Dual-reactive hyperbranched polymer synthesis through proton transfer polymerization of thiol and epoxide groups

Article abstract of DOI:10.1021/ma500920z

A new synthesis of hyperbranched polymers through proton transfer polymerization of thiol and epoxide groups is presented. For this, an AB ₂ monomer bearing two epoxides and a thiol groups is synthesized. Base-catalyzed proton transfer polymerization of this monomer led to the formation of a polythioether-based hyperbranched polymer with a 65-69% degree of branching and carrying about 2% of disulfide-based structural defects. This polymer contained two reactive sites, a hydroxyl group and an epoxide unit, distributed throughout the branched scaffold. The epoxide groups could be employed in anchoring an alkyl, aryl, or ethylene oxide chain through a thiol-epoxy reaction, while the hydroxyl groups produced during the polymerization and the first functionalization reactions could be engaged in attaching positively charged primary ammonium groups to the branched backbone. These sequential postpolymerization modifications transformed the general dual-reactive scaffold into dual-functionalized hyperbranched materials with potential utility in the arena of gene delivery applications.

Full text of DOI:10.1021/ma500920z

Article
pubs.acs.org/Macromolecules
Dual-Reactive Hyperbranched Polymer Synthesis through Proton
Transfer Polymerization of Thiol and Epoxide Groups
Ikhlas Gadwal,‡ Selmar Binder,‡ Mihaiela C. Stuparu,§ and Anzar Khan*,‡
‡Department of Materials, ETH-Zurich, CH-8093 Zurich, Switzerland
̈
̈
§Institute of Organic Chemistry, University of Zurich, Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: A new synthesis of hyperbranched polymers
through proton transfer polymerization of thiol and epoxide
groups is presented. For this, an AB2 monomer bearing two
epoxides and a thiol groups is synthesized. Base-catalyzed
proton transfer polymerization of this monomer led to the
formation of a polythioether-based hyperbranched polymer
with a 65−69% degree of branching and carrying about 2% of
disulfide-based structural defects. This polymer contained two
reactive sites, a hydroxyl group and an epoxide unit, distributed
throughout the branched scaffold. The epoxide groups could be employed in anchoring an alkyl, aryl, or ethylene oxide chain
through a thiol−epoxy reaction, while the hydroxyl groups produced during the polymerization and the first functionalization
reactions could be engaged in attaching positively charged primary ammonium groups to the branched backbone. These
sequential postpolymerization modifications transformed the general dual-reactive scaffold into dual-functionalized hyper-
branched materials with potential utility in the arena of gene delivery applications.
(Scheme 1). This synthesis is based upon proton transfer
polymerization of thiol and epoxide groups. The resulting
polymers represent a general and dual-reactive scaffold that can
be functionalized in a precise fashion with two distinctly
different functionalities.
INTRODUCTION
■
Since Flory’s theoretical work in 1952, the field of hyper-
branched polymers has flourished.1−9 Elegant synthetic
approaches have been developed, effects of the branched
architecture on the material properties have been elucidated,
self-assembling properties have been considered, and these
unique architectures have been demonstrated to be of
considerable utility in a wide range of applications.2−9 Despite
these developments, heterodual-functionalization approaches of
the hyperbranched scaffold remain relatively few.9 This
limitation is noteworthy, as capability of heterofunctionalization
will allow for development of a functionalized materials
platform suited for targeting sophisticated applications. For
example, in the biomedical arena, introduction of a long alkyl
chain for cell permeation10,11 or an ethylene oxide chain for
stealth properties12 along with a complexation site (such as a
chemically charged ammonium group)13 can give rise to well-
defined bifunctional materials with potential applicability in the
arena of siRNA delivery.10c,11,14 In this regard, a recent study
has shown that linear polymers carrying an ammonium group
and a lipophile (an alkyl/aryl moiety) were capable of forming
supramolecular complexes with siRNA and delivering it to
human colon carcinoma cells (HT-29-luc).11 In this design, the
positively charged ammonium groups interacted with the
negatively charged siRNA and the lipophilic chains allowed the
formed complex to cross the cell/endosome membrane. This
study, along with other works,10,15,16 underlines the importance
of developing new synthetic pathways to dual-functional soft
materials. Toward this end, in the present work, we present
development of a new synthesis to hyperbranched polymers
RESULTS AND DISCUSSION
■
The concept of proton transfer polymerization was elegantly
illustrated by Frec
́
het and co-workers in 1999.8a In this work,
the ring-opening reaction of an epoxide group by the phenol
nucleophile was employed as the polymerization process. In
this system, it was established that after initiation with a
catalytic amount of a hydroxide ion (70 °C), the generated
alkoxide anion does not undergo propagation but rather a
thermodynamically driven proton exchange reaction with the
phenol group. The phenolate anion created by this proton
transfer reaction then becomes active and propagates the epoxy
ring-opening (polymerization) reaction. In a later report, acid
groups were used instead of a phenol to obtain hydrolyzable
polyesters.8b We envisaged that the thiol-epoxy reaction16 could
also be employed for the preparation of the hyperbranched
polymers through a similar proton transfer mechanism
(Scheme 1). Since this reaction operates under ambient
conditions, the polymerization in this system could be carried
out at room temperature. Furthermore, the resulting polymers
́
would differ from Frechet’s polyethers as the sulfur atom
Received: May 5, 2014
Revised: July 8, 2014
Published: July 16, 2014
© 2014 American Chemical Society
5070
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
a
Scheme 1. Schematic Representation of the Proton Transfer Polymerization of Thiol and Epoxide Groups
a
The wavy lines do not represent chemical bonds and are used to simplify the structure and the underlying concept.
