SiO2 nano-
spheres,15 to our knowledge this is the first example of a
diblock polyester possessing differentiated blocks by exploit-
ing the distinct azide-alkyne and thiol-ene reactions. More-
over, this work demonstrates the ready adaptability of
organic catalysis to these functional lactones, further extend-
ing their utility in polymer synthesis. In addition, these
polyesters gave access to crosslinked nanoparticles, using
the alkyne-containing block for crosslinking, and leaving the
alkene-containing block for subsequent nanoparticle
modification.
added by syringe, and the reaction mixture was stirred at
room temperature until monomer conversion reached 70–
80%, as judged by H NMR spectroscopy (we note that incu-
1
bation of the benzyl alcohol/TBD solution was required for
successful polymerization). Polymerizations were conducted
at 2 M monomer concentration in toluene, using 2 mol %
TBD relative to monomer, and monomer-to-initiator ratios
([M]0/[I]0) of ꢀ140. Catalyst loadings of 2 mol % (relative to
monomer) were needed to polymerize each of the alkene
and alkyne-functionalized monomers 1–4, about four times
that needed for unsubstituted d-VL and e-CL.12 The polymer
products were isolated by precipitation into cold methanol,
typically in ꢀ85% yield. Attempts to achieve higher mono-
mer conversion using longer reaction time led to higher PDI
values, especially for monomer 2, presumably due to trans-
esterification at depleted monomer concentration.
Homopolymers formed from the functional lactones 1, 2, and
4 were colorless oils, whereas TMS-PgVL 3 was an off-white
powder; incorporation of significant amounts of d-VL and e-
CL as comonomers gave solid polymer products in all
cases.10 The TBD-catalyzed polymerizations of functional
lactones 1–4 proceeded much more rapidly than analogous
polymerizations using Sn(Oct)2-mediated catalysis: TBD gave
high monomer conversion in minutes to <2 h, whereas the
tin-mediated polymerizations required 24 h or more.
RESULTS AND DISCUSSION
Table 1 summarizes polymerization conditions and charac-
terization data for the isolated aliphatic polyesters. Molecular
weights derived from 1H NMR spectra of the polymers (by
end-group analysis) were found to be in close agreement
with, or slightly lower than, gel permeation chromatography
(GPC)-estimated values obtained by eluting in THF (cali-
brated with polystyrene standards). End-group analysis inte-
grated phenyl protons of the initiator (7.32 ppm) against
pendent alkyne (2.05 ppm) or alkene (5.04 and 5.70 ppm)
protons. By allowing the polymerizations to reach ꢀ70–85%
conversion, homopolymers with molecular weights ranging
from 12 to 15 kDa, with PDI values of ꢀ1.1–1.2, were
obtained, as given in Entries 1–6 of Table 1.
Figure 1 shows the structures of lactone monomers 1–4
used in this study, specifically a-allyl-d-valerolactone (AVL,
1), a-propargyl-d-valerolactone (PgVL, 2), TMS-protected
PgVL (TMS-PgVL, 3), and a-propargyl-e-caprolactone (PgCL,
4). The diblock copolymers p(AVL-b-PgVL) (5) and p[(TMS-
PgVL)-b-PgVL] (6) are also shown.
TBD-Catalyzed Polymerization of Functional
Lactones 1–4
Lactones 1–4 were synthesized as reported previ-
ously6,14,16,17 and tested in homopolymerization reactions
using TBD catalysis. The polymerizations were conducted in
flame-dried Schlenk flasks, using benzyl alcohol as initiator
and a toluene solution of TBD. The benzyl alcohol/TBD mix-
ture was stirred for ꢀ30 min, after which monomer was
We wanted to investigate the polymerization kinetics of
functional monomers 1–4 relative to conventional (unsubsti-
2
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TABLE 1 Results of Lactone Polymerizations Using 2 mol % TBD with Respect to Monomera
d
b
Time
(min)
Conv
(%)b
Mn
Mtheor
MNMR
Feed
Ratio
Entry
Polymer
(g molꢂ1 c
)
PDIc
(g molꢂ1
)
(g molꢂ1
)
Compb
1
2
3
4
5
6
7
8
9
10
a
pAVL
46
15
85
86
85
88
76
71
87
56
73
85
15,300
14,400
13,700
12,000
15,000
15,500
29,000
19,000
12,500
13,100
e
1.04
1.12
1.09
1.03
1.23
1.11
1.03
1.07
1.07
1.17
16,000
16,600
25,000
19,000
12,000
10,000
28,700
27,000
14,900
13,000
15,500
16,000
17,400
8,800
–
–
pPgVL
–
–
p(TMS-PgVL)
pPgCL
20
–
–
120
180
5
40/20f
20/20f
90/45f
23
–
–
pCL
11,700
11,000
21,000
22,000
14,800
8,800
–
–
pVL
–
–
p(AVL-b-PgVL)e
p[(TMS-PgVL)-b- PgVL]g
p(PgCL-b-AVL)h
p(PgVL-co-VL)i
50/50
50/50
50/50
60/40
51/49
55/45
50/50
65/35
Polymerizations used 2 mol % TBD relative to monomer, 2 M mono-
2 mol % TBD relative to first monomer reacted, AVL.
Reaction time of first/second monomer.
f
mer concentration, and [M]0/[I]0 ¼ 140.
b
g
h
i
Relative monomer compositions determined by 1H NMR
2 mol % TBD relative to first monomer reacted, TMS-PgVL.
2 mol % TBD relative to first monomer reacted, PgCL.
2 mol % TBD relative to total monomer (PgVL þ VL).
spectroscopy.
c
Measured by GPC in THF relative to polystyrene standards.
d
Calculated from monomer molecular weight, [M]0/[I]0, and percent
conversion.
tuted) versions. Thus, the rates of these TBD-catalyzed poly-
merizations were examined and are reported in Table 2 as
apparent rate constant (Kapp) values for each the monomer.
Aliquots were withdrawn during the course of the polymer-
ization, quenched with a benzoic acid solution in CDCl3, and
analyzed by 1H NMR spectroscopy. Monomer concentrations
(conversions) at given time points were determined from the
methylene proton resonance of the lactone at 4.28 ppm, rela-
tive to the same protons in ring-opened (polymer) product
at 4.03 ppm. Rate constants were approximated by first-
order kinetics using:
version, and Kapp is obtained from the slope of the plot of
[ln(1/1 ꢂ p)] versus time.
Among functional monomers 1–4, allyl-substituted AVL 1
(Kapp
¼
0.037) exhibited the slowest polymerization,
whereas the other lactones polymerized similarly, with Kapp
values determined experimentally for d-VL (0.258), PgVL 2
(0.274), and TMS-PgVL 3 (0.274). Interestingly, all of the
substituted d-valerolactones polymerized faster than e-CL
using TBD, in contrast to that observed with Sn(oct)2-medi-
ated polymerization of the same monomers.6,14,17–19 Each po-
lymerization showed a linear dependence of molecular weight
on conversion, as seen in Figure 2 for PgCL 4 (others given in
the Supporting Information), indicative of good control over
the ring-opening and chain growth process using TBD cataly-
sis in conjunction with these functionalized lactones.
lnð½Mꢁ0=½MꢁÞ ¼ kK½TBDꢁ0½ROHꢁ0t ¼ Kapp
t
where [M]0 is the initial monomer concentration, [M] is
monomer concentration at time t, k is the polymerization
rate constant, K is the equilibrium constant for the formation
of a TBD/ROH/M complex at zero percent monomer conver-
sion,12 and [TBD]0 and [ROH]0 are the initial concentrations
of catalyst and benzyl alcohol, respectively. [M]0/[M] is
equivalent to 1/(1 ꢂ p), where p represents monomer con-
Copolymer Synthesis
TBD-catalyzed polymerization of functional lactones 1–4 also
allowed excellent control over the formation of copolymers,
TABLE 2 Measured Kapp for VL, CL, AVL (1), PgVL (2),
(TMS-PgVL) (3), and PgCL (4)
Monomer
Kapp
VL
0.258
CL
0.0064
0.0374
0.274
AVL
PgVL
TMS-PgVL
PgCL
0.274
0.0105
FIGURE 2 Increase in number-average molecular weight (Mn;
y-axis) with monomer conversion (x-axis) in the polymerization
of PgCL (4).
