Synthesis of atactic and isotactic poly(1,2-glycerol carbonate)s: Degradable polymers for biomedical and pharmaceutical applications

Article abstract of DOI:10.1021/ja402558m

The synthesis and characterization of atactic and isotactic linear poly(benzyl 1,2-glycerol carbonate)s are reported. The poly(benzyl 1,2-glycerol carbonate)s were obtained via the ring-opening copolymerization of rac-/(R)-benzyl glycidyl ether with CO

Full text of DOI:10.1021/ja402558m

Communication
pubs.acs.org/JACS
Synthesis of Atactic and Isotactic Poly(1,2-glycerol carbonate)s:
Degradable Polymers for Biomedical and Pharmaceutical
Applications
Heng Zhang and Mark W. Grinstaff*
Departments of Biomedical Engineering and Chemistry, Boston University, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: The synthesis and characterization of
atactic and isotactic linear poly(benzyl 1,2-glycerol
carbonate)s are reported. The poly(benzyl 1,2-glycerol
carbonate)s were obtained via the ring-opening copoly-
merization of rac-/(R)-benzyl glycidyl ether with CO2
using [SalcyCoIIIX] complexes with high carbonate linkage
selectivity and polymer/cyclic carbonate selectivity
(>99%). Deprotection of the resultant polymers afforded
poly(1,2-glycerol carbonate)s with a functionalizable
pendant primary hydroxyl group. Poly(1,2-glycerol carbo-
nate) showed a remarkable increase in degradation rate
compared to poly(1,3-glycerol carbonate) with a t1/2 ≈ 2−
3 days. These polymers fulfill an unmet need for a readily
degradable biocompatible polycarbonate.
Figure 1. Chemical structures of a linear poly(1,3-glycerol carbonate)
and poly(1,2-glycerol carbonate).
glycerol carbonate)s using readily available starting material
benzyl glycidyl ether (1), the hydrolytic kinetic resolution of 1
using Jacobsen’s catalyst and subsequent polymerization to
afford the chiral isotactic polymer, the deprotection of the
benzyl to afford the polymer with a primary hydroxyl group,
and the degradation rate of the polymer.
Linear poly(1,3-glycerol carbonate)s are synthesized via ring-
opening polymerization of the six-membered cyclic 3-
benzyloxytrimethylene carbonate2b,10 or dimethylacetal dihy-
droxyacetone carbonate6b,11 monomers. Postpolymerization,
the benzyl group is hydrogenated or the ketone is reduced to
afford a hydroxyl group, respectively. Although these routes
provide ample materials, the monomers require 2−3 steps for
preparation and the resulting polymers possess a secondary, less
reactive hydroxyl for subsequent use and are usually of broad
molecular distribution. Poly(1,2-glycerol carbonate)s would
likely be challenging to synthesize via the ring opening of the
corresponding five-membered cyclic glycerol carbonate mono-
mer, as five-membered cyclic carbonate monomers are
thermodynamically stable and, generally, unreactive toward
ring-opening polymerization.12 However these polymers may
be accessed via the ring-opening copolymerization of the
corresponding glycidyl ether with CO2. Given the elegant work
of Coates,13 Darensbourg,14 Lu,15 and Nozaki16 on expoxide
ring-opening copolymerization with carbon dioxide using metal
salen catalysts, we explored this approach to prepare linear
poly(1, 2-glycerol carbonate)s.
lycerol based polymers are of widespread interest for
G
industrial, cosmetic, and pharmaceutical applications.
Various polymer architectures from linear to dendritic are
reported for pure polyglycerol ethers and carbonates as well as
coploymers with hydroxyacids, for example, to give polyether
esters or polycarbonate esters.1 Within the biomedical arena,
these polymers possess the following advantages: (1) a free
hydroxyl for functionalization with chemotherapeutic agents,
antibacterial compounds, anti-inflammatory agents,2 fluorescent
tags,3 or material property modifiers;4 (2) a defined
biodegradation route to afford nontoxic and nonacidic
byproducts, e.g., glycerol and carbon dioxide; (3) physical
properties ranging from semicrystalline or amorphous materials
based on the polymer or copolymer composition; and (4)
amenability to manufacturing methods such as electrospin-
ning.5 In many ways, these polymers provide users the
capabilities of well-known polymers like PLA (polylactic acid)
or PLGA (poly(lactic-co-glycolic acid)) with the additional
benefits of an easily modifiable structure and nonacidic
products upon biodegradation. These advantages have been
put to use, and poly(1,3-glycerol carbonate)2b,6 based
biomaterials are being investigated as drug-loaded buttressing
films for the prevention of tumor recurrence after surgical
resection,7 particles for drug delivery,3,6a,8 and coatings for the
prevention of seroma.9 Surprisingly, linear poly(1,2-glycerol
carbonate)s are far less explored (Figure 1), and yet, one would
hypothesize that these materials would degrade more readily
than the 1,3-glycerol analogs fulfilling an unmet need for readily
degradable biocompatible polycarbonates. Herein, we report a
facile and efficient method to synthesize linear atactic poly(1,2-
The benzyl protected poly(1,2-glycerol carbonate) was
synthesized via ring-opening copolymerization of benzyl
glycidyl ether (BGE), 1, with CO2 (220 psi) using the
[SalcyCoIIIX] complexes, 2a−2e, shown in Figure 2. We first
examined a series of catalysts with different axial ligands
including nitrate, chloride, bromide, trichloroacetate, and 2,4-
dinitrophenoxy (DNP) (Table 1). All of the resultant polymers
Received: March 12, 2013
Published: April 23, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
plex was a more thermally stable and robust catalyst (even
under diluted solutions) for CO2/epoxide polymerizations,20
we investigated this catalyst, 3, for the polymerization of
monomer 1 (Figure 2). Catalyst 3 was synthesized following a
slightly modified literature procedure (see SI for details).20 The
polymers ranged in Mn from 30 to 50 kg/mol, contained >99%
carbonate linkage with >97% polycarbonate selectivity, and
possessed narrow PDIs (Table 2). Increasing the temperature
Table 2. Copolymerization of rac-BGE with CO2 Using
a
Catalyst 3
Mn
catalyst
loading
temp
(°C)
turnover freq.
