Synthesis and Characterization of Poly(glyceric Acid Carbonate): A Degradable Analogue of Poly(acrylic Acid)

Article abstract of DOI:10.1021/jacs.5b07911

The synthesis and characterization of a degradable version of poly(acrylic acid), poly(glyceric acid carbonate), are reported. Specifically, atactic and isotactic poly(benzyl glycidate carbonate)s are obtained via the ring-opening copolymerization of rac-/(R)-benzyl glycidate with CO₂ using a bifunctional rac-/(S,S)-cobalt salen catalyst in high carbonate linkage selectivity (>99%) and polymer/cyclic carbonate selectivity (～90%). Atactic poly(benzyl glycidate carbonate) is an amorphous material with a T_g (glass transition temperature) of 44 °C, while its isotactic counterpart synthesized from enantiopure epoxide and catalyst is semicrystalline with a T_m (melting temperature) = 87 °C. Hydrogenolysis of the resultant polymers affords the poly(glyceric acid carbonate). Poly(glyceric acid carbonate) exhibits an improved cell cytotoxicity profile compared to poly(acrylic acid). Poly(glyceric acid carbonate)s also degrade remarkably fast (t_1/2 ≈ 2 weeks) compared to poly(acrylic acid). Cross-linked hydrogels prepared from poly(glyceric acid carbonate) and poly(ethylene glycol) diaziridine show significant degradation in pH 8.4 aqueous buffer solution compared to similarly prepared hydrogels from poly(acrylic acid) and poly(ethylene glycol) diaziridine.

Full text of DOI:10.1021/jacs.5b07911

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Article
Synthesis and Characterization of Poly(glyceric acid
carbonate): A Degradable Analogue of Poly(acrylic acid)
Heng Zhang, Xinrong Lin, Stacy Chin, and Mark W. Grinstaff
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07911 • Publication Date (Web): 17 Sep 2015
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Synthesis and Characterization of Poly(glyceric acid carbonate): A
Degradable Analogue of Poly(acrylic acid)
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Heng Zhang, Xinrong Lin, Stacy Chin and Mark W. Grinstaff*
Departments of Chemistry and Biomedical Engineering, Boston University, Boston, Massachusetts 02215, United States
*Corresponding author E-mail: mgrin@bu.edu
KEYWORDS: poly(acrylic acid), polycarbonate, glyceric acid, glycerol, biocompatible, degradable, hydrogel, isotactic.
ABSTRACT: The synthesis and characterization of a degradable version of poly(acrylic acid) – poly(glyceric acid carbonate) – are
reported. Specifically, atactic and isotactic poly(benzyl glycidate carbonate)s are obtained via the ring-opening copolymerization of
rac-/(R)-benzyl glycidate with CO2 using a bifunctional rac-/(S,S)-Cobalt salen catalyst in high carbonate linkage selectivity
(>99%) and polymer/cyclic carbonate selectivity (~90%). Atactic poly(benzyl glycidate carbonate) is an amorphous materials with
a Tg (glass transition temperature) of 44 °C, while its isotactic counterpart synthesized from enantiopure epoxide and catalyst is
semicrystalline with a Tm (melting temperature) = 87 °C. Hydrogenolysis of the resultant polymers affords the poly(glyceric acid
carbonate)s. Poly(glyceric acid carbonate) exhibits an improved cell cytotoxicity profile compared to poly(acrylic acid).
Poly(glyceric acid carbonate)s also degrade remarkably fast (t1/2 ≈ 2 weeks) compared to poly(acrylic acid). Cross-linked hydrogels
prepared from poly(glyceric acid carbonate) and poly(ethylene glycol) diaziridine show significant degradation in pH 8.4 aqueous
buffer solution compared to similarly prepared hydrogels from poly(acrylic acid) and poly(ethylene glycol) diaziridine.