[M]0/[I] ¼ 140 at 2 mol% TBD relative to monomer; [M]0 ¼ 2 M in
toluene.
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FIGURE 3 Representative GPC traces of (a) p(AVL-b-PgVL) synthesized by one-pot sequential addition of monomers, (b) p(AVL-b-
PgVL) synthesized by the ‘‘macroinitiator’’ method, and (c) p(PgCL-b-AVL) synthesized by one-pot sequential addition of
monomers.
including diblock copolymer structures. For example, the
diblock copolyester p(AVL-b-PgVL) 5, possessing pendent
alkene (A) and alkyne (propargyl, Pg) groups, was prepared
by sequential monomer addition. AVL 1 was added to a pre-
incubated benzyl alcohol/TBD solution and stirred for 40
min to reach ꢀ80% conversion; PgVL was then added, and
the mixture was stirred for an additional 20 min. The poly-
mer product was isolated by precipitation into cold metha-
nol. GPC traces of the first block (pAVL) and the final diblock
copolymer showed clear evidence of chain extension [Fig.
3(a)]. The relative monomer composition in the copolymer
correlated closely to the feed ratio, as determined by 1H
NMR spectroscopy, integrating alkene (5.04 and 5.70 ppm)
and alkyne (2.01 ppm) proton resonances against the back-
bone methylene group adjacent to the oxygen [4.03 ppm;
Fig. 4(a)]. Evidence to support the desired diblock copolymer
architecture was given by 13C NMR spectroscopy, which
showed two distinct peaks in the carbonyl region at 175.2
ppm (AVL block) and 173.8 ppm (PgVL block), whereas the
random copolymer p(PgVL-co-VL) showed multiple peaks for
each of the carbonyl resonances centered at 173.7 (PgVL)
and 172.7 (VL) ppm [Fig. 4(b,c)]. The GPC trace of p(AVL-b-
FIGURE 4 (a) 1H NMR spectrum of p(AVL-b-PgVL); (b,c) carbonyl resonances of the 13C NMR spectra for (b) p(AVL-b-PgVL) and (c)
p(PgVL-co-VL).
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PgVL) was monomodal with low polydispersity (1.03) [Fig.
3(a)], indicating the ability of TBD to maintain a well-con-
trolled polymerization. We note some instances where a
slight low molecular weight shoulder (or molecular weight
broadening) was observed, indicative of incomplete initiation
of the second block (Supporting Information).
20 min at room temperature, and isolating the copolymer by
precipitation into cold methanol. The feed ratio was reflected
in the final composition, as observed by 1H NMR (Table 1).
1H NMR analysis of aliquots removed during the course of
the polymerization showed that the amount of incorporated
PgVL remained constant throughout the polymerization,
rather than significantly favoring initial incorporation of ei-
ther monomer. 13C NMR spectroscopy suggested the forma-
tion of a random copolymer structure, with multiple peaks
for each carbonyl resonance [centered at 172.7 ppm for the
PgVL block and 173.7 ppm for the VL block; Fig. 4(c)]. These
copolymers, obtained in ꢀ85% yield, are colorless oils at
50% PgVL content; they appear waxy at lower PgVL incorpo-
ration (10–30%) and are white solids at low PgVL content
where fewer pendent groups are available to interrupt poly-
ester solidification/crystallization.
To prepare p[(TMS-PgVL)-b-PgVL] (6), TMS-PgVL was added
to an incubated benzyl alcohol/TBD solution and stirred for
20 min. PgVL was then added, the reaction mixture was
stirred for 20 min, and the polymer recovered by precipita-
tion into cold methanol. The relative monomer composition
of the isolated diblock copolymer was determined by 1H
NMR spectroscopy, by integrating the terminal alkyne proton
signal (2.01 ppm) against the backbone methylene (4.03
ppm) and trimethylsilyl (0.11 ppm) protons. For both p(AVL-
b-PgVL) and p[(TMS-PgVL)-b-PgVL], diblock polyesters with
molecular weights of 20,000–30,000 g molꢂ1 were obtained
with low PDI (ꢀ1.2). Overall, molecular weights determined
by GPC in THF compared closely with theoretical values and
those derived from NMR spectroscopy end-group analysis;
the final monomer compositions observed (51/49 for p(AVL-
b-PgVL) and 55/45 for p[(TMS-PgVL)-b-PgVL]) closely
reflected the feed ratios.
The successful random copolymerization of VL with PgVL
stems from similar propagation rates of the two monomers
in the presence of TBD. As AVL homopolymerization pro-
ceeds much slower than VL and PgCL, we examined the pos-
sibility of forming diblock polyesters in a simultaneous, one-
pot copolymerization of these monomers. Copolymerization
of VL with AVL, and PgCL with AVL, was performed by intro-
ducing a 1:1 molar ratio of the monomers to a previously
incubated benzyl alcohol/TBD solution. However, random
or gradient copolymers were obtained, as indicated by the
appearance of multiple carbonyl peaks in the 13C NMR
spectra (as opposed to the two distinct carbonyl resonan-
ces in the diblock structures). Monitoring polymer compo-
sition during the course of the polymerization, by 1H NMR
spectroscopy on withdrawn aliquots, suggested a gradient
copolymer formation. Lactones with faster apparent rates
of homopolymerization (VL over AVL and AVL over PgCL)
were incorporated preferentially into the polymer back-
bone at the early time-frame of the polymerization. Upon
depletion of the faster polymerizing monomer, the amount
of incorporated comonomer increased until the final
observed polymer composition reflected the monomer feed
ratio.
The diblock copolymer p(AVL-b-PgVL) was also prepared
using a ‘‘macroinitiator’’ method, by isolating the homopoly-
mer of the first block (pAVL) by column chromatography for
subsequent initiation of PgVL. The pAVL macroinitiator was
incubated in solution with TBD for 15 min; then, PgVL was
added, and the resulting mixture stirred for 20 min. The iso-
lated p(AVL-b-PgVL) copolymer showed two distinct peaks
in the carbonyl region of the 13C NMR spectrum (175.2 and
173.8 ppm), and the molecular weight obtained by GPC in
THF (Mn ¼ 29,000) matched closely to the theoretical (Mtheor
¼ 28,700) and NMR (MNMR ¼ 21,000) derived values. How-
ever, the presence of a low molecular weight shoulder in the
GPC trace [Fig. 3(b)] suggests that the one pot sequential
addition method [Fig. 3(a)] is preferable, at least in this case,
over the macroinitiator approach.
Functionalized caprolactone PgCL 4 was also used for
diblock copolymer preparation by one pot sequential addi-
tion. For example, after benzyl alcohol/TBD incubation, PgCL
was added and stirred for 90 min; then, AVL was added, and
the reaction mixture stirred for another 45 min. The final
polymer contained 50% AVL, which correlated well with the
feed ratio, and had a molecular weight of 12,500 g molꢂ1
(by GPC in THF), closely matching the theoretical (14,900)
and NMR-derived (14,800) molecular weights. The 13C NMR
spectrum of the final polymer confirmed diblock copolymer
formation, showing two distinct carbonyl resonances (175.2
ppm for the AVL block and 174.2 ppm for the PgCL block).
The GPC trace was monomodal with narrow PDI [1.07;
Fig. 3(c)].
Taken together, the polymerization results described above
confirm the capability of TBD as an organic catalyst to poly-
merize lactones carrying functional groups a to the carbonyl
group, giving homopolymer and copolymer materials effi-
ciently, with little interruption from transesterification, as
indicated by low PDI values (ꢀ1.2) obtained up to relatively
high monomer conversion (ꢀ85%). With these polymers in
hand, we then examined the utility of p(AVL-b-PgVL) in
nanoparticle formation and subsequent modification using
CuAAC and thiol-ene reactions.