(h−1
selectivity
(% PPC)
(kg/mol)/
Figure 2. Synthesis of poly(benzyl 1,2-glycerol carbonate)s (PBGCs)
b
no.
)
PDI
using [SalcyCoIIIX]/PPNY.
1
2
3
4
5
2000:1
2000:1
4000:1
10000:1
10000:1
4000:1
20
40
40
40
60
40
148
362
328
288
620
235
>99
>99
>99
>99
97
34.9/1.10
33.6/1.11
48.1/1.13
38.1/1.09
32.2/1.14
37.3/1.15
Table 1. Axial Ligand Effect on the Polymerization of rac-
BGE with Carbon Dioxide Using [(S,S)-SalcyCoIIIX]/
[PPN]Y
a
c
turnover freq.
(h−1
selectivity
(% PBGC)
Mn
(kg/mol)
6
>99
b
no. catalyst
)
PDI
a
The reactions were performed in neat rac-BGE (3.81 mL, 25 mmol)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2e
2e
123
142
146
160
140
150
200
96
94
32.3
34.4
19.7
25.5
41.3
33.6
27.3
1.13
1.12
1.15
1.09
1.10
1.13
1.12
in a 45 mL autoclave under 220 psi of CO2 pressure to 50%−60%
conversion using catalyst 3. All resultant poly(benzyl 1,2-glycerol
carbonate)s (PBGCs) contain >99% carbonate linkage, determined by
73
b
1H spectroscopy. All resultant polymers exhibit a bimodal
96
c
98
distribution; the values are averaged over two peaks. The reaction
was performed in 1 mL of toluene.
c
>99
87
cd
,
a
The reactions were performed in neat rac-BGE (3.81 mL, 25 mmol)
or decreasing the catalyst loading afforded an increase in the
catalyst turnover number with the greatest value, 620 h−1,
achieved at a temperature of 60 °C and a 10000:1 monomer-to-
catalyst ratio, with slightly compromised polymer selectivity
(97%). Running the reaction in 1 mL of toluene at a 4000:1
catalyst loading (entry 6, Table 2) resulted in nearly complete
conversion (>97%) of the monomer. The poly(benzyl 1,2-
glycerol carbonate) polymers were soluble in DCM, THF, and
toluene, but not in alcohols or water.
Given the encouraging results above, we next synthesized a
chiral, isotactic version of the polymer and compared it to an
atactic version of the polymer. A hydrolytic kinetic resolution of
monomer 1 was performed with Jacobson’s catalyst in greater
than 98% yield to afford the R-enantiomer, following a
published procedure.21 Subsequent polymerization of the R-
enantiomer with CO2 using catalyst 3 afforded an isotactic
polymer 4 of 20.3 kg/mol with a PDI of 1.11 (Scheme 1). The
atactic polymer was prepared by copolymerization of rac-BGE
with CO2 using [rac-SalcyCoIIIDNP].22 The isotactic nature of
in a 45 mL autoclave under 220 psi of CO2 pressure with 1000:1:1 rac-
BGE/[(S,S)-SalcyCoIIIX]/[PPN]Cl loading at 22 °C for 4 h. All
resultant poly(benzyl 1,2-glycerol carbonate)s (PBGCs) contain >99%
b
carbonate linkage, determined by 1H spectroscopy. All resultant
polymers exhibit a bimodal distribution; the values are averaged over
c
two peaks. The reaction was performed with cocatalyst [PPN]DNP.
d
The reaction was performed at 50 °C.