§
INTRODUCTION
Poly(acrylic acid) and its copolymer with other hydrophilic
monomers are produced on the multi-million ton scale per
year. These polymers are extensively used in applications such
as water/sewage treatment, cleaning detergents, adhesives,
cosmetics, as well as drug delivery, and serve as workhorse
polymers of the chemical industry.1 Despite its widespread use
for both practical applications and fundamental studies,
poly(acrylic acid) suffers from poor degradability because of
its all-carbon backbone (Figure 1). It is well established that
only oligomers of poly(acrylic acid) with molecular weights
(MWs) less than 600 g/mol (degree of polymerization < 8) are
biodegradable2-6 and yet, the molecular weights of most indus-
trially relevant poly(acrylic acid)s are well above this value.
For example, low molecular weight poly(acrylic acid)s used
for detergent applications have an average MW of 4000 –
5000 g/mol.2 Furthermore, unlike structural materials (e.g.,
plastics) that can be easily collected and assorted for recycling
or waste treatment such as land filling, composting and incin-
eration, water soluble polymers, e.g., poly(acrylic acid)s, are
difficult to recover. Thus, there is significant interest in de-
gradable PAA analogs. Within the pharmaceutical and bio-
medical sectors, there is a demand for such polymers that ex-
hibit both biodegradability and biocompatibility for applica-
tion ranging from drug delivery to tissue engineering.7-9
Figure 1. Chemical structures of linear poly(acrylic acid) (left)
and poly(glyceric acid carbonate) (right).
ymer of choice for industry. Our strategy departs from these
previous approaches in that a degradable carbonate linkage is
introduced in the polymer backbone giving a structural mimic
of poly(acrylic acid) – namely, poly(glyceric acid carbonate).
This strategy is atom efficient, provides a site for degradation
at every repeating unit, and affords safe, nontoxic, and renew-
able degradation products – CO2 and glyceric acid.
However, the synthesis of this structural class of poly(1,2-
carbonate) is challenging. Traditional polycarbonates are pre-
pared either by ring-opening polymerization of cyclic car-
bonates or polycondensation of diols with phosgene. Both
routes are not favored for poly(1,2-carbonate). Five-membered
cyclic carbonate are remarkably thermodynamically stable,
and ring-opening polymerization does not occur under mild
conditions or proceeds with extensive decarboxylation under
vigorous condition (with the exception of trans-fused bicyclic
ring structures), unlike poly(1,3-carbonate)s which are pol-
ymerized from six-membered cyclic carbonates.12-14 And, at-
tempts to polycondense 1,2-diols mainly produce 5-membered
cyclic carbonates instead of 1,2-linked polycarbonates.15
To solve these challenges, a number of approaches have
been explored such as oligomer chain extension, vinyl
polymerization, etc.2,10,11 However, these approaches are still
acrylate-based with the idea of introducing fragile points such
as hydrolyzable or oxidizable sites into the all-carbon polymer
backbone. Despite these efforts, limited commercial success
has been achieved and poly(acrylic acid) still remains the pol-
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Table 1. Synthesis of Poly(benzyl glycidate carbonate) Using [SalcyCoIIIX] Complexes 1-3
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Catalyst
loading
Conversion
(%)
Turnover
Freq. (h-1)
Selectivity
(% polymer)
#
Catalyst
Temp.
Mn (kg/mol)
PDI
11
21
3
1
500:1
500:1
65
67
62
70
58
59
67
69
66
-
-
-
-
25 °C
25 °C
25 °C
25 °C
40 °C
25 °C
25 °C
25 °C
25 °C
2
-
-
-
-
3a
3a
3a
3a
3a
3b
3a
500:1
12
11
18
8
90
89
55
85
92
93
90
14.2
21.4
18.1
27.2
24.2
30.5
32.2
1.18
1.19
1.21
1.22
1.19
1.14
1.23
4
1000:1
1000:1
1000:1
1000:1
1000:1
2000:1
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10
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8
13
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10
9
The reactions were performed in neat rac-BG (1.42 ml, 10 mmol) in an 8 mL autoclave under 220 psi CO2 pressure unless otherwise noted. All resultant
poly(benzyl glycidate carbonate)s (PBGC's) contain >99% carbonate linkage, as determined by 1H NMR spectroscopy. 1The only product formed was the
cyclic carbonate. The binary system 1 was used for entry 1 and the [SalcyCoIIIX]:[PPN]DNP ratio was 1:1. 2The reaction was performed in 0.4 mL toluene.