Polyester Nanoparticle Formation
The orthogonal nature of thiol-ene and CuAAC reactions was
implemented to prepare functional nanoparticles from
p(AVL-b-PgVL), bearing one block of pendent alkenes and
one block of pendent alkynes. Crosslinking of the alkyne-con-
taining PgVL block was accomplished in dilute solution, with
Random copolymers from these functionalized lactones were
also prepared using TBD catalysis. For example, p(PgVL-co-
VL) was prepared by adding PgVL and d-VL simultaneously
to an incubated benzyl alcohol/TBD solution, stirring for
1,8-diazido-3,6-dioxaoctane (prepared according to
a
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FIGURE 5 Crosslinked nanoparticles obtained by CuAAC of p(AVL-b-PgVL) (5) with 1,8-diazido-3,6-dioxaoctane and subsequent
thiol-ene reactions using thiols 7–9.
published procedure19
)
in
a
1:1 azide-to-alkyne ratio
tration giving larger particles at a constant alkyne-to-cross-
linker ratio of 2:1. At alkyne concentrations of 3.6, 54, and
215 mM, the crosslinked nanoparticles obtained had average
hydrodynamic diameters of 13 6 0.5, 18 6 1, and 41 6
0.8 nm, respectively. As expected, higher alkyne (and thus
polymer) concentration increases the extent of interchain
coupling, resulting in larger nanostructures.
(Fig. 5). For nanoparticle formation and CuAAC crosslinking,
p(AVL-b-PgVL) was dissolved in degassed CH2Cl2 and stirred
with 1,8-diazido-3,6-dioxane, copper(I) bromide (1.0 equiv
with respect to alkyne) and N,N,N0,N0,N00-pentamethyldiethy-
lenetriamine (PMDETA; 2.0 equiv with respect to alkyne) at
room temperature overnight. Nanoparticle size was con-
trolled by varying the alkyne concentration during the
CuAAC reaction (while the alkyne-to-azide ratio was kept
constant). Three concentrations of alkyne were used:
[3.6 mM], [54 mM], and [215 mM].
Crosslinked p(AVL-b-PgVL) nanoparticles were characterized
further by TEM (staining with phosphotungstic acid, PTA) to
give additional evidence supporting the presence of discrete
polyester nanostructures. TEM samples were prepared by
drop-casting a CH2Cl2 solution of nanoparticles onto a TEM
grid. Figure 7(a) shows spherical nanoparticles, about 10–20
nm diameter, formed from crosslinked p(AVL-b-PgVL) (0.36
mg mLꢂ1), correlating closely to the DLS-derived size. This
image also shows a worm-like connectivity, in which many
of the particles appear to merge into a continuous structure.
This feature is most likely a concentration effect, though the
potential influence of the staining reagent has not been ruled
out. In contrast to Figure 7(a), the TEM image of Figure
7(b), from a 0.18 mg mLꢂ1 solution of nanoparticles, showed
a less-extensive network due to the lower concentration
used. Nanoparticles modified with dodecanethiol [Fig. 7(c)],
exhibited no propensity to form networks, and by TEM were
seen as discrete structures. Furthermore, AFM images of
Nanoparticle Characterization
The crosslinked polyester nanoparticles were characterized
by 1H NMR spectroscopy, transmission electron microscopy
(TEM), and dynamic light scattering (DLS). Nanoparticle for-
mation was monitored by 1H NMR spectroscopy, noting the
disappearance of the terminal alkyne protons (2.01 ppm)
and differentiation of peaks b and c (methine protons, Fig.
6) after diazide crosslinking of the PgVL block. We noticed
that the polyester resonances corresponding to the cross-
linked block (2.6–3.0 ppm) appeared broader than the sig-
nals representing the alkene-functional block (2.1–2.4 ppm),
a likely consequence of their constrained conformation in so-
lution when crosslinked; the alkene peaks themselves were
unchanged (5.04 and 5.70 ppm; Fig. 6).
unstained nanoparticles (0.36 mg mLꢂ1
, drop cast in
DLS measurements of these polyester nanoparticles in
CH2Cl2 indicated that nanoparticle size was controllable by
varying the alkyne concentration, with higher alkyne concen-
dichloromethane onto a silicon wafer) revealed roughly
spherical nanoparticles (ꢀ60 nm diameter) and no worm-
like networks [Fig. 7(d)]. Nanoparticle diameter determined
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FIGURE 6 1H NMR spectrum of polyester nanoparticles obtained following click cycloaddition/crosslinking of p(AVL-b-PgVL) 5
with 1,8-diazide-3,6-dioxaoctane.
by AFM (60-nm diameter, 4-nm height) is larger than that
observed by DLS (10–20 nm), which can be explained by a
flattening of the structures on the substrate for these
measurements.
The CuAAC crosslinking of p(AVL-b-PgVL) 5 yields polyester
nanoparticles possessing available alkene groups. To examine
the accessibility of the alkenes following crosslinking, a
range of thiols (shown in Fig. 5) was tested for nanoparticle
FIGURE 7 TEM images of crosslinked nanoparticles formed from (a) p(AVL-b-PgVL), 0.36 mg mLꢂ1; (b) p(AVL-b-PgVL), 0.18 mg
mLꢂ1; (c) p(AVL-b-PgVL), and subsequently modified by dodecanethiol, 0.36 mg mLꢂ1; and (d) AFM image of crosslinked nanopar-
ticles formed from p(AVL-b-PgVL), 0.36 mg mLꢂ1
.
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FIGURE 8 Schematic representation showing diblock polyesters differentiated using simultaneous thiol-ene/thiol-yne reactions
[p(AVL-b-PgVL) 5], or modified using sequential azide/alkyne and thiol-ene click chemistries orthogonally [p(PgCL-b-AVL)], yielding
distinct diblock copolymers in both cases.
functionalization by thiol-ene coupling. We chose dodecane-
thiol 7 as a simple hydrophobic thiol, PC-terminated thiol
(PC-thiol) 8 as a hydrophilic example, and rhodamaine thiol
9 as a fluorescent example. Both thermal and photoinitiated
thiol-ene conditions8 were tested. For dodecanethiol modifi-
cation, 2,20-azobisisobutyronitrile (AIBN; 0.5 equiv with
respect to alkene) and p(AVL-b-PgVL) 5 with dodecanethiol
(5.0 equiv) were stirred in degassed DMF at 80 ꢃC for sev-
eral hours, and the dodecane-modified nanoparticles were
isolated by dialysis against CH2Cl2. 1H NMR spectroscopy of
the resulting nanoparticles showed no vinyl signals, indicat-
ing efficient alkene-to-dodecyl conversion. DLS measure-
ments indicated an increase in nanoparticle size from 10 to
19 nm following dodecanethiol grafting. The thiol-ene reac-
tions using PC-thiol 8 and rhodamine thiol 9 used 2,2-dime-
thoxy-2-phenylacetophenone (DMPA) as photoinitiator in
degassed DMF (or DMF/MeOH in the case of PC-thiol graft-
ing), with stirring at room temperature under a UVP Black
Ray UV lamp emitting at ꢀ365 nm. 1H NMR spectroscopy
showed loss of alkene and the appearance of signals stem-
ming from the PC (from 2.9 to 4.2 ppm) or the rhodamine
(from 6.2 to 7.9 ppm) moiety. DLS measurements indicated
an increase in nanoparticle size following these grafting reac-
tions, from 10 to 69 nm upon PC-thiol addition and from 11
to 23 nm with the addition of rhodamine-thiol. Whereas the
polyester nanoparticles possessing unreacted alkenes were
soluble only in organic solvents, such as CH2Cl2 (and not in
methanol), the PC-modified nanoparticles were not soluble
in CH2Cl2, and therefore, they are isolated by dialysis in
methanol. PC-grafted nanoparticles were soluble in water
when, as far as could be seen spectroscopically, most or all
of the alkenes were converted to PC groups. The larger sizes
observed with PC-grafted nanoparticles are likely due to
swelling in the solvent (methanol) used for DLS-characteriza-
tion of these structures.