present within the polymer backbone may also, if required, be
oxidized, functionalized, and degraded under mild conditions or
used as an adhesion promoter.17 These polymers would carry
epoxide and hydroxyl reactive groups. Alteration of these
moieties through thiol-epoxy and esterification reactions would
then lead to the formation of a bifunctionalized polythioether-
based hyperbranched polymer.
Monomer Synthesis. To test this hypothesis, an AB2
monomer carrying two epoxide groups and a thiol moiety
was synthesized in two steps (Scheme 2). In the first step,
commercially available olefin, 1, was partially epoxidized using
m-chloroperbenzoic acid. The resulting diepoxide, 2, was then
subjected to a photoinitiated free-radical coupling reaction with
a dithiol molecule 3, yielding the desired AB2 monomer 4, in a
highly reproducible manner and in an isolated yield of 80−85%.
The free-radical chemistry was chosen for the last step as it
offered a chemically neutral environment. This attribute was
deemed essential in gaining synthetic access to a molecule that
carried thiol and epoxide groups placed on the same molecule.
This is due to the fact that reactions operating under acidic or
basic conditions may have resulted in premature opening of the
epoxide groups. The free-radical coupling reaction could be
monitored with the help of 1H NMR spectroscopy as the olefin
proton resonances of 2 located in the region of 5−6 ppm
(designated “e’ and ‘f” in Figure 1) disappeared after the
reaction and new signals for the newly formed methylene
groups in 4 could be observed (designated “e’ and ‘f” in Figure
1). In addition to these, the monomer showed typical proton
5071
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
Scheme 2. Synthesis of Bi-Functionalized Hyperbranched Polymers
resonances of the epoxide units in the range of 2−4 ppm while
a triplet from the thiol proton could be observed at 1.6 ppm
(Figure 1). The purity of monomer 4 could also be verified
with the help of elemental analysis, which showed that the
theoretical ratio of elements (C, H, O, N, and S) were in good
agreement to the experimentally determined values (Figure S1,
Supporting Information). The monomer was stored in dilute
organic solutions, at low temperatures, and under inert
atmosphere as material gelation was observed upon its storage
in pure form under ambient conditions.
5072
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
1
Figure 1. H NMR of precursors 1 and 2, and monomer 4. For an emphasis on the 1−5 ppm area (monomer 4), please see Figure 10
Table 1. Polymerization of Monomer 4
entry
catalyst (mol %)
T (°C)
time (h)
solvent
THF
Mn (g/mol)
Mw (g/mol)
PDI (Mw/Mn)
yield (%)
1
2
3
4
5
6
7
TEA (7)
25
25
25
25
25
25
25
23
23
23
23
23
23
48
−
−
6000
6100
6700
6900
7000
−
−
13 100
14 000
15 700
15 900
13 400
−
−
2.16
2.29
2.34
2.30
1.91
−
−
80
78
80
84
80
TEA (14)
TBAF (7)
TBAF (14)
LiOH (7)
LiOH (14)
LiOH (7)
THF
THF
THF
THF/H2O
THF/H2O
THF/H2O
Plausible Polymerization Mechanism. In the present
system, the thiol group of an AB2 monomer could be
deprotonated by catalytic amounts of a base and the resulting
thiolate nucleophile would attack the less hindered site of the
epoxide unit as established in numerous small molecular as well
as polymeric systems (Scheme 1).16,18,19 The alkoxide unit thus
formed will be rapidly protonated due to its high basicity (pKa
∼ 17)20 by either the aliphatic thiol group (pKa ∼ 9−10)21
through inter- or intramolecular proton transfer or by the
typical wet/protic nature of the reaction medium or by the
water generated during the reaction (e.g., while using a
hydroxide base). This thermodynamically driven proton
transfer step is critical in quenching the alkoxide anion and
its potential to start an anionic ring-opening polymerization of
the epoxides. The proton transfer step would either result in
the formation of another thiolate anion directly or regeneration
of the catalyst (e.g., a hydroxide anion). Thus, newly formed
thiolate anion would be ready for attacking another epoxide
ring and creation of a second alkoxide anion. Repetition of
these two steps: (i) thiolate formation by the alkoxide anion or
the catalyst present in the system, and (ii) epoxide ring-opening
reaction by the thiolate anion, would result in the formation of
a polymeric product. Since the monomer carries two-epoxide
units, the polymerization reaction would proceed with
branching, yielding a hyperbranched architecture.