3The reaction was performed under 440 psi CO2 pressure.
Given the design criterion of a carbonate linkage in the main
chain of the polymer, we considered the synthetic strategy of
catalytic copolymerization of epoxide/CO2. This polymeriza-
tion method is one of several exciting advances in polymer
chemistry,16-19 and is receiving increasingly more attention for
both environmental and economical reasons. Moreover, the
catalytic epoxide/CO2 copolymerization provides a platform
for synthesizing poly(1,2-glycerol carbonate)s that are other-
wise not accessible by traditional methods, such as by ring-
opening polymerization of the corresponding cyclic carbonate
or polycondensation of 1,2-diols.15,20,21 In addition, glycerol-
and glycerol derivative-based polymers are of widespread
interest and various polymers with different compositions and
architectures have been synthesized22-32 and evaluated for a
range of biomedical applications.33-37 Herein, we reported the
first synthesis of poly(glyceric acid carbonate). Specifically,
atactic and isotactic poly(benzyl glycidate carbonate)s are
synthesized via the ring-opening copolymerization of rac-/(R)-
benzyl glycidate with CO2 using a bifunctional rac-/(S,S)-
cobalt salen catalyst, the deprotection of benzyl protected pol-
ymer to give poly(glyceric acid carbonate)s, the degradation of
the polymer in aqueous conditions, and its cytotoxicity profile.
Finally, we describe a cross-linked hydrogel prepared from
poly(glyceric acid carbonate) and characterize the degradation
rate compared to a similarly prepared poly(acrylic acid) hy-
drogel.
§
RESULTS AND DISCUSSION
At the outset of the project, we anticipated that post-
polymerization oxidation of poly(1,2-glycerol carbonate)38
may offer a facile method to access poly(glyceric acid car-
bonate) (Scheme 1A). However, under a range of well-known
mild and selective oxidation conditions such as Heyns oxida-
tion,39 RuCl3-catalyzed oxidation,40 and TEMPO-mediated
oxidation,41 we were unable to obtain the desired product ei-
ther due to backbone scission or difficulty of isolation. (See
SI)
Monomer Design/Synthesis and Polymerization Chemis-
try. As poly(glyceric acid carbonate) was not readily prepared
from poly(1,2-glycerol carbonate), we investigated a direct
approach and prepared monomer 4, which bears a benzyl pro-
tected carboxylic acid, and three Co Salen catalysts (binary
catalyst system 1 and bifunctional catalysts 2 and 342-44) for the
polymerization reaction (Scheme 1). Given the literature prec-
edent on the use of the 2,4-dinitrophenolate (DNP) axial lig-
and and the resulting high selectivity for polymer over the
cyclic carbonate, it was used as both the axial ligand and the
counter anion for all of the catalysts.17,19 Benzyl glycidate
Scheme 1. (A) Attempts to synthesize poly(glyceric acid car-
bonate) by oxidation of poly(1,2-glycerol carbonate). (B) Copol-
ymerization of benzyl glycidate with CO2 using binary and bi-
functional [SalcyCoIIIX] catalysts.
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(BG) 4 was synthesized via an efficient two-step esterifica- chromatography (SEC) analysis revealed molecular weights
tion-oxidation route in high overall yield (~80%).45 The co-
polymerization of 4 and CO2 was investigated using both the
binary and bifunctional [SalcyCoIIIX] complexes, 1-3, as
shown in Scheme 1B. Under the screening condition (neat
epoxide, 500:1 catalyst loading, 25 °C and 220 psi CO2 pres-
sure), the binary catalyst system 1 and the bifunctional catalyst
2 were inactive for polymerization. Only the cyclic carbonate
product was formed. The lack of activity of catalyst 2 towards
BG was surprising given the fact that this catalyst is highly
active towards a range of epoxide substrates including ones
possessing an electron-withdrawing group, such as styrene
oxide and epichlorohydrin.46,47 Importantly, bifunctional cata-
lyst 3, bearing a quaternary ammonium salt on the ligand
framework, catalyzed the copolymerization.