Thiol-ene/yne Functionalization of p(AVL-b-PgVL)
Alkene-/alkyne-substituted diblock polyester copolymers
also proved useful as precursors to highly functional polyest-
ers, using (1) simultaneous (one-step) thiol-ene/yne grafting
chemistry and (2) thiol-ene and CuAAC reactions performed
in two steps. Thiol-ene/yne functionalization of p(AVL-b-
PgVL) 5 provides a mechanism for grafting along the polyes-
ter backbone to afford polymer structures with twice the
grafting density on the alkyne block (introducing 2 thiols
per alkyne) relative to the alkene block [Fig. 8(a)]. To exam-
ine simultaneous thiol-ene/yne functionalization, p(AVL-b-
PgVL) 5 was subjected to thermal thiol-ene reaction condi-
tions with dodecanethiol 7 (5.0 equiv relative to total
alkene/alkyne) and AIBN (0.5 equiv) in degassed DMF at 80
ꢃC. After 3 h, a high conversion was indicated by complete
disappearance of both the alkene (5.04 and 5.70 ppm) and
1
the alkyne (2.01 ppm) proton peaks in the H NMR spectrum,
and GPC analysis of the final polymer indicated an increase in
molecular weight (Mn; from 13,900 to 22,800 g molꢂ1),
although narrow PDI values (1.1–1.3) were maintained.
The orthogonality of CuAAC and thiol-ene chemistries was
demonstrated for p(PgCL-b-AVL), using a,x-PEG-750-mono-
methyl ether azide (m-PEG750-N3) and dodecanethiol 7 in se-
quential grafting reactions to yield amphiphilic block copo-
lyesters [Fig. 8(b)], with the azide/alkyne reaction
performed first to prevent the unwanted radical thiol-yne
chemistry. CuAAC coupling of a-methoxy-x-azido PEG (PEG-
azide)16 with the diblock precursor was performed first in a
water/THF (1:4) mixture using copper(II) sulfate and so-
dium ascorbate and stirring the reaction for 15 h at 80 ꢃC.
Excess m-PEG750-N3 was removed by dialysis, and trace cop-
per was removed using CuprisorbTM, giving the PEGylated
polyester as a hygroscopic solid in 90% yield after lyopholi-
zation. Triazole and PEG protons were observed in the 1H
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NMR spectrum, and the allyl group remained intact as sup-
ported by the unchanged integration ratio between the
alkene protons at 5.04 and 5.70 ppm, and the oxymethylene
protons of the polymer backbone at 4.00 ppm. The disap-
pearance of the terminal alkyne peak at 2.05 ppm indicated
complete consumption of alkyne. Furthermore, the 13C NMR
spectrum showed the appearance of the triazole carbons at
144.94 and 122.70 ppm, as well as the methylene carbons
connecting the triazole to PEG (69.6 and 50.1 ppm). An
increase in molecular weight (Mn) was observed by GPC
(from 12,500 to 24,800 g molꢂ1), with significant deviation
from the theoretical molecular weight of 56,000 g molꢂ1
explained by the extensive branching (grafting) of the struc-
ture. The PDI value of the final polymer remained low
(ꢀ1.1) owing to the mild CuAAC conditions that allow func-
tionalization in the absence of substantial polyester degrada-
tion. Typically, trace amounts m-PEG750-N3 remained follow-
ing the initial purification (by dialysis or precipitation), as
seen by the presence of a small peak at long retention time by
GPC (Supporting Information). Dodecanethiol was then
attached to the PEGylated polyester by thiol-ene grafting using
DMPA as photoinitiator. PEGylated p(AVL-b-PgVL) was dis-
solved in a DMF solution containing dodecanethiol 7 and
DMPA, and the solution was degassed by three freeze–pump–
thaw cycles, then irradiated at 365 nm for 8 h. The product
was collected by precipitation into cold hexane and obtained
as a slightly yellow, waxy solid in 80% yield. High alkene con-
minopropyl)carbodiimide hydrochloride (EDC; >98%),
DMAP (99%), sodium azide (98%), rhodamine B (dye con-
tent ꢀ95%), 3-bromopropylamine hydrobromide (98%), po-
tassium thioacetate (>98%), dimethylamine (40 wt % solu-
tion in water), 1-dodecanethiol (ꢄ98%), 11-bromoundecanol
(ꢀ98%), DMPA (99%), trimethylamine (99%), triethylamine
(>99%), AIBN (98%), and PTA were purchased from Sigma–
Aldrich. d-Valerolactone (99%) was purchased from Acros
Organics. Copper(II) sulfate pentahydrate (99.6%) was pur-
chased from Fisher Scientific. Ethylene chlorophosphate
(95%) was purchased from Alpha Aesar and distilled prior
R
to use. Dialysis tubing (Spectra/PorV Membrane molecular
weight cutoff, MWCO ¼ 6000–8000) was purchased from
VWR International. Carbon-coated copper grids were pur-
chased from Electron Microscopy Sciences. Sodium ascorbate
(Source Naturals) and CuprisorbTM (Marine Depot) were
used as received. d-Valerolactone, benzyl alcohol, triethyl-
amine, and methylene chloride were dried and distilled over
calcium hydride. THF and toluene were distilled over so-
dium/benzophenone ketyl. AIBN was recrystallized from
methanol. All other materials were used without further pu-
rification. PEG-azide was synthesized using
procedure.6
a literature
Instrumentation
NMR spectra were recorded using a Bruker DPX300 or
Bruker Avance400 spectrometer with the residual solvent
signal as calibration. Molecular weight and PDI values were
determined by GPC, eluting in THF, and estimated relative to
polystyrene standards [from Scientific Polymer Products;
peak-average molecular weight (Mp) 503, 700, 1306, 2300,
4760, 12,400, 196,700, and 556,000 g molꢂ1]. The GPC was
equipped with a three-column set (Polymer Laboratories
300 ꢅ 7.5 mm, 2 Mixed-D, 50 Å) and a refractive-index de-
tector (Waters R4010); or with three PL Gel 5 lm MIXED-D
300 ꢅ 7.5 mm2 columns and a multiangle light scattering
detector (DAWN EOS), viscometer (Viscostar), and refractive
index detector (Optilab rEX) with a flow rate of 0.75 mL
minꢂ1. UV/vis absorbance was recorded on a Perkin-Elmer
Lambda 25 UV/vis spectrometer. IR data was recorded on a
Perkin-Elmer Spectrum One FTIR spectrometer equipped
with a universal attenuated total reflection sampling acces-
sory. AFM imaging was carried out in air with the tapping
mode using a Nanoscope III Dimension 3000 microscope
(Veeco Digital Instruments) with silicon probe cantilevers.
DLS measurements were made using a Nano-ZS instrument,
model ZEN3600 (Malvern Instruments, UK). TEM was per-
formed on a JEOL 2000 FX MARK II 200 keV microscope.
1
version was achieved, as seen by H NMR spectroscopy, noting
the disappearance of the vinyl peaks at 5.04 and 5.70 ppm.
The 13C NMR spectrum further supported the absence of ole-
fin in the product. The originally overlapping carbonyl signals
of PEGylated p(AVL-b-PgVL) became two distinct peaks, in
accord with the block structure derived from the parent copo-
lyester, and characterization by GPC revealed an increase in
molecular weight (Mn; from 24,800 to 29,000 g molꢂ1).
In summary, we demonstrated ready synthetic access to highly
functional aliphatic polyesters and the efficient modification of
these structures using orthogonal CuAAC and thiol-ene chem-
istries. TBD-catalyzed ROP of alkene- and alkyne-substituted
lactone monomers proved useful for the preparation of the
corresponding aliphatic polyesters in excellent yield and with
low PDI. Diblock copolymers prepared in this way were suita-
ble for orthogonal chemistries, crosslinking the polymers by
CuAAC to give polyester nanoparticulate materials that were
amenable to further functionalization by thiol-ene chemistry.
Functionalities ranging from hydrophilic solubilizing groups to
fluorescent moieties were introduced successfully to the nano-
particles, showing the modular nature of this approach. Taken
together, this work opens new routes to functional, biodegrad-
able polyesters of interest for tailored delivery and controlled
release applications, and that considerably extend the tool box
of structures available for such applications.