Scaffold Synthesis. To confirm the aforementioned
hypothesis, polymerization of monomer 4 was carried out in
the presence of a catalytic amount of triethylamine (TEA) in
tetrahydrofuran (THF) and in an argon atmosphere at room
temperature. This reaction, however, did not produce any
polymer. This result is not surprising considering that pKa of
TEA and aliphatic thiols are in a similar range. Hence, it is likely
that TEA fails to act as an efficient base at room temperature in
THF. Therefore, the polymerization catalyst was then changed
to tetrabutylammonium fluoride (TBAF). TBAF is soluble in a
variety of organic solvents as well as water, and known to be a
good catalyst for the thiol-epoxy reaction.16e,18 This reaction
produced polymers with molecular weights ranging from 6 to 7
kDa at room temperature (Table 1). To further investigate the
polymerization reaction, lithium hydroxide (LiOH) was used as
the polymerization catalyst. This catalyst has been used with
significant success for the thiol−epoxy coupling reaction in
small molecular19 as well as polymeric16 systems. This change,
however, did not alter the outcome of the polymerization
reaction. Moreover, using a higher catalyst loading and
increasing the polymerization time did not result in any
significant changes in the average molecular weight of the
5073
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
1
Figure 2. H NMR of the polymerization mixture as a function of time. Signals from TBAF, THF, tetramethylsilane (TMS), and chloroform are
marked with an asterisk. For a focus on 1−5 ppm area (polymer 5), please see Figure 11
1
Figure 3. H NMR of polymers 5, 10, and 14-Boc (also see Figures S3 and S4). For an emphasis on the 1−5 ppm area (polymer 5), please see
Figure 11
obtained materials (Table 1). Presumably, the steric hindrance
to the nucleophilic focal point increases with the progression of
the reaction and leads to an intrinsic limitation of the
achievable molar mass. It is clear that more experiments are
necessary to investigate this aspect. Therefore, the polymer-
ization data presented here should be considered preliminary.
However, it should be mentioned that the polymerization
reaction could be repeated in a reproducible manner. Figure 2
shows a series of 1H NMR spectra obtained from the
polymerization mixture as a function of polymerization time.
Compared to the sharp signals of the monomer, the polymer
signals were broadened (Figure 2). IR spectroscopy confirmed
that the carbonyl stretch at 1670 cm−1 of the monomer 4
remained unperturbed under the polymerization conditions
(Figure S2). A broad band belonging to the newly generated
hydroxyl groups could be located at 3400 cm−1. The dual-
reactive scaffold was observed to become insoluble upon
storage in its dry state. Therefore, after synthesis, the polymer
was stored in an organic solution at low temperatures. The
functionalized polymers (discussed henceforth), however, were
perfectly stable in dry state and at room temperature.
5074
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
Scaffold Bifunctionalization. The epoxide groups in
polymer 5 could be subjected to a functionalization reaction
with a thiol-functionalized long alkyl chain (6), an ethylene
oxide chain (7), or an aromatic naphthalene unit (8). The
alkyl/aryl chains are known to endow membrane permeation
properties10,11 whereas the ethylene-oxide chains are known to
provide water solubility and stealth properties.12 The
functionalization reactions could be examined with the help
1
of H NMR spectroscopy (Figures 3 and S3−S4). This study
indicated complete consumption of the epoxide units and
appearance of the proton resonances belonging to the
triethylene glycol and dodecyl groups in the range of 0.9−1.4
and 3.3−3.7 ppm, in polymers 9 and 10, respectively. In case of
polymer 11, aromatic resonances could be observed in the
range of 7−8.5 ppm. These polymers were found to be
insoluble in water but soluble in a range of common laboratory
solvents including THF, chloroform, dichloromethane, and
dimethylformamide (DMF). A complete consumption of the
residual epoxides (1H NMR, Figures 3 and S3 and S4)
indicated that the degree of the first functionalization was
nearly quantitative. The second functionalization was achieved
through esterification of the secondary hydroxyl groups of the
hyperbranched scaffold 9, 10, and 11 with the t-butoxycarbonyl
(Boc)-protected acid molecule 12. A successful second
functionalization was evident by the appearance of a signal at
5.3 ppm from the proton located adjacent to the newly formed
ester group and the proton resonance signal of the Boc unit at
1.3 ppm (Figures 3 and S3 and S4). On the basis of this, the
degree of second functionalization was calculated to be over
Figure 5. GPC traces of polymer 5 (solid line), 9 (dash line), and 13-
Boc (dot line) (also see Figures S7−8).