significantly lower than theoretical values and monomodal
distribution with narrow molecular weight distribution (PDI
<1.20) (Figure S17). This result is in contrast to most of the
previously reported systems where bimodal distributions were
observed likely due to trace amount of water acting as chain
transfer agent, leading to two populations of polymers with
different molecular weights.19,38,48 However, a MALDI-TOF
study revealed that the polymer consists of a major and a mi-
nor population with overlapping molecular weight distribution
and the signals match [1.0 (H) + 178.1 (BG) + 222.1×n (CO2-
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alt-BG)
+ 1.0 (H) +
23.0 (Na+)] and [183.3 (2,4-
dinitrophenolate) + 178.1 (BG) + 222.1×n (CO2-alt-BG) +
178.1 (BG) + 1.0 (H) + 23.0 (Na+)], respectively (Figure 2).
Structurally, these two sets of signals correspond to popula-
tions with distinct end groups – e.g., a major population bear-
ing hydroxyl groups on the chain ends and a minor population
bearing a 2,4-dinitrophenoxy and a hydroxyl group on each
end (Figure 2). This result is consistent with the fact that trace
As shown in Table 1, 3 effectively catalyzed the copolymer-
ization of BG with CO2 to afford poly(benzyl glycidate car-
bonate) with excellent carbonate linkage selectivity (>99%)
and high polymer/cyclic carbonate selectivity (>90%) to give
high molecular weight polymers with narrow molecular
weight distribution. The polymers are of high regioregularity
and showed a head-to-tail connectivity of 92% (Fig. S5) The
catalyst activity, however, was significantly lower than that
reported for the polymerization of benzyl glycidyl ether (~15
h-1 vs. ~150 h-1, respectively).38 This is likely a result of the
electron withdrawing effect of the carbonyl group. Decreasing
the catalyst loading from 500:1 to 1000:1 resulted in a slight
decrease in activity and polymer selectivity, and a significant
increase in molecular weight (MW) while increasing the tem-
perature to 40 °C afforded a significant decrease in polymer
selectivity (Table 1, entry 5). Performing the reaction in tolu-
ene gave >90% monomer conversion with compromised activ-
ity (8 h-1) and polymer selectivity (80%) while the MW re-
mained similar, presumably due to both decreased polymer
selectivity and trace amount of water introduced by toluene.
Figure 3. (A) 13C carbonyl region of atactic (left) and isotactic
(right) poly(benzyl glycidate carbonate). (B) Differential scan-
ning calorimetry (DSC) trace of (a) atactic (b) isotactic
poly(benzyl glycidate carbonate).
amount of water serves as chain transfer agent, leading to a
population of telechelic species with two hydroxyl chain end
besides the population of polymer chains that are initiated by
DNP.
Figure 2. A MALDI-TOF spectrum of poly(benzyl glycidate
carbonate) with molecular weight ~ 5000 g/mol. NOTE: The
structures assigned to major and minor populations above are one
representative of the regioisomeric structures. Regioisomeric
structures (in-chain and chain end) give the same mass.
Hydrolytic Kinetic Resolution (HKR) of Benzyl Glyci-
date and Synthesis of an Isotactic Version of the
Poly(benzyl glycidate carbonate). Given the encouraging
results above, we synthesized an isotactic version of
poly(benzyl glycidate carbonate). The hydrolytic kinetic reso-
lution (HKR) of BG had not been previously reported. The
HKR of racemic BG using (R,R)-SalcyCoIIIOTs provided (R)-
BG in >90% yield with >98% enantiomeric excess (Figure
S15).49,50 Copolymerization of (R)-BG with CO2 using the
enantiopure S-catalyst 3b19,51 afforded a polymer with an iso-
Polymer Microstructure. All the resultant polymers are
highly region-regular with a head-to-tail selectivity of 92% by
13C NMR. The carbonyl region of the 13C NMR spectrum also
showed the atactic nature of the polymer obtained from race-
mic BG and racemic catalyst (Figure S5). Size exclusion
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Figure 5. Degradation behavior of PGAC and PAA in water and
DMF.