TEM Images
TEM images were obtained using a JEOL 2000FX microscope
operating at an accelerating voltage of 200 keV. Polymer sol-
utions (0.5 mg in 1 mL of 2-propanol and 0.4 mL of acetoni-
trile) were mixed with five drops of 3 wt% PTA solution in
2-propanol for a negative stain and sonicated for 5 min.
Samples were prepared by slowly dipping the carbon-coated
copper grid into the polymer solution three times and drying
at room temperature.
EXPERIMENTAL
Materials
Benzyl alcohol, calcium hydride, copper(I) bromide (CuBr,
98%), PMDETA, 99%, TBD (98%), N-ethyl-N0-(3-dimethyla-
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AFM Images
Copolymer Synthesis
Polymer solutions (0.36 mg mLꢂ1) were drop cast onto a sil-
icon surface. AFM images were taken on a Digital Instru-
ments Dimension 3100 microscope operated in tapping
mode using standard silicon nitride probes. Height and
Copolymer syntheses were carried out following a procedure
similar to that for the homopolymers. All polymerizations
were conducted at room temperature under nitrogen, in a
flame-dried two-neck Schlenk flask sealed with a rubber sep-
tum. Benzyl alcohol was added to a TBD solution (0.04 M) in
toluene and stirred for 20 min, at a monomer-to-initiator ra-
tio of 140:1, relative to the first monomer added (in the case
of the diblock copolymers) or to the total number of moles
of monomer (for the random copolymer). For the diblock
copolymers, the monomer with the faster rate of homopoly-
merization was added first and allowed to reach ꢀ80% con-
version; then, the second monomer was added and polymer-
ized to 80% conversion. For the random copolymer
synthesis, the two monomers were added simultaneously. In
all cases, the total monomer concentration was 2 M in tolu-
ene, while the amount of TBD used was 2 mol % relative to
the first monomer added (for diblock copolymers) or to the
total number of moles of monomer (for random copolymers).
Polymerizations were terminated by precipitation into cold
methanol. Residual catalyst and unreacted monomers were
removed from the isolated copolymers by repeated precipita-
tion into cold methanol. Aliquots of the final crude reaction
mixture were characterized before precipitation, as well as
before addition of the second monomer, in the case of the
phase images were taken at scanning speeds of 6 lm sꢂ1
.
DLS Measurements
DLS was performed on
ZEN3600 (Malvern Instruments, UK). Samples were dis-
solved in dichloromethane or methanol and filtered through
a 0.45-lm filter prior to each measurement. Values reported
are size distribution by volume.
a Nano-ZS instrument, model
Monomer Synthesis
Allyl-valerolactone,16 propargyl-valerolactone,6 TMS-pro-
tected propargyl-valerolactone,14 and propargyl-caprolac-
tone17 were synthesized as reported previously.
Homopolymer Synthesis
Polymerizations were carried out at room temperature under
nitrogen in a flame-dried Schlenk flask. Benzyl alcohol was
added to a toluene solution of TBD (0.04 M) and stirred for
30 min prior to introducing monomer at a monomer-to-ini-
tiator ratio of 140:1. The monomer concentration was 2 M in
toluene, while TBD was 2 mol % relative to monomer. Poly-
merizations were terminated by precipitation into cold meth-
anol. Residual catalyst and unreacted monomer were
removed from the isolated polymer by repeated precipitation
into cold methanol. Aliquots of the final crude reaction mix-
tures were obtained just prior to precipitation and quenched
by a 1 M benzoic acid solution in CDCl3, followed by deter-
mination of percent monomer conversion using 1H NMR
spectroscopy.
1
diblock copolymer, to determine percent conversion using H
NMR. Aliquots were quenched using a 1M benzoic acid solu-
tion in CDCl3.
Example Diblock Synthesis: p(AVL-b-PgVL) 5
To a previously incubated solution of benzyl alcohol (5.27
lL, 5.1 ꢅ 10ꢂ2 mmol) and TBD (0.04 M in toluene, 3.58 mL,
0.143 mmol), AVL 1 (1.0 g, 7.14 mmol) was added, and the
reaction mixture was stirred at room temperature, under
nitrogen, for 40 min. An aliquot was taken and quenched
with a 1 M benzoic acid solution in CDCl3. PgVL 2 was added
(0.98 g, 7.1 mmol), and the reaction mixture was stirred at
room temperature for 20 min. The polymerization was then
quenched by precipitation into cold methanol, and p(AVL-b-
PgVL) was isolated as a colorless oil. 1H NMR (CDCl3, 300
MHz): d (CHCl3 ¼ 7.26 ppm), 5.70 (m, 1H, CH2¼¼CH), 5.04
(m, 2H, CH2¼¼CH), 4.08 (m, 4H, CH2OC¼¼O), 2.2–2.6 (br m,
6H, CHC¼¼O þ CH2CBCH þ CH2CH¼¼CH2), 2.05 (s, 1H,
CBCH), 1.66 (m, 8H, CHCH2CH2CH2O AVL þ CHCH2CH2CH2O
PgVL). 13C NMR (CDCl3, 75 MHz): d (CHCl3 ¼ 77.16 ppm)
175.2 (C¼¼OAVL), 173.8 (C¼¼OPgVL), 135.2 (CH¼¼CH2AVL), 117.1
(CH¼¼CH2AVL), 80.9 (CBCHPgVL), 70.3 (CBCHPgVL), 64.1
(CH2OAVL), 64.0 (CH2OPgVL), 44.8 (CHC¼¼OAVL), 44.0
(CHC¼¼OPgVL), 36.5 (CH2CH¼¼CH2AVL), 28.1 (CH2CH2CH2AVL),
Example Homopolymer Synthesis: pVL
To a previously incubated solution of benzyl alcohol (5.5 lL,
5.31 ꢅ 10ꢂ2 mmol) and TBD (0.04 M in toluene, 3.7 mL,
0.148 mmol), VL (0.69 mL, 7.4 mmol) was added, and the
mixture was stirred at room temperature, under nitrogen, for
5 min. The polymerization was then quenched by precipita-
tion into cold methanol, and pVL was isolated as colorless oil.
Synthesis of pAVL
Synthesis of pAVL was performed following the general pro-
cedure for all homopolymers, with a reaction time of 40 min,
before precipitating into methanol.
Synthesis of pPgVL
Synthesis of p-PgVL was performed following the general
procedure for all homopolymers, with a reaction time of 20
min, followed by precipitation into methanol.
27.4
(CH2CH2CH2PgVL),
26.5
(CHCH2CH2AVL),
26.1
Synthesis of p(TMS-PgVL)
(CHCH2CH2PgVL), 21.1 (CH2CBCPgVL).
Synthesis of p(TMS-PgVL) was performed following the gen-
eral procedure for all homopolymers, with a reaction time of
20 min, followed by precipitation into methanol.
Synthesis of p(PgCL-b-AVL)
To a stirred solution of TBD (0.04 M in toluene, 3.6 mL,
0.060 mmol) and benzyl alcohol (11 lL, 0.106 mmol), PgCL
4 (1.13 g, 7.43 mmol) was added, and the mixture was
stirred for 1.5 h. An aliquot (ꢀ50 lL) was taken for GPC and
1H NMR analyses. AVL 1 (1.04 g, 7.43 mmol) was added, and
the reaction mixture was stirred for 70 min. The
Synthesis of pPgCL
pPgCL was prepared following the general procedure for all
homopolymers, with a reaction time of 2 h and 45 min, fol-
lowed by precipitation into methanol.
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1
polymerization was terminated by adding benzoic acid, and
the polymer was isolated by precipitation into cold methanol
and hexane to afford 1.67 g (93%) of a colorless viscous liq-
uid. The overall monomer conversion was 83% and the com-
position of final polymer was found to be the same as feed
ratio in accord with conversion determined for each block.