S8). However, some changes are observed after the second
functionalization. This is most likely due to an increased
solubility of the esterified products and solubilization of the
oligomers in diethyl ether. Thermal analysis of the polymers
suggested that the glass transition temperature (Tg) of the
reactive scaffold decreased upon introduction of alkyl and
ethylene oxide chains and increased with the introduction of
the aromatic groups in the polymeric structure (Figures 6 and
S9 and S10, Table 2). The Tg increased further upon
substitution with the Boc-protected and positively charged
glycine units.
1
90% through area integration analysis in H NMR spectrosco-
py. Finally, the Boc groups could be removed under acidic
conditions. In deuterated dimethyl sulfoxide (DMSO-d6), the
ammonium signal could be observed at 8.4 ppm (Figures 4 and
Figure 6. DSC traces of polymers 5, 9, 13-Boc, and 13 (also see
Figures S9 and S10).
1
Figure 4. H NMR of dual-functionalized polymer 14 in DMSO-d6
and D2O (also see Figures S5 and S6).
Determination of Degree of Branching. To investigate
the degree of branching in present polymers, model
compounds mimicking the linear, terminal, and dendritic
units of the hyperbranched scaffold were synthesized. Figure
S5 and S6). These bifunctionalized cationic hyperbranched
polymers (13−15) were completely soluble in water. There-
1
fore, H NMR study could also be carried out in deuterated
1
water (D2O), which confirmed that the signal at 8.4 ppm in
DMSO-d6 belonged to the ammonium group as it could no
longer be observed in D2O due to a fast exchange with
deuterium. The first functionalization reaction did not change
the polydispersity of the materials significantly as could be
observed in the gel permeation chromatograms of the precursor
polymer and its functionalized structures (Figures 5 and S7 and
7 shows the H NMR of these compounds. Because of the
overlapping of signals and presence of residual epoxide groups,
1H NMR data could not be used to assign the linear, terminal,
and dendritic units in polymer 5. Therefore, signals arising from
the carbonyl groups were used for the assignment and area
integration analysis.3a,22 Figure 8 shows the 13C NMR (13C
frequency of 176 MHz) of the model compounds and polymer
5075
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
Table 2. Glass Transition Temperature of the Prepared Polymers
polymer
5
9
10
11
13-Boc
14-Boc
15-Boc
13
14
15
Tg (°C)
10
4
−21
42
23
24
58
51
47
85
1
Figure 7. H NMR of the model compounds mimicking the linear, dendritic, and terminal structures.
Figure 8. 13C NMR (13C frequency of 176 MHz) of the model compounds and polymer 5.
5. As expected, the carbonyl groups in 13C NMR, assigned as a,
b, and c in Figure 8, had different identities depending upon the
substitution pattern. In hydroxy-substituted compounds, signal
splitting was observed presumably due to the interaction of the
5076
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
Figure 9. 13C NMR (13C frequency of 176 MHz) of precursor polymer 5, and functionalized polymers 9, 10, and 11.
carbonyl with the proton of the hydroxyl unit through
hydrogen bonding interaction. With the help of these
compounds, the 13C-signals of the carbonyl groups in polymer
5 could be assigned to terminal, linear, and dendritic structures.
It was observed that the signals were shifted by 0.2−0.3 ppm in
the case of polymer. Nonetheless, separation of the signals
allowed for area integration analysis to be performed (Figure
S11). However, in order to account for the nuclei’s different
relaxation times, a pulse delay of 20 s was given to record the
13C NMR spectrum. Through area integration analysis and
input of these values into the equation described by Hawker,
Scheme 3. Preparation of Disulfide Dimer 16
Lee, and Frec
́
het,3a the degree of branching in the present
polymers could be calculated to be about 69% (please see the
Supporting Information for further information). However,
given the relatively low molecular weight of the present
polymers, application of the equation given by Holter, Burgath,
̈
and Frey23 indicated a degree of branching of 65%.
The assignment to the linear, terminal, and dendritic unit was
further confirmed by recording the 13C NMR of polymers 9,
10, and 11 (Figure 9). These polymers had been subjected to
the first functionalization reaction in which all the epoxide
groups were consumed. Therefore, the triazine ring in these
polymers represented the substitution pattern of a dendritic
unit. 13C NMR of these polymers exhibited lack of signals in
the vicinity of 149 ppm, indicating that assignment of these
signals to the terminal and linear units was correct.
dimer 16 was subjected to DTT treatment in THF (23 h).
However, epoxide rings of this molecule were observed to be
consumed under these conditions. In light of this, function-
alized polymers 10 and 11 (having no residual epoxide units)
were subjected to DTT in THF for 23 h. The reaction mixture
was then subjected to a GPC analysis. If the disulfide defects
were present in a significant amount then the polymer is
expected to be broken-down into smaller entities. The GPC
analysis, however, did not show any significant change in the
molecular weight distribution or the signal intensity profile of
polymers 10 and 11 after subjecting them to the reducing
conditions (Figure 12 and Figure S12). This indicated that the
Studying the Disulfide-Originated Structural Defects.
