Ring-Opening Copolymerization of Maleic Anhydride with Functional Epoxides: Poly(propylene fumarate) Analogues Capable of Post-Polymerization Modification

Article abstract of DOI:10.1002/anie.201807419

Three functional epoxides were copolymerized with maleic anhydride to yield degradable poly(propylene fumarate) analogues. The polymers were modified post-polymerization and post-printing with either click-type addition reactions or UV deprotection to eit

Full text of DOI:10.1002/anie.201807419

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Accepted Article
Title: Ring-opening Copolymerization of Maleic Anhydride with
Functional Epoxides to Yield Poly(propylene fumarate)
Analogues Capable of Post-polymerization Modification
Authors: Yusheng Chen, James A Wilson, Shannon R Petersen, Derek
Luong, Sahar Sallam, Jialin Mao, Chrys Wesdemiotis, and
Matthew Leonard Becker
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807419
Angew. Chem. 10.1002/ange.201807419
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10.1002/anie.201807419
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COMMUNICATION
Ring-opening Copolymerization of Maleic Anhydride with
Functional Epoxides to Yield Poly(propylene fumarate)
Analogues Capable of Post-polymerization Modification
Yusheng Chen[a], James A. Wilson[a], Shannon R. Petersen[a], Derek Luong[a], Sahar Sallam[b], Jialin
Mao[b], Chrys Wesdemiotis[a][b] and Matthew L. Becker*[a][c]
Abstract: Three functional epoxides were copolymerized with maleic
anhydride to yield degradable poly(propylene fumarate) analogues.
The polymers were modified post-polymerization and post-printing
with “click”-type addition reactions or UV deprotection in order to
attach bioactive species or increase the hydrophilicity. Successful dye
attachment, induced wettability and improved cell spreading show the
viability of these analogues in biomaterials applications.
concentration specific methods for attaching bioactive molecules
would be advantageous, but these opportunities are limited as few
bioactive species are able to survive thermal processing,
photochemical printing and/or post-printing irradiation processes.
Due to the highly quantitative yields, rapid orthogonal
addition and mild reaction conditions,[19] “click”-type addition
reactions have been used widely to form polymer-bioactive
molecule conjugated compounds.[20],[21] The addition of bioactive
molecules in order to enhance cell attachment, growth and
proliferation via “click” chemistry has been demonstrated in
multiple studies using a Huisgen 1,3-dipolar cycloaddition.[22],[23]
Additionally, with the appropriate reactive handle, these reactions
can be performed post-polymerization or post-printing so that
bioactive conjugates are not subjected to harsh processing or
irradiation. Thus, incorporating reactive handles at the chain end
or within the backbone may afford a route to “click” modifiable
PPF analogues. [24],[25]
Degradable polyesters have been used widely in regenerative
medicine applications.[1],[2],[3],[4] While many of these materials
have enjoyed clinical and commercial success, efforts to broaden
the scope of chemical, mechanical and degradation properties
have proven challenging.[3],[5],[6] The most widely used synthetic
polyesters in biomedical applications are poly(L-lactic acid)
(PLLA),[7],[8],[9],[10] poly(lactic acid-co-glycolic acid) (PLGA) and
poly(휀-caprolactone) (PCL).[11],[12] However, as a consequence of
long degradation times, acidic degradation products and limited
handles for post-polymerization modification, new materials with
well-defined properties and easily accessible functional handles
are needed.[13]
Another widely investigated degradable polyester is
poly(propylene fumarate) (PPF). PPF is resorbable upon
degradation and contains an alkene group in its backbone, which
facilitates photochemical crosslinking and 3D printing via
stereolithographic methods.[14] PPF has generated substantial
interest for use as patient specific bone scaffolds as its modulus
when crosslinked is near that of cancellous bone.[15] Despite its
potential in regenerative medicine, PPF lacks inherent
osteoconductive and osteoinductive properties known to
stimulate bone growth. Previous studies have shown that PPF
scaffolds preloaded with a number of pharmaceuticals, short
peptide chains and biologically active molecules help promote cell
attachment, growth, differentiation and proliferation.[16],[17],[18]
However, most reports of PPF functionalization are non-specific,
physical interactions. Thus, covalent, regioselective and
Traditionally, PPF has been synthesized via step-growth
polymerization, which requires both elevated temperature and
reduced pressure and typically results in modest yields, broad
molecular mass distribution (ÐM) and byproducts that must be
removed prior to use.[26] Various copolymerization strategies of
epoxides, anhydrides and lactones have been investigated
previously to produce a wide range of polyesters.[27] [28] [29] [30]
,
,
,
Recently, PPF was synthesized using an alternating ring-opening
copolymerization (ROCOP) of maleic anhydride (MA) and
propylene oxide (PO) to produce poly(propylene maleate) (PPM),
which was subsequently isomerized to produce PPF.[31] [32] [33] [34]
,
,
,
This approach results in a much higher degree of control of the
material properties and the use of two monomer species offers
multiple sites for post-polymerization chain functionalization. We
recently demonstrated the utility of magnesium 2,6-di-tert-butyl-4-
methylphenoxide (Mg(THF)2(BHT)2) in the production of end-
functionalized PPF via ROCOP.[25] In this study, both
Megastokes® 673-azide dye and a GRGDS peptide were
attached to the propargyl functionalized chain-end after scaffold
crosslinking to demonstrate the feasibility of using the reactive
handles and “click” type reactions for post-printing bioconjugate
addition.
