Overcoming Barriers in Polycarbonate Synthesis: A Streamlined Approach for the Synthesis of Cyclic Carbonate Monomers

Article abstract of DOI:10.1021/acs.macromol.0c02880

Accessing cyclic carbonate monomers on a large scale is critical for the development of any new carbonate-based materials platform. The synthesis of carbonate monomers can be a challenging and tedious endeavor requiring multiple synthetic steps and purifications. To address this, we report a drastically improved process for the synthesis of carbonate monomers via a two-step route that avoids the use of hazardous triphosgene or chloroformate reagents. This process enables rapid access to a broad array of functional groups on the carbonate monomer and the monomers generated from the procedure can readily be polymerized via ring-opening polymerization.

Full text of DOI:10.1021/acs.macromol.0c02880

pubs.acs.org/Macromolecules
Article
Overcoming Barriers in Polycarbonate Synthesis: A Streamlined
Approach for the Synthesis of Cyclic Carbonate Monomers
Eddy W. P. Tan, James L. Hedrick, Pedro L. Arrechea, Tim Erdmann, Vivien Kiyek, Simon Lottier,
Yi Yan Yang, and Nathaniel H. Park*
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ABSTRACT: Accessing cyclic carbonate monomers on a large scale is critical for the development of any new carbonate-based
materials platform. The synthesis of carbonate monomers can be a challenging and tedious endeavor requiring multiple synthetic
steps and purifications. To address this, we report a drastically improved process for the synthesis of carbonate monomers via a two-
step route that avoids the use of hazardous triphosgene or chloroformate reagents. This process enables rapid access to a broad array
of functional groups on the carbonate monomer and the monomers generated from the procedure can readily be polymerized via
ring-opening polymerization.
monomers would greatly accelerate the overall research and
development of future polycarbonate-based materials.
INTRODUCTION
■
Aliphatic cyclic carbonates are a versatile and widely used
monomer scaffold for the preparation of polycarbonates,
copolymers, and non-isocyanate polyurethanes.1−3 These
materials find application in a variety of domains including
drug-delivery vehicles,4−6 antimicrobial materials,7−9 macro-
molecular chemotherapeutics,10,11 covalent adaptable net-
works,12 materials for three-dimensional (3D) printing,13
surface patterning,14,15 heavy-metal sequestration,16 magnetic
resonance imaging contrast agents,17 computed tomography
imaging,18 solid-phase electrolytes for ion transport,19,20 and
luminescent polymers for white light generation.21 One of the
most commonly used monomer precursors is 2,2-bis-
(hydroxymethyl)propionic acid (bis-MPA; Figure 1A) as the
installment of various functional groups via esterification
enables fine-tuning of the properties of the derived polymers.
Despite the low monetary cost of bis-MPA and the breadth of
materials utilizing cyclic bis-MPA-based carbonate monomers,
their synthesis usually requires multiple steps, the use of toxic
reagents, and tedious purifications.22−27 These factors result in
high labor and process costs, creating a barrier to further
discovery of new functionalized polycarbonate materials and
the commercialization thereof. This is in stark contrast to other
monomer platforms, such as methacrylates, where diversifica-
tion is typically accessible in one step from commercially
available precursors. Thus, the development of improved
methods for the synthesis and purification of carbonate
Currently, there are several published routes (two to five
steps) employed to obtain carbonate monomers from bis-MPA
(Figure S1).22−27 The primary challenges for many of these
approaches is the installment of the functional group R via
esterification and the cyclization of the 1,3-diol to the
carbonate (Figure 1A). Some routes rely on protection−
deprotection schemes leading to additional synthetic steps
(Figure S1A and S1B).25,27 In addition, these methods rely on
the use of triphosgene or chloroformate reagents to cyclize the
diol intermediate to the carbonate. Finally, the resulting
monomers often require repeated purification since low
concentrations of impurities in the final synthetic step can
initiate the oligomerization of the carbonate monomer upon
storage or affect the molecular weight distribution for an
otherwise well-controlled polymerization.15,23
To avoid some of the aforementioned challenges, our group
had published the use of bis(pentafluorophenyl) carbonate to
simultaneously cyclize bis-MPA and install an activated
pentafluorophenyl ester handle for further functionalization
Received: December 30, 2020
Published: February 10, 2021
https://dx.doi.org/10.1021/acs.macromol.0c02880
© 2021 American Chemical Society
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Figure 1. Polycarbonate materials development via bis-MPA-based monomers: state-of-the-art versus new routes from this work. (A) Material
development using automated synthetic platforms, (B) comparison of synthetic efforts for cyclic guanidine-functionalized carbonate. See refs 7, 28
and Figure S1A for information on previous routes to 3c. (C) New routes from this work to cyclic carbonate monomers using acid-promoted
carbonate formation. Abbreviations: ROP = ring-opening polymerization, CDI = carbonyldiimidazole, and EDC·HCl = N-ethyl-N′-(3-
dimethylaminopropyl)carbodiimide hydrochloride.