A potential issue in the present synthesis may be the formation
of disulfide-based structural defects. To examine this aspect,
monomer 4 was oxidized with the help of sodium iodide in the
presence of hydrogen peroxide to afford the corresponding
disulfide dimer 16 (Scheme 3). A 1H NMR examination of the
prepared disulfide dimer revealed that the methylene group
located adjacent to the disulfide defect resonated at a different
position then the methylene group located adjacent to a thiol or
a thio-ether moiety (Figure 10). This signal could also be
1
content of the disulfide defects, as corroborated by the H
NMR study, would be low in the prepared polymers.
1
observed in the H NMR of polymer 5. An area integration
CONCLUSIONS
analysis revealed that the content of such disulfide-originated
structural defects amounted to about 2% (Figure 11). To
further study this aspect, the prepared polymers were subjected
to reducing conditions known to break the disulfide linkages in
synthetic polymers.24 For this, dithiothreitol (DTT) was used
as the reducing agent in THF at room temperature. Initially,
■
In conclusion, a new synthesis of hyperbranched polymers is
developed. In this scheme, proton transfer polymerization of an
AB2 monomer, carrying two epoxide and a thiol units,
produced a double-reactive and general hyperbranched scaffold
at room temperature. The degree of branching in these
5077
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
1
Figure 10. H NMR of monomer 4 and disulfide dimer 16.
polymers was calculated to be 65−69% based upon the 13C
NMR studies. While a carefully carried out model compound
study suggested the presence of about 2% structural defects
originating from the formation of disulfides. The epoxide units
of these polymers could be modified with lipophilic alkyl or
phenyl groups, known for their membrane penetration
properties, or with ethylene oxide chains, known for their
stealth properties. These polymers were also subjected to a
second functionalization reaction. This reaction allowed for
installation of a positively charged primary ammonium site,
known for its complexation capability with a siRNA molecule,
into the polymer structure. Therefore, bivalent materials, of
interest to the gene delivery applications, could be obtained
starting from a general and novel dual-reactive polythioether-
based hyperbranched scaffold obtained through a newly
developed proton transfer polymerization between thiol and
epoxide groups.
Figure 11. 1H NMR of polymer 5 and disulfide dimer 16. The dashed
line indicates the signal originating from the disulfide defect.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis and characterization details. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*(A.K.) E-mail: anzar.khan@mat.ethz.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Figure 12. GPC traces of polymer 10 before (solid line) and after
(dashed line) treatment with DTT (please also see Figure S12 for
polymer 11).
The authors are greatly indebted to the reviewers and the editor
of this work for raising pertinent questions, offering
suggestions, and for constructive criticism. A.K. thanks A. D.
Schluter for support.
̈
5078
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
Zech, C.; Voit, B.; Komber, H. Macromol. Chem. Phys. 1998, 199,
2655−2664. (f) Fan, Z.; Lederer, A.; Voit, B. Polymer 2009, 50, 3431−
3439.
(6) (a) Moers, C.; Nuhn, L.; Wissel, M.; Stangenberg, R.;
Mondeshki, M.; Berger-Nicoletti, E.; Thomas, A.; Schaeffel, D.;
Koynov, K.; Klapper, M.; Zentel, R.; Frey, H. Macromolecules 2013, 46,
REFERENCES
■
(1) (a) Flory, P. J. J. Am. Chem. Soc. 1952, 74, 2718−2723. (b) Flory,
P. J. Principles of Polymer Chemistry; Cornell University Press: Ithaca,
NY, 1953; Chapter 9.
(2) For review articles please see: (a) Frec
Gitsov, I.; Leon, J. W. J. Macromol. Sci., Part A: Pure Appl. Chem. 1996,
́
het, J. M. J.; Hawker, C. J.;
9544−9553. (b) Klein, R.; Schull, C.; Berger-Nicoletti, E.; Haubs, M.;
̈
33, 1399−1425. (b) Sunder, A.; Mulhaupt, R.; Haag, R.; Frey, H. Adv.
̈
Kurz, K.; Frey, H. Macromolecules 2013, 46, 8845−8852. (c) Nuhn, L.;
Mater. 2000, 12, 235−239. (c) Gao, C.; Yan, D. Prog. Polym. Sci. 2004,
29, 183−275. (d) Yates, C. R.; Hayes, W. Eur. Polym. J. 2004, 40,
1257−1281. (e) Voit, B. J. Polym. Sci., Part A: Polym. Chem. 2005, 43,
2679−2699. (f) Voit, B.; Ledere, A. Chem. Rev. 2009, 109, 5924−5973.
Schull, C.; Frey, H.; Zentel, R. Macromolecules 2013, 46, 2892−2904.