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 5.71 (m,
1H, CH2¼¼CH), 5.03 (m, 2H, CH2¼¼CH), 4.04 (m, 4H, CH2O),
2.15–2.6 (br m, 6H, CHC¼¼O þ CH2CBCH þ CH2CH¼¼CH2),
2.0 (s, 1H, CBCH), 1.66 (m, 8H, CHCH2CH2CH2O AVL þ
CHCH2CH2CH2CH2O PgCL), 1.37 (m, 2H, CHCH2CH2CH2CH2O
PgCL). 13C NMR (CDCl3, 75 MHz): d (CHCl3¼¼77.16 ppm)
175.2 (C¼¼OAVL), 174.2 (C¼¼OPgCL), 135.2 (C¼¼CAVL), 117.1
(C¼¼CAVL), 81.3 (CBCHPgCL), 70.2(CBCHPgCL), 64.4(CH2OPgCL),
64.0 (CH2OAVL), 44.8 (CHC¼¼OAVL), 44.4 (CHC¼¼OPgCL), 36.5
(CH2C¼¼C), 28.4 (CH2CH2OPgCL), 28.0 (CHCH2AVL), 26.5
(CHCH2CH2AVL), 24.6 (C¼¼OCHCH2PgCL), 23.4 (C¼¼OCHCH2-
CH2PgCL), 21.1 (CH2CBCPgCL).
yield. H NMR and mass spectrometry confirmed the identity
of the product. 1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26
ppm) 8.24 (1H, d), 7.88 (1H, m), 7.82 ppm (1H, m), 7.47 (1H,
d), 7.10 (2H, d), 7.03 (2H, d), 6.98 (2H, d), 3.65 (8H, q), 3.30
(2H, t), 3.10 (2H, t), 1.67 (2H, m) 1.21 (12H, t). low resolution
mass spectrometry FAB: (m/z): [MþH]þ calculated from
C
31H37BrN3O2 562.2; found 562.5. To a solution of R1
(0.326 g, 0.553 mmol) in anhydrous DMF (ꢀ5mL), potassium
thioacetate (0.0630 g, 0.553 mmol) was added, and the
resulting solution was stirred at 60 ꢃC for 6 h. After cooling to
room temperature, the reaction mixture was diluted with
dichloromethane and washed exhaustively with water and
brine to remove DMF. The organic layer was dried over
magnesium sulfate and concentrated on a rotary evaporator to
yield R2 as a pink oil in 80% yield. 1H NMR and mass
1
spectrometry confirmed the identity of the product. H NMR
(CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 8.24 (1H, d), 7.88
(1H, m), 7.82 ppm (1H, m), 7.47 (1H, d), 7.10 (2H, d), 7.03 (2H,
d), 6.98 (2H, d), 3.65 (8H, q), 3.15 (2H, t), 2.65 (2H, t), 2.34
(3H, s), 1.45 (2H, m), 1.21 (12H, t). low resolution mass
spectrometry FAB: (m/z): [MþH]þ calculated from
Synthesis of p[(TMS-PgVL)-b-PgVL] 6
p-(TMS-PgVL)-b-PgVL 6 was synthesized following the gen-
eral procedure given above, with TMS-PgVL 3 added first,
stirring for 23 min, then addition of PgVL 2, with continued
stirring for 20 min.
C
33H40N3O3S 558.3; found 558.6. To a solution of R2 (0.26 g,
0.44 mmol) in THF (ꢀ3 mL), dimethylamine (40 wt % solution
in water; 19.9 mg, 0.442 mmol) was added, and the mixture
was stirred at room temperature, under a nitrogen atmo-
sphere, overnight. The mixture was diluted with dichloro-
methane and the organic layer was washed with water (3ꢅ)
and brine (3ꢅ), dried over magnesium sulfate and concen-
trated on a rotary evaporator to yield rhodamine-thiol 9 as an
Synthesis of p(PgVL-co-VL)
p-PgVL-co-VL was synthesized by simultaneous addition of
PgVL 2 and VL to an incubated solution of benzyl alcohol
and TBD and stirred for 23 min.
Synthesis of 1,8-Diazido-3,6-dioxaoctane
1
odorous pink oil in 70% yield. H NMR and MS confirmed the
To a solution of 1,2-bis(2-chloroethoxy) ethane (0.90 g, 4.81
mmol) in water/acetone (1:1) was added sodium azide (1.90
g, 28.9 mmol) and a trace of sodium iodide. The reaction
mixture was stirred at 50 ꢃC overnight, then diluted with
water, filtered over Celite, and extracted with dichloromethane.
The combined organic layers were dried over magnesium sul-
fate and concentrated on a rotary evaporator to yield 1,8-dia-
zido-3,6-dioxaoctane as a clear, slightly yellow oil in 86% yield.
IR: 2100 cmꢂ1. Note: For safety considerations, due to the rel-
atively low (C þ O):N ratio of 1.33:1, this reaction was per-
formed at <1 g of 1,8-diazido-3,6-dioxaoctane, and the com-
pound was stored as a solution in dichloromethane.
identity of the product.
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 8.24 (1H,
d), 7.88 (1H, m), 7.82 ppm (1H, m), 7.47 (1H, d), 7.10 (2H,
d), 7.03 (2H, d), 6.98 (2H, d), 3.65 (8H, q), 3.15 (2H, t), 2.65
(2H, t), 1.45 (2H, m), 1.21 (12H, t). LRMS FAB: (m/z):
[MþH]þ calculated from C31H41N3O2S 516.3; found 514.0
and 1029.0 (disulfide-linked dimer).
Synthesis of PC-Thiol 8
To a solution of 11-bromoundecanol (3.00 g, 26.3 mmol) in
DMF, potassium thioacetate (5.60 g, 21.9 mmol) was added,
and the reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was diluted with dichlorome-
thane and washed with water. The combined organic layers
were dried over magnesium sulfate and concentrated on a
rotary evaporator to yield 11-thioacetylundecanol as an off-
white powder. In a flame-dried two-neck round bottom flask,
a solution of 11-thioacetylundecanol (1.85 g, 8.2 mmol) and
triethylamine (1.3 mL, 9.08 mmol) in anhydrous THF (20
mL) was added; the flask was equipped with septum, stir
bar, and nitrogen inlet. Ethylene chlorophosphate (0.84 mL,
9.1 mmol) was added dropwise, and the resulting mixture
allowed to warm to room temperature, followed by contin-
ued stirring for 1 h. The formed solid was removed by vac-
uum filtration over Celite, using a blanket of nitrogen, then
the volatiles were removed by rotary evaporation, and the
isolated product taken to the next step without further puri-
fication. The crude product was dissolved in anhydrous
Synthesis of Rhodamine-Thiol 9
Rhodamine B (0.40 g, 0.85 mmol), 3-bromopropylamine
hydrobromide (0.186 g, 0.851 mmol), EDC (0.198 g, 1.28
mmol), and DMAP (0.311 g, 2.55 mmol) were added to dry
dichloromethane (ꢀ50 mL) and stirred at room temperature
overnight. The organic layer was washed with saturated
sodium bicarbonate solution (3ꢅ), 1 M hydrochloric acid (1ꢅ),
and brine (3ꢅ), dried over magnesium sulfate, and concen-
trated on a rotary evaporator to yield R1 as a pink oil in 65%
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acetonitrile (22 mL) and cooled to 0 ꢃC in a glass pressure
vessel. Trimethylamine (3.6 mL, 38 mmol) was added, and
the mixture was heated at 70 C overnight. The reaction mix-
solve), PC-thiol (1.57 equiv with respect to alkene) was
added in a small amount of degassed methanol (just enough
to dissolve) and DMPA (0.2 equiv with respect to alkene),
and the mixture was stirred overnight at room temperature
under a UVP Black Ray UV bench lamp, which emits at
ꢀ365 nm. The crude reaction mixture was transferred to a
ꢃ
ture was slowly cooled to precipitate the product, which was
isolated by filtration to yield thioacetyl-PC as a brown, oily
solid. Thioacetyl-PC (1.84 g, 4.48 mmol) was dissolved in
methanol (5 mL), diluted with THF (20 mL), and stirred
under nitrogen. To this solution, a 40 wt % solution of dime-
thylamine was added dropwise in water (5.66 mL, 44.8
mmol), and the reaction mixture was stirred at room tem-
perature overnight. Volatiles were removed under vacuum,
and residual water was removed by lyophilization to give
PC-thiol 8 as a brown solid in 66% yield.
R
Spectra/PorV dialysis membrane (MWCO ¼ 6000–8000) and
dialyzed against methanol overnight.