[a] Y. Chen, S. R. Petersen, Dr. J. A. Wilson, D. Luong, Prof. M. L. Becker
Department of Polymer Science, The University of Akron
Akron, OH 44325 (USA)
However, in order to adopt a functional backbone strategy in
the production of PPF,[35] [36] [37]
either PO or MA must be modified.
,
,
E-mail: becker@uakron.edu
[b] Dr. S. Sallam, J. Mao, Prof. C. Wesdemiotis
Department of Chemistry, The University of Akron
Akron, OH 44325 (USA)
The functionalization of MA significantly alters the reactivity of the
alkene group,[38] which will decrease or sacrifice the ability of PPF
to undergo photo-crosslinking reactions. Alternatively, epoxides
can be modified easily to incorporate a pendent functional group
[c] Prof. M. L. Becker
Department of Biomedical Engineering, The University of Akron
Akron, OH 44325 (USA)
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10.1002/anie.201807419
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COMMUNICATION
into the chain.[39],[40] Using a functional monomer approach, the
stoichiometry of the respective epoxide can be controlled and
multifunctional polymer chains are possible.[41],[42],[43] Herein, we
utilize ROCOP of MA and functional epoxides to produce a series
of chlorine, propargyl and o-nitrophenyl functionalized PPF
analogues that can undergo post-polymerization and post-print
type reactions for the rapid attachment of bioactive conjugates.
While epichlorohydrin (EC) has been demonstrated in the
literature to copolymerize with MA,[31],[33],[44] so far no example has
been shown to introduce propargyl or o-nitrophenyl moieties into
PPF analogues.
one major distribution was observed by MALDI-ToF MS, which
corresponds to a benzyl alcohol-initiated chain and a 190 Da
repeat unit corresponding to EC and MA (Figure S4B). The
successful synthesis of poly(epichlorohydrin fumarate) (PEF)
demonstrates that this polymerization can be used to
copolymerize modified epoxides with MA without unwanted side
reactions.
After successfully synthesizing a chlorine functionalized PPF
analogue, “clickable” and UV-sensitive epoxides containing an
alkyne or o-nitrophenyl group were synthesized. Glycidyl
propargyl
nitrophenyl)methoxy)methyl)oxirane (NMMO) were synthesized
using
phase transfer agent catalyzed system.[46] The
ether
(GPE)
and
2-(((2-
In order to explore the viability of Mg(THF)2(BHT)2 catalyzed
ROCOP with functional epoxides (EP), equimolar quantity of EC
and MA were copolymerized under sealed, dry and inert
conditions, using benzyl alcohol as an initiator at a 2 M
concentration in toluene. The reaction mixture was heated at 80
oC for 24 hours (Scheme 1). After quenching, the solution was
a
copolymerization of these monomers with MA was conducted
following the same synthetic procedure as that of PEF (Scheme
1). It should be noted that propargyl alcohol was used as the
initiator for poly(NMMO fumarate) (PNMMOF) synthesis in place
of benzyl alcohol since the proton resonances of the benzyl
alcohol and o-nitrophenyl groups coincide. 1H NMR spectroscopic
analysis of the resultant poly(GPE fumarate) (PGPEF) and
PNMMOF, showed proton resonances at δ = 2.49 ppm and δ =
7.35-8.15 ppm, which correspond to the protons from the
propargyl alcohol alkyne and aromatic o-nitrophenyl protons,
respectively (Figures 1, S7).
o
precipitated into an equimolar quantity of warm (40 C) hexanes
in order to remove residual MA and catalyst. The recovered
polymer, poly(epichlorohydrin maleate) (PEM), was characterized
using 1H NMR spectroscopy. As a consequence of the difference
in chemical structure compared to PPM, the proton resonances
corresponding to the methylene adjacent to the chlorine atom are
shifted downfield to δ = 3.75 ppm rather than δ = 1.25 ppm, which
corresponds to the pendent methyl group of PPM.
Scheme 1. Synthesis and post-polymerization modification of poly(propylene
fumarate) analogues that incorporate functional epoxides using magnesium 2,6-
di-tert-butyl-4-methylphenoxide.