̈
(d) Schull, C.; Gieshoff, T.; Frey, H. Polym. Chem. 2013, 4, 4730−
̈
4736. (e) Schull, C.; Frey, H. Polymer 2013, 54, 5443−5455. (f) Skaria,
̈
S.; Thomann, R.; Gomez-Garcia, C. J.; Vanmaele, L.; Loccufier, J.;
Frey, H.; Stiriba, S.-E. J. Polym. Sci., Part A: Polym. Chem. 2014, 52,
1369−1375.
́
(g) Calderon, M.; Quadir, M. A.; Sharma, S. K.; Haag, R. Adv. Mater.
2010, 22, 190−218. (h) Konkolewicz, D.; Monteiro, M. J.; Perrier, S.
Macromolecules 2011, 44, 7067−7087. (i) Segawa, Y.; Higashihara, T.;
Ueda, M. Polym. Chem. 2013, 4, 1746−1759. (j) Jin, H.; Huang, W.;
Zhu, X.; Zhou, Y.; Yan, D. Chem. Soc. Rev. 2012, 41, 5986−5997.
(7) (a) Weinhart, M.; Becherer, T.; Schnurbusch, N.; Schwibbert, K.;
Kunte, H.-J.; Haag, R. Adv. Eng. Mater. 2011, 13, B501−B510.
(b) Steinhilber, D.; Seiffert, S.; Heyman, J. A.; Paulus, F.; Weitz, D. A.;
Haag, R. Biomaterials 2011, 32, 1311−1316. (c) Fischer, W.; Quadir,
M. A.; Barnard, A.; Smith, D. K.; Haag, R. Macromol. Biosci. 2011, 11,
1736−1746. (d) Zill, A.; T. Licha, K.; Haag, R.; Zimmerman, S. C.
New J. Chem. 2012, 36, 419−427. (e) Kurniasih, I. N.; Liang, H.;
(k) Khandare, J.; Calderon
2012, 41, 2824−2848.
(3) (a) Hawker, C. J.; Lee, R.; Frec
1991, 113, 4583−4588. (b) Uhrich, K. E.; Hawker, C. J.; Frec
J.; Turner, S. R. Macromolecules 1992, 25, 4583−4587. (c) Hawker, C.
J.; Frechet, J. M. J.; Grubbs, R. B.; Dao, J. J. Am. Chem. Soc. 1995, 117,
10763−10764. (d) Hawker, C. J.; Chu, F. Macromolecules 1996, 29,
4370−4380. (e) Frechet, J. M. J.; Henmi, M.; Gitsov, I.; Aoshima, S.;
́
, M.; Dagia, N. M.; Haag, R. Chem. Soc. Rev.
́
het, J. M. J. J. Am. Chem. Soc.
het, J. M.
́
Moschwitzer, V. D.; Quadir, M. A.; Radowski, M.; Rabe, J. P.; Haag, R.
̈
́
New J. Chem. 2012, 36, 371−379. (f) Paulus, F.; Weiss, M. E. R.;
Steinhilber, D.; Nikitin, A. N.; Schutte, C.; Haag, R. Macromolecules
́
̈
Leduc, M. R.; Grubbs, R. B. Science 1995, 269, 1080−1083.
2013, 46, 8458−8466. (g) Thengarai, V. S.; Keilitz, J.; Haag, R. Inorg.
(f) Malmstrom, E.; Hult, A. Macromolecules 1996, 29, 1222−1228.
̈
Chim. Acta 2014, 409, 179−184.
(g) Kumar, A.; Ramakrishnan, S. Macromolecules 1996, 29, 2524−
(8) (a) Chang, H.-T.; Frec
2313−2314. (b) Gong, C.; Frec
4997−4999. (c) Emrick, T.; Chang, H.-T.; Frec
Macromolecules 1999, 32, 6380−6382. (d) Hecht, S.; Emrick, T.;
Frechet, J. M. J. Chem. Commun. 2000, 313−14. (e) Emrick, T.;
Chang, H.-T.; Frechet, J. M. J.; Woods, J.; Baccei, L. Polym. Bull. 2000,
45, 1−7.
(9) For functionalization aspects, please see: (a) Haag, R.; Stumbe,
́
het, J. M. J. J. Am. Chem. Soc. 1999, 121,
het, J. M. J. Macromolecules 2000, 33,
het, J. M. J.
́
2530. (h) Weimer, M. W.; Frechet, J. M. J.; Gitsov, I. J. Polym. Sci., Part
́
A: Polym. Chem. 1998, 36, 955−970. (i) Liu, M.; Vladimirov, N.;
Frechet, J. M. J. Macromolecules 1999, 32, 6881−6884. (j) Gao, C.;
́
́
Yan, D. Chem. Commun. 2001, 107−108. (k) Guan, Z. J. Am. Chem.
Soc. 2002, 124, 5616−5617. (l) Stiriba, S.-E.; Kautz, H.; Frey, H. J. Am.