(Figure S1C).24 Although this approach was effective in
accessing a broad variety of functional carbonate monomers,
the transesterification step provided 50−90% yields, required
extended reaction times, and necessitated chromatographic
purification, which can be inconvenient at a larger scale.24,29
To improve on this process, Malkoch and co-workers
developed an alternative process using N,N′-carbonyldiimida-
zole (CDI) to generate an isolable imidazole ester intermediate
that is converted to the carbonate monomer in separate
esterification−cyclization step (Figure S1D).23 Although
demonstrated successfully on a multigram scales, the yields
varied between 23 and 43% and required purification by
chromatography.
Dimethyl carbonate has also been investigated as a reagent
for carbonate formation from diols.26 In the case of a bis-MPA
ester diol, however, an extended reaction time was required
and the product was contaminated with substantial amounts of
a linear bis-carbonate byproduct (Figure S1F). Carbon dioxide
has been reported as a reagent capable of synthesizing cyclic
carbonates of different ring sizes (Figure S1G). However, the
yields were modest (21−80%) and produced significant
amounts of oligomeric side products.30,31 To overcome the
limitations of these previous methodologies, we report two
complementary strategies for accessing a broad scope of bis-
MPA carbonate monomers in a two-step synthetic sequence.
alkyl (or benzyl/allyl) halide, which favors Route A. In other
cases, the functional group precursor is available as alcohol
and, therefore, Route B is better suited (Figure 1C).
The critical step in both routes is the cyclization of the 1,3-
diol to the carbonate and hinges on the successful employment
of CDI as the carbonyl source. CDI was chosen for its ease of
handling, low cost, and diminished toxicity compared to
triphosgene or ethyl chloroformate. Furthermore, CDI exhibits
improved reactivity compared to dimethyl- or diphenylcar-
bonate, which typically requires higher temperatures and
prolonged reaction times.3,26 The phenolic carbonate alter-
natives also necessitate the removal of super-stochiometric
amounts of a phenol byproduct, significantly complicating the
purification procedures. In contrast, the imidazole byproducts
from CDI are easily removed via acidic aqueous extraction.
Previous reports of the CDI facilitated cyclization 1,3-diols
required lengthy reaction times, undesirable chlorinated
solvents, and portion-wise addition of the reagent.20,32 Here,
we felt an improved protocol for CDI cyclizations could be
achieved through a judicious choice of reaction conditions and
a careful analysis of the reaction intermediates.
We began our investigation of the identified two-step
synthetic routes to carbonate monomers with Route A. The
first-step of alkylation in Route A of the bis-MPA carboxylic
acid has been performed using hydroxide (KOH), carbonate
(K2CO3 or Cs2CO3), and organic bases.4,33−35 The common
use of dimethyl formamide (DMF) in these procedures
complicates the workup and purification of the bis-MPA
ester diol product due to its high-boiling point and miscibility
in aqueous and organic solvents. To avoid DMF, we found that
the combination of triethylamine (Et3N) or N,N-diisopropy-
lethylamine (DIEA) in acetonitrile facilitated the alkylation
with a variety of alkyl halides, cleanly affording the bis-MPA
ester diols after an aqueous workup or following crystallization
(Figure S2).