Following
a previously reported procedure, PEM was
isomerized using diethylamine.[45] The resonance corresponding
to the alkene protons at δ = 6.32 ppm shifted downfield to δ = 6.90
ppm, which confirmed the change from cis to trans
stereochemistry. Two separate resonances appeared at δ = 4.40-
4.60 ppm as a consequence of regiochemical differences during
the ring-opening of epichlorohydrin, which resolves to a greater
extent after isomerization (Figure S4A).
Matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry (MALDI-ToF MS) was used to determine the repeat
unit molecular mass and end-group fidelity. Before isomerization,
Figure 1. Comparison of 1H NMR spectra and MALDI-ToF MS plots before and
after CuAAC of PGPEF and benzyl azide.
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MALDI-ToF MS analysis of each polymer further confirmed
the end-group fidelity and molecular mass of the repeat units for
PGPEF (210 Da) and PNMMOF (307 Da) (Figures 1, S9). The
distributions were also used to determine the molecular mass of
each polymer. Each polymer showed no ether linkages in the
backbone according to the mass spectra, indicating that no
homopolymerization of epoxide occurred even when using
epoxides with higher reactivity.
Additionally, different monomer feed ratios and targeted
molecular masses within the expected 3D printable range was
investigated (Table 1). It is worth noting that as the steric bulk of
the epoxides increases, the glass transition temperature (Tg)
decreases. This implies that pendent functional groups from
comonomer functionalization can be used to modify the Tg of the
polymer and produce room-temperature fluid PPF analogues.
This is advantageous as current, printable PPF resin formulations
contain ~50% solvent, reactive diluent and other fillers.[15]
CuAAC cycloaddition (Figure S12). Fluorescence microscopy
was used to image a thin film of PGPEF post-addition which was
then compared to a film with no dye attached (Figure S13). Also,
a TEM grid was used as a mask, which proves that selective dye
attachment is achievable (Figure 2). As expected, the areas of
the thin film exposed to fluorescent dye showed significantly
higher intensity under fluorescence microscopy.
For the PNMMOF post-polymerization modification, the
photochemical deprotection reaction was monitored by UV/Visible
spectroscopy. The maximum absorbance of the starting polymer
solution was at 260 nm. After 20 minutes of 365 nm UV treatment,
the absorption peak at 260 nm decreased and two new absorption
peaks appeared at 290 and 315 nm. This corresponds to the π-
π* transition of the aromatic side product (o-nitroso
benzaldehyde) which shows that the o-nitrophenyl group was
cleaved by UV light. However, if the UV light was employed for
more than 20 minutes, these two peaks disappeared, which may
indicate other photochemical reactions of the aromatic by-product
(Figure 3).[47] The reaction was further monitored by 1H NMR
spectroscopy, which confirmed cleavage of o-nitroso
benzaldehyde from the polymer backbone (Figures S14, 15).
After 240 minutes of UV treatment, a different UV absorption
curve was observed than that of PPF with a propargyl alcohol
end-group, implying that the hydroxyl functionalized polymer,
poly(glycidol fumarate) (PGF) was obtained.
Figure 2. Fluorescence microscopy image of Megastokes® 673-azide dye
attached PGPEF thin film. Under 673 nm filter at 10x magnification with TEM
grid as mask, the dark regions correspond to the PGPEF film areas that were
covered by the TEM grid, the red shows the areas of the PGPEF film exposed
to the dye.
To ensure this is a viable strategy for bioconjugate addition, it
is necessary to prove that the added functionalities are able to
undergo post-polymerization modification. For each functional
epoxide,
one
specific,
orthogonal
post-polymerization
modification was selected. The alkyne groups of PGPEF
underwent the copper(I)-mediated azide-alkyne cycloaddition
(CuAAC) in CHCl3 with benzyl azide or with a fluorescent dye on
the surface of a polymer thin film. The o-nitrophenyl group in
PNMMOF was deprotected by 365 nm UV light with THF as
solvent (Scheme 1).
After the cycloaddition of benzyl azide, the resultant PGPEF
was characterized by MALDI-ToF MS in order to detect the
difference in the mass of the repeat unit and the extent of
conversion. The repeat unit molecular mass was observed to
increase from 210 Da to 343 Da, with the additional 133 Da
attributable to the mass of benzyl azide. Moreover, the significant
shift to a higher mass region from the same DP peak indicated
the addition of benzyl azide group to each alkyne (Figures 1). In
the 1H NMR spectra, the new proton resonance at δ = 7.50 ppm
and disappearance of proton resonance at δ = 2.50 ppm indicated
the formation of triazole structure as a consequence of the
Figure 3. UV/visible spectra during photochemical reaction of PNMMOF as a
function of irradiation time. Before the photoreaction, the polymer solution
maximum absorption was at around 260 nm, as treatment time increased, the
absorption decreased, and peaks emerged at 290 and 315 nm related to the
aromatic side products.