Chem. Soc. 2002, 124, 9698−9699. (m) Jia, Z.; Chen, H.; Zhu, X.; Yan,
D. J. Am. Chem. Soc. 2006, 128, 8144−8145. (n) Gorodetskaya, I. A.;
Choi, T.-L.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 12672−12673.
(o) Sinananwanich, W.; Ueda, M. J. Polym. Sci., Part A: Polym. Chem.
2008, 46, 2689−2700. (p) Huang, W.; Su, L.; Bo, Z. J. Am. Chem. Soc.
2009, 131, 10348−10349. (q) Segawa, Y.; Higashihara, T.; Ueda, M. J.
Am. Chem. Soc. 2010, 132, 11000−11001. (r) Han, J.; Zhao, B.; Gao,
Y.; Tang, A.; Gao, C. Polym. Chem. 2011, 2, 2175−2178. (s) Min, K.;
Gao, H. J. Am. Chem. Soc. 2012, 134, 15680−15683. (t) Chatterjee, S.;
Ramakrishnan, S. ACS Macro Lett. 2012, 1, 593−598. (u) Han, J.; Li,
S.; Tang, A.; Gao, C. Macromolecules 2012, 45, 4966−4977. (v) Han,
J.; Zhao, B.; Tang, A.; Gao, Y.; Gao, C. Polym. Chem. 2012, 3, 1918−
1925. (w) Liu, N.; Vignolle, J.; Vincent, J.-M.; Robert, F.; Landais, Y.;
Cramail, H.; Taton, D. Macromolecules 2014, 47, 1532−1542.
(x) Thurecht, K.; Blakey, J. I.; Peng, H.; Squires, O.; Hsu, S.;
Alexander, C.; Whittaker, A. K. J. Am. Chem. Soc. 2010, 132, 5336−
5337. (y) Xu, J.; Tao, L.; Liu, J.; Bulmus, V.; Davis, T. P.
Macromolecules 2009, 42, 6893−6901.
́
́
́
J.-
F.; Sunder, A.; Frey, H.; Hebel, A. Macromolecules 2000, 33, 8158−
8166. (b) Ambade, A. V.; Kumar, A. J. Polym. Sci., Part A: Polym. Chem.
2004, 42, 5134−5145. (c) Saha, A.; Ramakrishnan, S. Macromolecules
2009, 42, 4028−4037. (d) Roy, R. K.; Ramakrishnan, S. Macro-
molecules 2011, 44, 8398−8406. (e) Samuel, A. Z.; Ramakrishnan, S.
Macromolecules 2012, 45, 2348−2358. (f) Li, S.; Han, J.; Gao, C.
Polym. Chem. 2013, 4, 1774−1787. (g) Li, S.; Gao, C. Polym. Chem.
2013, 4, 4450−4460. (h) Kurniasih, I. N.; Liang, H.; Kumar, S.; Mohr,
A.; Sharma, S. K.; Rabe, J. P.; Haag, R. J. Mater. Chem. B 2013, 1,
3569−3577. (i) Deng, X.-X.; Cui, Y.; Du, F.-S.; Li, Z.-C. Polym. Chem.
2014, 5, 3316−3320. (j) Han, J.; Zheng, Y.; Zhao, B.; Li, S.; Zhang, Y.;
Gao, C. Sci. Rep. 2014, DOI: 10.1038/srep04387.
̆
(10) (a) Incani, V.; Lavasanifar, A.; Uludag, H. Soft Matter 2010, 6,
2124−2138. (b) Som, A.; Tezgel, A. O.; Gabriel, G. J.; Tew, G. N.
Angew. Chem., Int. Ed. 2011, 50, 6147−6150. (c) Tezgel, A. O.;
Gonzalez-Perez, G.; Telfer, J. C.; Osborne, B. A.; Minter, L. M.; Tew,
G. N. Mol. Ther. 2013, 21, 201−20. (d) Hennig, A.; Gabriel, G. J.;
Tew, G. N.; Matile, S. J. Am. Chem. Soc. 2008, 130, 10338−10344.
(e) Som, A.; Tezgel, A. O.; Gabriel, G. J.; Tew, G. N. Angew. Chem.,
Int. Ed. 2011, 50, 6147−6150. (f) Som, A.; Reuter, A.; Tew, G. N.
Angew. Chem., Int. Ed. 2012, 51, 980−983.
(4) (a) Konkolewicz, D.; Gray-Weale, A.; Perrier, S. J. Am. Chem. Soc.
2009, 131, 18075−18077. (b) Liu, B.; Kazlauciunas, A.; Guthrie, J. T.;
Perrier, S. Macromolecules 2005, 38, 2131−2136. (c) Konkolewicz, D.;
Poon, C. K.; Gray-Weale, A.; Perrier, S. Chem. Commun. 2011, 47,
239−241. (d) Semsarilar, M.; Ladmiral, V.; Perrier, S. Macromolecules
2010, 43, 1438−1443. (e) Konkolewicz, D.; Gaillard, S.; West, A. G.;
Cheng, Y. Y.; Gray-Weale, A.; Schmidt, T. W.; Nolan, S. P.; Perrier, S.