1
1
Figure 4. (A) H NMR of PBGAC in CDCl3. (B) H NMR of
atactic PGAC in DMSO-d6 after hydrogenolysis.
Degradation Study and Cytotoxicity of Poly(glyceric ac-
id carbonate). The rate of PGAC degradation in deionized
water was monitored by SEC and compared to that of a
poly(acrylic acid) with a similar molecular weight. In DI wa-
ter, PGAC showed significant degradation (t1/2 ~12 days) over
a 26-day period, while, as expected, no degradation occurred
for poly(acrylic acid) (Figure 5). In our recent paper, we re-
ported the synthesis of poly(1,2-glycerol carbonate) which
exhibited remarkably accelerated degradation rate compared to
poly(1,3-glycerol carbonate) and it was proposed that for
poly(1,2-glycerol carbonate)s, the accelerated degradation is a
consequence of an intramolecular attack of the primary hy-
droxyl group onto the carbonate backbone, leading to the for-
mation of the thermally stable five-membered cyclic car-
bonate. For PGAC, when the degradation was performed in
anhydrous DMF, which eliminated the hydrolysis mechanism,
PGAC exhibited negligible degradation over a 26-day period,
indicating that intramolecular cyclization of carboxylic group
onto the carbonate backbone to form O-carboxyanhydride did
not occur. This is likely a consequence of the combined low-
ered nucleophilicity, relatively higher rigidity of the carbox-
ylic acid group in PGAC compared to the primary hydroxyl
group in poly(1,2-glycerol carbonate), and the higher energy
of the resultant five-membered cyclic O-carboxyanhydride
structure compared to the five-membered cyclic carbonate. In
contrast, when PGAC is dissolved in pH buffer 8.4 it rapidly
tactic backbone and >95% head-to-tail selectivity (Figure 3A).
Degradation of isotactic PBGAC to cyclic carbonate while
conserving all stereogenic centers52 yielded (R)-cyclic car-
bonate and (S)-cyclic carbonate with a ratio of 94:6 (88%
e.e.), indicating that 5% of all the stereogenic centers in the
starting epoxide were inverted during the polymerization.
Isotactic poly(benzyl glycidate carbonate) is a semicrystal-
line polymer with a Tm (melting temperature) = 87 °C by DSC
(differential scanning calorimetry) (Figure 3B). In contrast,
atactic poly(1,2-benzyl glycidate carbonate), is an amorphous
material (Tg (glass transition temperature) = 44 °C). Interest-
ingly, poly(benzyl 1,2-glycerol carbonate)s were found to be
amorphous materials with a Tg of 8 °C regardless of tacticity.53
While compared to isotactic poly(benzyl 1,2-glycerol car-
bonate), the only structural difference is that isotactic
poly(benzyl glycidate carbonate) has a carbonyl instead of a
methylene, which contributes to the rigidity of the backbone.
Therefore, we tentatively attribute the observed increased
crystallinity to the effect of the side-chain carbonyl group,
which imparts backbone rigidity and facilitates inter-chain
packing to form greater crystalline region. A similar effect was
also observed for the isotactic version of poly(phenyl 1,2-
glycerol carbonate) reported by Lu et al. which was shown to
be a semicrystalline polymer with a Tm = 75 °C.54
degrades within
8 hours with formation of the O-
Deprotection of PBGAC and Characterization of PGAC.
The benzyl protecting group was removed by hydrogenolysis
to give poly(glyceric acid carbonate) (PGAC). Specifically,
atactic PBGAC (MW = 25.4 kg/mol, PDI 1.19, Table 1, entry
4) was dissolved in ethyl acetate:methanol = 3:1 with Pd/C (20
wt% loading) and pressurized to 400 psi of H2 at room tem-
carboxyanhydride structure, as determined by NMR (Figure
S22). This result can be explain by the more nucleophilic na-
ture of the sodium carboxylate formed on treatment of the pH
8.4 buffer solution. We propose that the degradation occurs
randomly along the carbonate backbone. In the dry state
PGAC remained stable over a few months, while poly(1,2-
perature for 8 h.38,55 After isolation of the polymer, H NMR
1
analysis revealed the aromatic peaks located at 7.1 – 7.2 ppm
were no longer present, confirming the loss of the benzyl
group (Figure 4). Isotactic PGAC was synthesized using the
same reaction condition. The result from SEC in water was
significantly higher than expected (~23 kg/mol) likely due to
hydrophobic aggregation in aqueous phase. When DMF was
used as the GPC eluent, the MW was measured to be ~ 15
kg/mol, which was in agreement with the theoretical value.