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Table 1. Copolymerization of maleic anhydride with different epoxides
[d]
[d]
[e]
[e]
Time
/h
ConversionMA
/%
Mn
Mn
Mw
[e]
Entry
DP
[MA]:[EP]:[I]:[Cat]
ÐM
Tg/oC
/kDa
/kDa
/kDa
1[a]
2[a]
3[b]
10
25
10
10:10:1:1
25:25:1:1
10:10:1:1
24
24
24
85
93
96
1.2
2.0
2.9
1.45
1.21
1.29
10
29
-5
3.7
2.6
3.2
1.3
1.1
1.4
4[b]
25
25:25:1:1
24
78
2.7
1.5
1.9
1.31
-2
5[c]
6[c]
10
25
10:10:1:1
25:25:1:1
24
24
65
80
1.0
1.6
2.0
3.3
2.3
4.9
1.20
1.50
11
-5
[a] EP = epichlorohydrin. [b] EP = glycidyl propargyl ether. [c] EP = 2-(((2-nitrophenyl)methoxy)methyl)oxirane. [d] Determined by 1H NMR
spectroscopy. [e] Determined by SEC against poly(styrene) standards.
Additionally, since hydroxyl groups only appear after
deprotection, it was expected that the polymer water solubility
should change significantly. PNMMOF and the deprotected
polymer PGF were put into water for one day at 25 °C. The PGF
was fully dissolved to yield a light yellow solution, while PNMMOF
remained insoluble. Further evidence was observed from a
contact angle measurement. Following deprotection, the water
contact angle on the PGF film was 35.11.8°, compared to the
PNMMOF film which has a contact angle of 58.42.0°. The
significant decrease of the contact angle value notes an increase
in the surface hydrophilicity, which has the potential to enhance
cell spreading and adhesion (Figure 4).[48] To demonstrate this,
mouse calvarial stem cells (MC3T3-E1) were cultured onto
PNNMOF and PGF coated glass slides for 48 h. Significantly
higher cell spreading was observed on the PGF thin films,
showing that the cells can sense the enhanced hydrophilicity of
the deprotected polymer (Figure S16). Additionally, surface
energy measurements showed that compared to PNMMOF
surface energy (28.14.0 mJ/m2), PGF thin film has a higher
surface energy (48.87.4 mJ/m2) (Table S2).
was obtained. All three EP monomers were confirmed in the
resultant polymer via 1H NMR spectroscopy and MALDI-ToF MS
analysis (Figure 5 and S10). Statistical sequencing of the
terpolymer was observed through the distribution of repeat unit
molecular masses. This tri-functional PPF analogue is presented
as a proof of concept and further investigation into functional
terpolymers is currently underway.
Figure 4. Static contact angle test results. The smaller contact angle of the
deprotected polymer film indicated formation of hydroxyl groups. The
existence of hydroxyl groups also changed polymer water solubility. The
slight yellow color of the polymer water solution shows that the deprotected
PNMMOF was released.
Figure 5. MALDI-ToF MS plots of target DP24 statistical terpolymers.
Finally, as a proof of versatility of this ROCOP method for the
production of PPF analogues, statistical terpolymers were
synthesized using equimolar EC, GPE and NMMO with the
corresponding quantity of MA under the same conditions as
above and a targeted DP of 24. After 24 h, 77% monomer
conversion of MA was achieved and a 2.2 kDa (Mn, SEC) polymer
In summary, a comonomer modification method based on
the ROCOP of MA with various epoxides was employed to yield
functionalized PPF analogues. The ability to incorporate
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Acknowledgements
The Ohio Department of Development’s Open Innovation
Platform “Akron Functional Materials Center” and 21st Century
Medical Technologies are acknowledged for financial support.
M.L.B is grateful for support from the W. Gerald Austen Endowed
Chair in Polymer Science and Polymer Engineering from the John
S. and James L. Knight Foundation. C.W. acknowledges support
from NSF (CHE-1308307). The authors acknowledge useful
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10.1002/anie.201807419
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
Yusheng Chen, James A. Wilson, Shannon R.
Petersen, Derek Luong, Sahar Sallam, Jialin
Mao, Chrys Wesdemiotis and Matthew L.
Becker*
Polyester
Poly(propylene
functionalization:
fumarate) was
functionalized with chlorine, alkyne
and nitrophenyl groups via ring-
opening copolymerization of modified
epoxides and maleic anhydride.
These polymers can be modified by
post-polymerization and post-printing
modification.
Page No. – Page No.
Ring-opening Copolymerization of
Maleic Anhydride with Functional
Epoxides to Yield Poly(propylene
fumarate) Analogues Capable of Post-
polymerization Modification
This article is protected by copyright. All rights reserved.