Organometallics 2011, 30, 1315−1318. (f) Koh, M. L.; Konkolewicz,
D.; Perrier, S. Macromolecules 2011, 44, 2715−2724. (g) Sinananwa-
nich, W.; Higashihara, T.; Ueda, M. Macromolecules 2009, 42, 994−
(11) Buerkli, C.; Lee, S. H.; Moroz, E.; Stuparu, M. C.; Leroux, J.-C.;
Khan, A. Biomacromolecules 2014, 15, 1707−1715.
(12) Caliceti, P.; Veronese, F. M. Adv. Drug Delivery Rev. 2003, 55,
1261−1277.
(13) Miyata, K.; Nishiyama, N.; Kataoka, K. Chem. Soc. Rev. 2012, 41,
2562−2574.
1001. (h) Kali, G.; Szesztay, M.; Bodor, A.; Ivan
Phys. 2007, 208, 1388−1393. (i) Kali, G.; Szesztay, M.; Bodor, A.;
Ivan, B. Macromol. Symp. 2013, 323, 37−41.
(5) (a) Potzsch, R.; Stahl, B. C.; Komber, H.; Hawker, C. J.; Voit, B.
́
, B. Macromol. Chem.
(14) Wagner, E. Acc. Chem. Res. 2012, 45, 1005−1013.
(15) (a) McEwan, K. A.; Slavin, S.; Tunnah, E.; Haddleton, D. M.
Polym. Chem. 2013, 4, 2608−2614. (b) Reinicke, S.; Espeel, P.;
Stamenovic, M. M.; Du Prez, F. E. ACS Macro Lett. 2013, 2, 539−543.
(c) Kakuchi, R.; Theato, P. Polym. Chem. 2014, 5, 2320−2325.
(d) Saha, A.; De, S.; Stuparu, M. C.; Khan, A. J. Am. Chem. Soc. 2012,
134, 17291−17297.
́
̈
Polym. Chem. 2014, 5, 2911−2921. (b) Potzsch, R.; Komber, H.; Stahl,
̈
B. C.; Hawker, C. J.; Voit, B. Macromol. Rapid Commun. 2013, 34,
1772−1778. (c) Karak1, N.; Roy, B.; Voit, B. J. Polym. Sci., Part A:
Polym. Chem. 2010, 48, 3994−4004. (d) Stumpe, K.; Komber, H.;
Voit, B. Macromol. Chem. Phys. 2006, 207, 1825−1833. (e) Maier, G.;
5079
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080

Macromolecules
Article
(16) (a) De, S.; Khan, A. Chem. Commun. 2012, 48, 3130−3132.
(b) Brandle, A.; Khan, A. Polym. Chem. 2012, 3, 3224−3227. (c) De,
̈
S.; Stelzer, C.; Khan, A. Polym. Chem. 2012, 3, 2342−2345. (d) Gadwal,
I.; Khan, A. Polym. Chem. 2013, 4, 2440−2444. (e) Cengiz, N.; Rao, J.;
Sanyal, A.; Khan, A. Chem. Commun. 2013, 49, 11191−11193.
(f) Gadwal, I.; Rao, J.; Baettig, J.; Khan, A. Macromolecules 2014, 47,
35−40. (g) Binder, S.; Gadwal, I.; Bielmann, A.; Khan, A. J. Polym. Sci.,
Part A: Polym. Chem. 2014, 52, 2040−2046.
(17) (a) Bearinger, J. P.; Terrettaz, S.; Michel, R.; Tirelli, N.; Vogel,
H.; Textor, M.; Hubbell, J. A. Nat. Mater. 2003, 2, 259−264.
(b) Napoli, A.; Valentini, M.; Tirelli, N.; Muller, M.; Hubbell, J. A. Nat.
̈
Mater. 2004, 3, 183−189. (c) Kramer, J. R.; Deming, T. J.
Biomacromolecules 2012, 13, 1719−1723.
(18) Albanese, D.; Landini, D.; Penso, M. Synthesis-Stuttgart 1994,
34−36.
(19) Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M.
Phosphorous, Sulfur, Silicon 2010, 185, 1550−1557.
(20) Reeve, W.; Erikson, C. M.; Aluotto, P. F. Can. J. Chem. 1979, 57,
2747.
(21) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 451−464.
(22) Malmstrom, E.; Johansson, M.; Hult, A. Macromolecules 1995,
28, 1698−1703.
(23) Holter, D.; Burgath, A.; Frey, H. Acta Polym. 1997, 48, 30−35.
̈
(24) Klaikherd, A.; Ghosh, S.; Thayumanavan, S. Macromolecules
2007, 40, 8518−8520.
5080
dx.doi.org/10.1021/ma500920z | Macromolecules 2014, 47, 5070−5080