RESULTS
■
We identified two potential synthetic strategies to access bis-
MPA carbonate monomers: Route A, alkylation (or Fischer
esterification) of the bis-MPA carboxylic acid to afford I,
followed by cyclization to the carbonate (Figure 1C), and
Route B, selective cyclization of bis-MPA to the corresponding
carbonate carboxylic acid II (Figure 1C), followed by N-ethyl-
N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDC·HCl) facilitating the esterification to afford the
monomer. The preference of route is dictated by the
availability of the appropriate precursors. In some cases, the
functional group precursor is commercially available as the
Moving on to the second synthetic step of Route A, we
examined a series of cyclization conditions using CDI with the
bis-MPA benzyl ester (S1a; Figure S2, Supporting Informa-
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a
Table 1. Optimization of 1,3-Diol Cyclization for Route A
b
product distribution (%)
b
entry
acid
none
none
acid equiv
temp (°C)
conversion (%)
2a
I
c
1
20
75
75
75
75
75
75
75
75
75
75
78
91
98
96
96
100
97
97
96
97
98
9
49
43
50
45
28
48
54
49
73
96
60
34
55
46
51
72
49
43
48
27
2
2
3
4
5
6
7
8
9
d
MsOH
p-TsOH
TFA
AcOH
PPTS
BzOH
AcOH
AcOH
AcOH
0.1
d
0.1
d
0.1
0.1
1
1
1
4
10
11
16
a
b
Reagents and conditions: 1a (1.0 equiv), CDI (1.5 equiv), EtOAc, rt, 5−10 min, then acid (1−16 equiv), rt−75 °C, and 1 h. Conversion and
c
d
1
product distribution determined by H NMR of the crude reaction mixture in CDCl3. Reaction time is 5 min. 1.0 equiv of acid resulted in
degradation. MsOH = methanesulfonic acid, TFA = trifluoroacetic acid, p-TsOH = p-toluenesulfonic acid, AcOH = acetic acid, PPTS = pyridinium
p-toluenesulfonic acid, BzOH = benzoic acid, and MeCN = acetonitrile.
a
Table 2. Optimization of Bis-MPA Cyclization for Route B
b
conversion at different time points (%)
entry
acid
acid equiv
temp (°C)
0.5 h
1 h
1.5 h
2 h
c
c
1
2
3
4
none
25
75
75
75
17
65
96
98
17
93
>99
>99
17
18
92
>99
>99
c
c
c
AcOH
AcOH
AcOH
1
4
16
91
>99
c
>99
a
Reagents and conditions: bis-MPA (1.0 equiv), Et3N (1.0 equiv), MeCN, rt, 5 min, then CDI (1.6 equiv), rt, 5 min, followed by AcOH (1−16
b
c
equiv), rt−75 °C, 2 h. Conversion as determined by 1H NMR in CDCl3. Presence of trace ring-opened byproduct detected by 1H NMR. AcOH
= acetic acid, MeCN = acetonitrile, Et3N = triethylamine, and EtOAc = ethyl acetate.
tion). Here, the addition of CDI to a solution of S1a in
of a variety of different acids on the product distribution
(Table 1). Substoichiometric amounts of acid (entries 3−6,
Table 1) provided similar product ratios as compared to the
heating of the reaction mixture in the absence of acid (entry 2,
Table 1). Increasing the equivalents of AcOH (entries 9−11,
Table 1) afforded the increased conversion to the desired
carbonate product, with 16 equiv affording nearly 96%
conversion to 2a within 1 h (entries 7−11, Table 1).
Subjecting the isolated bis-imidazole carbamate I to the same
reaction conditions afforded nearly identical results (Figure
S3B). Interestingly, an equivalent amount of N-acyl imidazole
was observed to form in the reaction mixture (Figures S3B and
S6). The presence of the N-acyl imidazole byproduct, in
combination with the observed CO2 gas evolution, suggests the
formation of an anhydride intermediate (D, Figure S4).