contained >99% carbonate linkage, as determined by 1H NMR,
and the selectivity for polycarbonate over cyclic carbonate
ranged from 73% to 98% depending on the axial ligand. The
selectivity was highest for DNP and lowest for bromide. When
DNP serves as both an axial ligand and a cocatalyst anion, the
highest selectivity was achieved. All resultant polymers showed
a head-to-tail selectivity of 92%. The catalyst activity, however,
was significantly lower than that reported for the polymer-
ization of propylene oxide (∼150 h−1 vs ∼500 h−1,13a,17
respectively). This may be a result of the more sterically
hindered side chain or trace water coordinating to the Co
reducing catalytic activity.18 Increasing the temperature to 50
°C led to moderately increased activity, but the selectivity was
still compromised. SEC analysis revealed molecular weights
significantly lower than theoretical values and bimodal but
narrow PDIs (<1.07 for each and <1.15 combined). A plot of
molecular weight versus conversion (see Supporting Informa-
tion (SI)) showed a linear increase of Mn with conversion.
These results are consistent with an immortal polymerization
mechanism involving fast and reversible chain transfer, as has
been reported for the polymerization of propylene oxide.13a19
As observed in the copolymerization of propylene oxide with
CO2, we also noticed that the cyclic carbonate product was
being produced when the conversion reached ∼70%. Based on
the work by Lu who reported that a tethered 1,5,7-
triabicyclo[4,4,0]-dec-5-ene coordinating [SalcyCoIIIX] com-
Scheme 1. Synthesis of Isotactic Poly(benzyl 1,2-glycerol
carbonate)
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Journal of the American Chemical Society
Communication
the polymer is evident from the 13C NMR spectrum as shown
in Figure 3. The atactic polymer is characterized by the
days. No degradation occurred over the 4 day period with
poly(1,3-glycerol carbonate). The increase in degradation is
attributed to the lower activation energy required for
intramolecular attack of the pendant 1° OH, compared to the
2° OH group in poly(1,3-glycerol carbonate), to the carbonate
linkage, as the 2° OH group requires greater movement of the
polymer backbone chain with formation of the thermodynami-
cally stable five-membered cyclic glycerol carbonate.
In summary a facile route to atactic and isotactic poly(1,2-
glycerol carbonate)s is reported via copolymerization of benzyl
glycidyl ether with CO2 using Co-salen complexes. These
polycarbonates, from simple and abundant starting materials,
expand the repertoire of readily degradable polymers available
for biomedical applications, including one that is chiral.
Currently used polymers are generally limited in composition
and functionalizability being based on pure polyhydroxyacids,
although a few significant exceptions exist including poly-
phosphoesters, copolymers of lactic acid with lysine or
xylofuranose, and hydroxyl/carboxyl-functionalized polycapro-
lactones.23 Continued investigation into new polymer compo-
sitions, methods of polymerization, and catalysts is critical to
meet the changing and varied demands of polymer properties
for medical devices, drug-device combinations, and tissue-
engineered scaffolds.
Figure 3. 13C carbonyl region of atactic (left) and isotactic (right)
polymer (125 MHz, CDCl3).
overlapping carbonyl peaks that are similar in intensity, while
the isotactic polymer exhibits one single sharp peak at 154.1
ppm. The 13C spectrum also shows a head-to-tail selectivity of
98%. When the polymer is dissolved in THF, it possesses a
specific rotation of −15.2° at 27 °C.
Next, the benzyl-protecting group of the primary hydroxyl of
the polymer was removed using hydrogenation. Specifically, the
atactic (Mn = 25.5 kg/mol; PDI 1.09; entry 4, Table 1) or
isotactic (20.3 kg/mol; PDI 1.11; 4) polymer was dissolved in
7:3 ethyl acetate/methanol with Pd/C (20% catalyst loading
based on Pd) and pressurized to 600 psi of H2 for 24 h. After
isolation of the polymer, NMR analysis revealed that the
aromatic peaks located at 7.1−7.2 ppm were no longer present,
confirming the loss of the benzyl group from the polymer. The
result from SEC analysis was consistent with the proposed
structure (Mn = 13.7 kg/mol; PDI 1.11 and 9.8 kg/mol; PDI
1.16, respectively). Hydrogenation reactions performed in THF
and DCM and at low H2 pressure did not give the deprotected
polymer. The poly(1,2-glycerol carbonate) is not soluble in
common organic solvent (DCM), but is soluble in DMF and
DMSO.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, NMRs, and SEC traces. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
mgrin@bu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by BU.
Finally, the rate of poly(1,2-glycerol carbonate) degradation
in DMF at 37 °C was monitored by SEC and compared to that
of a poly(1,3-glycerol carbonate). As shown in Figure 4, atactic
and isotactic poly(1,2-glycerol carbonate)s degrade significantly
faster than poly(1,3-glycerol carbonate) with a t1/2 of ∼2−3
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