PGAC was isolated as a white polymer. It is soluble in polar
aprotic or protic solvent such as dimethylformide, dimethyl-
sulfoxide, water, and methanol, while not soluble in relatively
non-polar solvent such as tetrahydrofuran and dichloro-
methane.
Figure 6. Cytotoxicity study for PGAC against NIH Fibroblast
3T3 cells at different concentrations.
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glycerol carbonate) degraded as monitored by IR (infrared
its copolymer with other hydrophilic polymers have been used
spectroscopy).27
extensively in preparing hydrogels for various applications.58-
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Thus, the degradability of a PGAC based hydrogel was
The cytotoxicity of PGAC was evaluated at various concen-
trations against NIH fibroblast 3T3 cells for 24 hours and
compared to PAA. As shown in Figure 6, PGAC showed no
observable cytotoxicity at low concentrations and started to
show toxicity at 1 mg/mL. This value is close to some of the
previously reported anionic polymers.56,57 Poly(acrylic acid)
showed a similar cytotoxicity profile with a slightly lower cell
viability at 1 mg/mL and a sharp decrease in cell viability
when the concentration was increased from 1 mg/mL to 3
mg/mL.
evaluated by preparing a hydrogel using efficient aziridine
cross-linking chemistry61,62 and compared to that of a hydrogel
prepared wtith poly(acrylic acid). Specifically, PEG diaziri-
dine were synthesized by Michael addition of methyl aziridine
with PEG diacrylate (MW = 3700 g/mol) in one step to afford
pure PEG diaziridine product without the need for further pu-
rification. PEG diaziridine was then mixed with PGAC in
DMF for gelation, followed by dialysis to remove DMF (Fig-
ure 7).
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As shown in Figure 8, the PGAC hydrogel with a cross-
linking degree (mole of aziridine/mole of acid unit) of 15%
Hydrogel Preparation and Study. Poly(acrylic acid) and
Figure 7. Cross-linking chemistry used to prepare the PGAC-PEG diaziridine based hydrogels.
Figure 8. (Upper Panel) Degradation study of hydrogels prepared from PGAC with PEG diaziridine (with nile red dye) with 15% de-
gree of cross-linking in pH 8.4 NaHCO3 solution; (Lower Panel) Rheological study of PGAC and PAA gels under different conditions.
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This work was supported in part by the NSF (DMR-1410450 and
DMR-1507081). NMR facilities at Boston University are support-
ed by the NSF (CHE-0619339).
was stable in deionized (DI) water but it underwent rapid deg-
radation in a pH 8.4 NaHCO3 solution over a two-hour period
as monitored by a significant change in G’ from 5.8×104 to
1
2
3.8×103 Pa. Importantly, the corresponding PAA hydrogel
with the same degree of cross-linking showed no observable
degradation in DI water and in a pH 8.4 NaHCO3 solution
over a two-hour period. Increasing the degree of cross-linking
to 25% has negligible effect on degradation kinetics, which is
consistent with the fact that the degradation mainly occurs via
the backbone of PGAC. Interestingly, in a 7.4 PBS buffer, the
PGAC hydrogel, although slower, still underwent significant
degradation as monitored by the decrease in the G’ from 5.8
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Paik, Y. H.; Simon, E. S.; Swift, G. Hydrophilic
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poly(acrylic acid) – poly(glyceric acid carbonate) –, is de-
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ASSOCIATED CONTENT
Experimental procedures and characterization data. This material
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AUTHOR INFORMATION
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Corresponding Author
* E-mail: mgrin@bu.edu
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