Subsequent reaction of the anhydride intermediate (D, Figure
acetonitrile leads to the formation of two distinct products
1
within 5 min as observed by H NMR analysis of the crude
reaction mixture (entry 1, Table 1). The minor product was
identified as the cyclic carbonate monomer 2a and the major
product was believed to be the bis-imidazole carbamate I
(Table 1). By employing excess CDI, the exclusive formation
of I allowed for its isolation and characterization (Figure S3A)
to confirm its identity.
Prior work has demonstrated that the Brønsted acid
activation of imidazole carbamates can be utilized for the
synthesis of esters and oxazolidinones.36−38 As using Brønsted
acids to promote cyclization of bis-imidazole carbamates to
carbonates has not been reported, we hypothesized that I
could be activated with an acid to afford the carbonate product
2a (Table 1). To test this hypothesis, we investigated the effect
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Figure 2. Scale-up purification of 2l. (A) Scheme of the purification reaction. (B) Photograph of the engineered packed-column setup modified
from a commercially available apparatus (for details, see Figure S8, Supporting Information). (C) Temperature traces observed during the
purification process. Top, middle, and bottom in the figure key refer to the external thermocouple placement on a packed column. Impure liquid is
introduced from the bottom of the column and purified liquid is collected at the top of the column.
S4) with imidazole would produce the observed byproducts
and lead to the cyclic carbonate product (Figure S4). While
this is not the only possible mechanism, similar ones have been
proposed for other acid-promoted reactions with imidazole
carbamates in the literature.37
Based on the results in Table 1, AcOH was selected as the
promoter for cyclization. In addition to rate enhancements, the
use of AcOH has additional advantages such as (1) low cost,
(2) ease of removal during workup via azeotropic distillation
using toluene or heptane, (3) tolerance of many acid-labile
protecting groups, and (4) a significantly lower propensity to
catalyze the polymerization of cyclic carbonate monomers as
compared to stronger acids.39
The isolation and purification of 2l required additional effort
as the standard aqueous workup protocol afforded variable
yields, presumably due to the increased water solubility of the
carbonate. After examining many different workup or
extraction protocols, we found that the simple filtration of
the crude reaction mixture through a packed column of
Amberlyst 15 was sufficient to afford the desired product in
high yield and purity (Figure 2A).
To facilitate the purification of the crude reaction mixture on
a larger scale, we designed an automated apparatus employing
a removable packed bed charged with Amberlyst 15 resin (∼1
kg). The design incorporates a positive displacement pump to
force the diluted crude reaction solution through the column,
facilitating the purification (Figures 2B and S8A). The fluid is
introduced at the bottom of the column from a reservoir and
the purified solution is collected at the top of the column. In
our experiments, we found that a single column was capable of
purification of the monomer at the 100 g scale before
exhausting the capacity of the charged resin. By the use of
Swagelok quick connects incorporating internal valving, the
column can be replaced mid-campaign without the use of tools
or loss of reaction liquid. This feature allows for the
purification of an arbitrary amount of monomer limited by
the amount of the available resin. This system simplified the
workup and purification procedure on the scale-up and
afforded 2l in 95% yield.
We next sought to apply these conditions in Route B for the
one-pot synthesis of 2l (Table 2) from bis-MPA, a key
intermediate requiring three steps to prepare via the published
literature protocols (Figure S1, Route A).25 The primary
obstacle in extending the conditions identified in Route A to
the direct cyclization of bis-MPA is that carboxylic acids are
reactive toward CDI, leading to the formation of acyl
imidazoles.23,36 To mitigate this difficulty, we hypothesized
that the treatment of bis-MPA with an amine base such as
(Et3N or DIEA) would deactivate the carboxylic acid37 and
improve the solubility of bis-MPA. To evaluate this hypothesis,
we first treated bis-MPA with Et3N in acetonitrile, followed by
1
the addition of CDI. Analysis of the reaction mixture by H
NMR indicated a mixture of products similar to ones identified
in Route A (Table S1). The distribution of these intermediates
was dependent on the amount of CDI used, with the formation
of the acyl imidazole intermediate (III, Table S1) observed
only in small amounts by 1H NMR when a significant excess of
CDI was used (Table S1, entries 1 and 2).23 Addition of excess
AcOH facilitated the cyclization of the imidazole carbamate
intermediate (II, Table S1) to the corresponding cyclic
carbonate 2l within a reaction time of 1 h (Table 2, entries
3 and 4). We attempted to isolate II as its salt (Figure S5A),
although a complex mixture of products was obtained.