1H NMR (CDCl3, 300 MHz): d (CHCl3¼7.26 ppm) 7.45 (1H,
br m), 5.70 (1H, m), 5.04 (2H, m), 4.49 (4H, m), 4.24 (2H,
m), 4.06 (2H, br m), 3.83 (2H, m), 3.62 (4H, m), 3.67 (2H,
m), 3.54 (4H, m), 3.25 (9H, s), 2.80 (3 H, br m), 2.67 (2H,
m), 2.36 (1H, br m), 1.61 (26H, m), 1.30 (16H, m).
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 4.24 (2H,
m), 3.83 (2H, m), 3.67 (2H, m), 3.25 (9H, s), 2.67 (2H, m),
1.64 (4H, m), 1.30 (16H, m).
Rhodamine Thiol Reactions. To a degassed solution of
p(AVL-b-PgVL) nanoparticles in anhydrous DMF (just enough
to dissolve the polymer), rhodamine thiol and DMPA (0.2
equiv with respect to alkene) were added, and the mixture
was stirred overnight at room temperature under a UVP
Black Ray UV bench lamp, which emits at ꢀ365 nm. The
Nanoparticle Formation using Azide-Alkyne Cycloaddition
with 1,8-Diazido-3,6-dioxaoctane and p(AVL-b-PgVL) 5
Nanoparticles were obtained using three concentrations of
alkyne in the reaction mixture: 0.00362, 0.0544, and 0.215
M. The general procedure was as follows: p(AVL-b-PgVL) 5
and 1,8-diazide-3,6-dioxaoctane (0.5 equiv with respect to
alkyne) were dissolved in dry, degassed dichloromethane.
Copper(I) bromide (1.0 equiv with respect to alkyne) and
PMDETA (2.0 equiv with respect to alkyne) were added, and
the solution is stirred at room temperature, under a nitrogen
atmosphere, overnight. The nanoparticles were isolated by
dialysis in dichloromethane/MeOH (1:1 v/v; MWCO ¼ 6000–
8000).
R
crude reaction mixture was transferred to a Spectra/PorV di-
alysis membrane (MWCO ¼ 6000–8000 g molꢂ1) and dia-
lyzed against dichloromethane/MeOH (1:1 v/v) overnight.
Orthogonal CuAAC and Thiol-ene Reactions
on p(PgCL-b-AVL)
CuAAC: p(PgCL-b-AVL) and m-PEG750-N3. Diblock copo-
lyester p(PgCL-b-AVL) (430 mg, 1.57 mmol alkyne) and m-
PEG750-azide (0.889 g, 1.15 mmol) were suspended in a so-
lution of water/THF (1:4 v/v, 10 mL). Sodium ascorbate (79
mg, 0.40 mmol) and copper(II) sulfate (50 mg, 0.20 mmol)
were added and the reaction mixture was stirred at 80 ꢃC
for 15 h under N2. The organic solvent was removed under
reduced pressure. Excess m-PEG750-N3 was removed by dia-
lyzing against dichloromethane for 3 days (MWCO 10 kDa).
To remove trace copper, the crude product was suspended in
20 mL deionized water and treated with CuprisorbTM until
the suspension become light yellow. The product was iso-
lated by lyophilization as a slightly yellow, hydroscopic pow-
der (1.11g, 90.6%).
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 7.45 (1H,
br m), 5.70 (1H, m), 5.04 (2H, m), 4.49 (4H, m), 4.06 (2H, br
m), 3.62 (4H, m), 3.54 (4H, m), 2.80 (3 H, br m), 2.36 (1H,
br m), 1.61 (22H, m).
Thiol-ene Modification of Nanoparticles
Both thermal and photoinitiated thiol-ene reactions8 were
used to further modify the p(AVL-b-PgVL) crosslinked nano-
particles. Thermal reactions were carried out in the presence
of AIBN at 80 ꢃC in DMF. Photoinitiated reactions used
DMPA as the initiator and were conducted at room tempera-
ture, irradiating at 365 nm in DMF.
GPC (THF, polystyrene standard) Mn ¼ 2.48 ꢅ 104 g molꢂ1
;
PDI ¼ 1.09. 1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26
ppm) 7.44 (s, 1H, R2C¼¼CH triazole), 5.66 (m, 1H, CH2¼¼CH),
4.98 (m, 2H, CH2¼¼CH), 4.43 (m, 2H, R2NCH2), 3.95 (m, 4H,
CH2OC¼¼O, lactones), 3.78 (m, 2H, R2NCH2CH2), 3.58 (br m,
70H, CH2CH2OPEG), 3.32 (s, 3H, CH3PEG), 2.92 (m, 1H,
CHC¼¼OPgCL), 2.76 (m, 2H, CH2C¼¼CPgCL), 2.10–2.45 (m, 3H,
Dodecanethiol Addition. To a degassed solution of p(AVL-
b-PgVL) nanoparticles in anhydrous DMF (just enough to dis-
solve the polymer), dodecanethiol (5.0 equiv with respect to
alkene) and AIBN (0.5 equiv with respect to alkene) were
added, and the mixture was stirred at 80 ꢃC overnight. The
R
reaction mixture was transferred to a Spectra/PorV dialysis
CHC¼¼OAVL þ CH2C¼¼CH2), 1.56 (m, 8H, CH2CH2CH2OPgCL
þ
CH2CH2OAVL), 1.28 (br m, 2H, CH2CH2CH2OPgCL). 13C NMR
(CDCl3, 75MHz) d (CHCl3 ¼ 77.16 ppm) 175.11 (C¼¼O),
144.95 (triazole R2C¼¼CR), 135.11 (C¼¼CH2), 122.70
(R2C¼¼CR triazole), 117.07 (C¼¼CH2), 71.9 (CH2OPEGCH3),
70.6 (CH2CH2OPEG), 69.6 (R2NCH2CH2O), 64.2 (CH2OPgCL),
64.0 (CH2OAVL), 59.0 (CH3PEG), 50.1 (R2NCH2CH2O), 45.4
(CHC¼¼OPgCL), 44.8 (CHC¼¼OAVL), 36.5 (CH2C¼¼C), 31.5
(CH2CR¼¼CR2PgCL), 28.5 (CH2CH2COPgCL), 28.0 (CHCH2AVL),
26.5 (CHCH2CH2AVL), 23.5 (C¼¼OCHCH2CH2PgCL).
membrane (MWCO ¼ 6000–8000) and dialyzed against
dichloromethane/MeOH (1:1 v/v) overnight.
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 7.45 (1H,
br m), 5.70 (1H, m), 5.04 (2H, m), 4.49 (4H, m), 4.06 (2H, br
m), 3.62 (4H, m), 3.54 (4H, m), 2.80 (3 H, br m), 2.51 (2H,
t), 2.36 (1H, br m), 1.61 (22H, m), 0.883 (3H, s).
PC-Thiol Reactions. To a degassed solution of p(AVL-b-
PgVL) nanoparticles in anhydrous DMF (just enough to dis-
12
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POLYMER SCIENCE
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Thiol-ene Addition of Dodecanthiol to p[(PgCL-g-
PEG750)-b-(AVL)]. p[(PgCL-g-PEG750)-b-(AVL)] (310 mg,
0.260 mmol alkene), 2,20-dimethoxy-2-phenylacetonphenone
(7.4 mg, 0.029 mmol), and dodecanethiol (0.14 mL, 0.58
mmol) were added to a vial equipped with a magnetic stir
bar. DMF (0.58 mL) was added, and the vial was sealed with
a rubber septum. The reaction mixture was degassed via
four freeze–pump–thaw cycles and irradiated at 365 nm for
8 h at room temperature. The reaction mixture was precipi-
tated into hexane. Upon the removal of solvent and drying
under vacuum overnight, the modified polymer (300 mg,
82%) was isolated as a slightly yellow, waxy solid.
ing Center on Polymers at the University of Massachusetts
(MRSEC-DMR-0820506).
REFERENCES AND NOTES
1 Detrembleur, C.; Mazza, M.; Halleux, O.; Lecomte, P.; Mecerreyes,
D.; Hedrick, J. L.; Jerome, R. Macromolecules 2000, 33, 14–18.