Subjecting this mixture to the reaction conditions did afford
smooth conversion to the carbonate 2l (Figures S5B and S7).
During attempts of purification, it was found that the process
generated significant heat as impurities were adsorbed onto the
packing material and at these increased scales, adiabatic
behavior was a concern. Since elevated temperature encourages
polymerization and reduces the yield of the monomer, both
modeling efforts and measurements with thermocouples were
employed to understand the temperature dynamics during
purification. As shown in Figure 2C (Figures S9−S12), the
temperatures at the top of the column reach a maximum as the
liquid is purified. To diminish the temperature change, extra
solvent (acetonitrile) was added prior to purification. The slow
addition of the reaction contents during the purification in
parallel with the ability to replace columns mid-campaign
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Figure 3. (A) Synthesis of carbonate monomers from functional diols. Reagents and conditions: 1,3-diol (1.0 equiv), CDI (1.5−1.8 equiv), MeCN
or EtOAc, rt, 5−10 min, then AcOH (10−16 equiv), reflux 2−16 h. aIsolated yield over two steps starting from bis-MPA. bIsolated yield over three
steps starting from methoxy-terminated polyethylene glycol (Mn = 350). (B) Esterification of 2l to bis-MPA carbonates. Reagents and conditions:
(i) alcohol (1 equiv), DMAP (0.1 equiv), 2l (1.5 equiv), DCM or MeCN, 0 °C, 0.5 h, (ii) EDC·HCl (1.5 equiv), 0 °C to rt, 16 h. Abbreviations:
DMAP = dimethylaminopyridine, DCM = dichloromethane, and EDC·HCl = N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride.
Figure 4. (A) Ring-opening polymerization of cyclic carbonates. (B) Flow reactor setup for polymerization of carbonate monomers. (C) Catalysts
used for ring-opening polymerization of carbonates.
would allow for arbitrarily larger scaled reactions (>100 g)
without “overheating”.
Having addressed the critical cyclization step and developed
a scalable purification method for 2l, we proceeded to evaluate
the synthetic scope of both routes in the preparation of a
variety of carbonate monomers (Figure 3). In the case of Route
B, the esterification of 2l could be accomplished using EDC·
HCl to afford the functional carbonate monomer (Figure 3B).
Notably, the methodology developed for Route A and Route B
enabled us to prepare carbonate monomers with a variety of
pendant functional groups, many of which have been
previously reported to be used in a variety of material
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a
Table 3. ROP Polymerization of Cyclic Carbonate Monomers
b
d
c
c
entry
monomer
polymer
mode
initiator
catalyst
time
conversion (%)
Mn (GPC)
Đ
1
2
3
4
5
6
7
2b
2b
2c
2e
2g
3a
3b
4a
4b
4c
4d
4e
4f
batch
batch
batch
flow
flow
batch
batch
mPEG5KOH
KOMe
mPEG5KOH
4-MBA
4-MBA
mPEG5KOH
mPEG5KOH
DBU
U-4-CF3
DBU
U-1-CF3
U-1-CF3
DBU
30 min
5 s
30 min
0.5 s
0.5 s
30 min
30 min
94
95
90
93
92
90
89
15.3
9.6
1.20
1.08
1.12
1.13
1.10
1.20
1.07
11.4
10.0
10.2
14.8
13.4
4g
DBU
a
Reagents and conditions: All batch polymerizations using mPEG5KOH as an initiator had a starting [M]0/[DBU]0/[I]0 ratio of 1:3:20 (entries 1,
3, 6, and 7). For entries 1, 3, and 6, [M]0 = 1 M, for entry 7 [M]0 = 0.5 M. For entry 2, [M]0/[Urea]0/[I]0 of 50:3:1 and [M]0 = 1.0. For entries 4
b
and 5, KH is used as a cocatalyst and [M]0/[Urea]0/[I]0/[KH]0 is 50:3:1:1 and 30:3:1:1, respectively. Time for flow reaction is the residence time
c
d
of the reactor. Determined by 1H NMR of the crude reaction mixture. Measured via advanced polymer chromatography (APC) in THF at 25 °C
calibrated using polystyrene standards. Abbreviations: KOMe = potassium methoxide, KH = potassium hydride, 4-MBA = 4-methylbenzyl alcohol,
and mPEG5KOH = poly(ethylene glycol) methyl ether, 5.0 KDa average Mn.
applications, in a less toxic and less labor- and time-intensive
manner. The monomers were readily isolated in high purity
following workup and purification (see Supporting Informa-
tion). Trimethylene carbonate (2m, Figure 3) was also found
to be sensitive to aqueous workup and was also purified via
filtration through Amberlyst 15 resin (see the Supporting
Information).
After demonstrating the effectiveness of both routes in the
synthesis of a broad array of cyclic carbonate monomers via
two different routes, we investigated their ability to undergo
ring-opening polymerization (ROP) under both batch and
flow conditions (Figure 4 and Table 3). In all cases, monomers
prepared via these methods led to the controlled synthesis of
different polycarbonate homopolymers or AB block copoly-
mers with predictable molecular weights and narrow dispersity.
The polymers synthesized under continuous flow conditions
exhibited very short residence times, consistent with our prior
work using flow platforms for polyester and polycarbonate
synthesis.40 The data for the polymerizations and resulting
polymers are summarized in Table 3.
shooting the acid-promoted cyclization of 1,3-diols;
polymerization of carbonate monomers; and character-
ization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Nathaniel H. Park − IBM Research-Almaden, San Jose,
California 95120, United States; orcid.org/0000-0002-
6564-3387; Email: npark@us.ibm.com
Authors
Eddy W. P. Tan − Institute of Bioengineering and
Nanotechnology, Singapore 138669, Singapore
James L. Hedrick − IBM Research-Almaden, San Jose,
California 95120, United States; orcid.org/0000-0002-
3621-9747
Pedro L. Arrechea − IBM Research-Almaden, San Jose,
California 95120, United States
Tim Erdmann − IBM Research-Almaden, San Jose, California
95120, United States
Vivien Kiyek − IBM Research-Almaden, San Jose, California
CONCLUSIONS
95120, United States
■
Simon Lottier − IBM Research-Almaden, San Jose, California
95120, United States
Yi Yan Yang − Institute of Bioengineering and Nanotechnology,
Singapore 138669, Singapore; orcid.org/0000-0002-
1871-5448
In summary, we have demonstrated a scalable and operation-
ally simple approach for the synthesis of a broad array of
functionalized carbonate monomers derived from bis-MPA.
This approach (1) obviates the need for toxic chloroformate or
phosgene-based reagents, (2) affords byproducts that are easily
removed during workup, (3) does not require anhydrous or
air-free conditions, (4) replaces the use of high-boiling and/or
toxic solvents such as DMF with ethyl acetate or acetonitrile
when possible, and (5) minimizes the number of synthetic
steps and improves the overall yield of the targeted monomers.
Furthermore, this work was motivated in part by the desire to
achieve a large-scale and easy monomer synthesis needed for
conducting polymerizations in continuous flow. Overall, the
time and cost savings of this approach removes barriers in the
synthesis and development of polycarbonate materials sourced
from bis-MPA.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.macromol.0c02880
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.E. acknowledges support by the German Alexander von
Humboldt Foundation through the Feodor Lynen Research
Fellowship.
ABBREVIATIONS
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.macromol.0c02880.
■
bis-MPA, 2-bis(hydroxymethyl)propionic acid; CDI, N,N′-
sı
carbonyldiimidazole
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