2 Trollsas, M.; Lee, V. Y.; Mecerreyes, D.; Lowenhielm, P.; Moller,
M.; Miller, R. D.; Hedrick, J. L. Macromolecules 2000, 33, 4619–4627.
3 Liu, M. J.; Vladimirov, N.; Frechet, J. M. J. Macromolecules
1999, 32, 6881–6884.
GPC (THF, Psty standard) Mn ¼ 4.11 ꢅ 104 g molꢂ1; PDI ¼
4 Mecerreyes, D.; Miller, R. D.; Hedrick, J. L.; Detrembleur, C.; Jer-
ome, R. J. Polym. Sci. Part A: Polym. Chem. 2000, 38, 870–875.
1
1.17. H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm) 7.43
5 Cooper, B. M.; Chan-Seng, D.; Samanta, D.; Zhang, X.; Parel-
kar, S.; Emrick, T. Chem. Commun. 2009, 7, 815–817.
(s, 1H, R2C¼¼CH triazole), 4.45 (m, 2H, R2NCH2), 3.98 (m, 4H,
CH2OC¼¼O, lactones), 3.81 (m, 2H, R2NCH2CH2), 3.60 (br m,
70H, CH2CH2OPEG), 3.34 (s, 3H, CH3PEG), 2.92 (m, 1H,
CHC¼¼OPgCL), 2.76 (m, 2H, CH2C¼¼C), 2.44 (br m, 4H,
CH2CH2SCH2(CH2)11CH3), 2.31 (br m, 1H, CHC¼¼OAVL), 1.4–
1.9 (m, 14H, CH2CH2CH2SCH2CH2(CH2)9CH3 þ CH2CH2CH2-
6 Parrish, B.; Breitenkamp, R. B.; Emrick, T. J. Am. Chem. Soc.
2005, 127, 7404–7410.
7 Parrish, B.; Emrick, T. Bioconjug. Chem. 2007, 18, 263–267.
8 Campos, L. M.; Killops, K. L.; Sakai, R.; Paulusse, J. M. J.;
Damiron, D.; Drockenmuller, E; Messmore, B. W.; Hawker, C. J.
Macromolecules 2008, 41, 7063–7070.
OPC þ CH2CH2OAVL), 1.28 (br, 20H, CH2CH2CH2OPgCL
þ
SCH2CH2(CH2)9CH3), 0.80 (br, 3H, SCH2CH2(CH2)9CH3). 13C
NMR CDCl3, 75 MHz) d (CHCl3 ¼ 77.16 ppm) 175.2 (C¼¼OAVL),
175.1 (C¼¼OPgCL), 144.9 (R2C¼¼CR), 122.70 (R2C¼¼CR), 71.9
(CH2OPEGCH3) , 70.6 (CH2CH2OPEG), 69.6 (R2NCH2CH2O), 64.2
(CH2OPgCL), 64.0 (CH2OAVL), 59.0 (CH3PEG), 50.1 (R2NCH2CH2O),
45.4 (CHC¼¼OPgCL), 44.8 (CHC¼¼OAVL), 32.2 (CH2SCH2), 32.1
(CH2SCH2), 31.9 (S(CH2)9CH2CH2CH3), 31.5 (CH2CR¼¼CR2PgCL),
29.6 (S(CH2)3(CH2)5(CH2)3CH3), 29.6 (CH2(CH2)2S(CH2)11CH3),
29.4 (S(CH2)2CH2(CH2)5CH2(CH2)2CH3), 29.0 (SCH2CH2(CH2)9-
CH3), 28.6 (CH2CH2COPgCL), 28.0 (CHCH2AVL), 27.3 (CH2CH2-
S(CH2)11CH3), 26.6 (CHCH2CH2AVL), 23.5 (C¼¼OCHCH2CH2PgCL),
22.7 (S(CH2)10CH2CH3), 14.14 (S(CH2)11CH3).
9 van der Ende, A. E.; Harrell, J.; Sathiyakumar, V.; Meschie-
vitz, M.; Katz, J.; Adcock, K.; Harth, E. Macromolecules 2010,
43, 5665–5671.
€
10 (a) Nederberg, F.; Connor, E. F.; Moller, M.; Glauser, T.;
Hedrick, J. L. Angew. Chem. Int. Ed. 2001, 40, 2712–2175; (b)
Trimaille, T.; Moeller, M.; Gurny, R. J. Polym. Sci. Part A:
Polym. Chem. 2004, 42, 4379–4391.
11 (a) Connor, E. F.; Nyce, G. W.; Myers, M.; Mock, A.; Hedrick,
J. L. J. Am. Chem. Soc. 2002, 124, 914–915; (b) Nyce, G. W.;
Glauser, T.; Connor, E. F.; Mock, A.; Waymouth, R. M.; Hedrick,
J. L. J. Am. Chem. Soc. 2003, 125, 3046–3056.
12 Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long,
D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R.
M.; Hedrick, J. L. Macromolecules 2006, 39, 8574–8583.
Simultaneous Thiol-ene/yne: p(AVL-b-PgVL)
13 (a) du Boullay, O. T.; Saffon, N.; Diehl, J.-P.; Martin-Vaca, B.;
Didier Bourissou, D. Biomacromolecules 2010, 11, 1921–1929;
(b) Jing, F.; Hillmyer, M. A. J. Am. Chem. Soc. 2008, 130,
13826–13827; (c) Fiore, F. G. L.; Jing, F.; Young, V. G., Jr.;
Cramer, C. J.; Hillmyer, M. A. Polym. Chem. 2010, 1, 870–877.
5 and Dodecanethiol
To a solution of p(AVL-b-PgVL) 5 (0.50 g, 3.6 mmol alkyne þ
alkene) in degassed dimethylformamide (30 mL), dodecanethiol
(3.64 g, 18.0 mmol) and AIBN (0.29 g, 1.80mmol) were added,
ꢃ
and the mixture was heated at 80 C for 3 h. The crude reac-
14 Cooper, B. M.; Emrick, T. J. Polym. Sci. Part A: Polym.
Chem. 2009, 47, 7054–7065.
tion mixture was transferred to a dialysis membrane (MWCO ¼
6000–8000) and dialyzed against dichloromethane for 2 days
to yield the product as a slightly yellow oil.
15 Li, G. L.; Wan, D.; Neoh, K. G.; Kang, E. T. Macromolecules
2010, 43, 10275–10282.
1H NMR (CDCl3, 300 MHz): d (CHCl3 ¼ 7.26 ppm), 4.08 (m, 4H,
CH2OC¼¼O), 2.48 (t, 2H, dodecanethiol), 2.2–2.6 (br m, 6H,
16 Parrish, B.; Quansah, J. K.; Emrick, T. J. Polym. Sci. Part A:
Polym. Chem. 2002, 40, 1983–1990.
17 Darcos, V.; Habnouni, S. E.; Nottelet, B.; Ghzaoui, A. E.;
Coudane, J. Polym. Chem. 2010, 1, 280–282.
CHC¼¼O
þ
CH2CBCH
þ CH2CH¼¼CH2), 1.66 (m, 10H,
CHCH2CH2CH2O AVL þ CHCH2CH2CH2O PgVL þ dodecanethiol),
€
˚
18 (a) Moller, M.; Kange, R.; Hedrick, J. L. J. Polym. Sci. Part A:
Polym. Chem. 2000, 38, 2067–2074; (b) Blanquer, S.; Tailhades,
J.; Darcos, V.; Amblard, M.; Martinez, J.; Nottelet, B.; Coudane,
J. J. Polym. Sci. Part A: Polym. Chem. 2010, 48, 5891–5898.
1.25 (m, 20H, dodecanethiol), 0.874 (t, 3H, dodecanethiol).
ACKNOWLEDGMENTS
The authors acknowledge financial support from the National
Science Foundation Materials Research Science and Engineer-
19 Withey, A. B. J.; Chen, G.; Nguyen, T. L. U.; Stenzel, M. H.
Biomacromolecules 2009, 10, 3215–3226.
WWW.MATERIALSVIEWS.COM
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