Sugar-Based Polymers from d-Xylose: Living Cascade Polymerization, Tunable Degradation, and Small Molecule Release

Article abstract of DOI:10.1002/anie.202012544

Enyne monomers derived from D-xylose underwent living cascade polymerizations to prepare new polymers with a ring-opened sugar and degradable linkage incorporated into every repeat unit of the backbone. Polymerizations were well-controlled and had living character, which enabled the preparation of high molecular weight polymers with narrow molecular weight dispersity values and a block copolymer. By tuning the type of acid-sensitive linkage (hemi-aminal ether, acetal, or ether functional groups), we could change the degradation profile of the polymer and the identity of the resulting degradation products. For instance, the large difference in degradation rates between hemi-aminal ether and ether-based polymers enabled the sequential degradation of a block copolymer. Furthermore, we exploited the generation of furan-based degradation products, from an acetal-based polymer, to achieve the release of covalently bound reporter molecules upon degradation.

Full text of DOI:10.1002/anie.202012544

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Sugar-Based Polymers from D-xylose: Living Cascade
Polymerization, Tunable Degradation, and Small Molecule
Release
Authors: Antonio Rizzo, Gregory I. Peterson, Atanu Bhaumik, Cheol
Kang, and Tae-Lim Choi
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RESEARCH ARTICLE
Sugar-Based Polymers from D-xylose: Living Cascade
Polymerization, Tunable Degradation, and Small Molecule
Release
†
†
†
Antonio Rizzo, Gregory I. Peterson, Atanu Bhaumik, Cheol Kang, Tae-Lim Choi*
Dedicated to Prof. Bert Meijer on the occasion of his 65th birthday and for his service to J. Polym. Sci., Wiley for 15 years.
Dr. A. Rizzo, Dr. G. I. Peterson, Dr. A. Bhaumik, Dr. C. Kang, Prof. T.-L. Choi
Department of Chemistry
Seoul National University
Seoul 08826, Republic of Korea
E-mail: tlc@snu.ac.kr
†
These authors contributed equally.
Supporting information for this article is given via a link at the end of the document
Abstract: Enyne monomers derived from D-xylose underwent living
cascade polymerizations to prepare new polymers with a ring-opened
sugar and degradable linkage incorporated into every repeat unit of
the backbone. Polymerizations were well-controlled and had living
character, which enabled the preparation of high molecular weight
polymers with narrow molecular weight dispersity values and a block
copolymer. By tuning the type of acid-sensitive linkage (hemi-aminal
ether, acetal, or ether functional groups), we could change the
degradation profile of the polymer and the identity of the resulting
degradation products. For instance, the large difference in
degradation rates between hemi-aminal ether- and ether-based
polymers enabled the sequential degradation of a block copolymer.
Furthermore, we exploited the generation of furan-based degradation
products, from an acetal-based polymer, to achieve the release of
covalently bound reporter molecules upon degradation.
polymers which contain thermally-sensitive or hydrolyzable esters
and sulfonate esters,1
enzymatically-cleavable azobenzenes. ROMP has been used to
prepare various partially degradable polymers by
copolymerization of monomers containing acid-sensitive acetals,
7-21
acid-sensitive acetals,
22
and
2
3
2
4-32
ketals, phosphoesters, and silyl ethers,
base-sensitive
esters,29 and redox/thiol-sensitive disulfides. In many cases, the
content of the degradable monomers was limited due to their poor
polymerization performance at higher incorporation ratios. Only a
few monomers, containing pH-sensitive enol ether,33 or
hemiaminal ether-based linkages,34-37 have been successfully
homopolymerized to achieve fully degradable ROMP polymers.
27
Of note, other metathesis polymers which contain degradable
linkages have been prepared,3
explored.
8-41
but their degradability was not
Degradable polymers have also been prepared via the
cascade metathesis polymerization of monomers bearing
terminal alkynes and cyclic alkenes (also referred to as tandem
ring-closing/ring-opening metathesis polymerization or enyne
Introduction
metathesis polymerization) using the third-generation Grubbs
catalyst (G3).42-46 This cascade metathesis polymerization
Olefin metathesis is a versatile method which has been
widely used for the formation of new carbon-carbon bonds in
organic synthesis.1,2 The basic metathesis reactions, ring-opening,
ring-closing, and cross metathesis, have also been applied to
polymer synthesis, giving ring-opening metathesis polymerization
(
Figure 1A) was first developed in our group using monomers that
do not yield degradable polymers.47 Mechanistic studies
supported that the catalyst first reacts with the alkyne then
undergoes intramolecular ring-closing and ring-opening steps
(
(
ROMP),3-5 cyclopolymerization,6,7 and acyclic diene metathesis
ADMET) polymerization,8-10 respectively. With the use of the
48
(
Figure 1B). Controlled living polymerizations were observed
for monomers with N- and di-substituted C-based linkers (at the X
popular Grubbs-type catalysts, these metathesis polymerizations
are generally tolerant to a wide-range of functional and reaction
conditions, and therefore, are ideal for preparing well-defined
functional polymers for a wide-range of applications.2,11,12 The use
of metathesis polymerizations to prepare fully degradable
materials, however, has been relatively under-explored. The
development of new degradable polymers has become an
important topic as their potential is being realized in various
industries.13-16
position between the cyclohexene and terminal alkyne, e.g., 1 and
2
; Figure 1C), however a monomer with an O linker (3) could only
be polymerized in a non-controlled fashion at low concentrations
to favor productive intramolecular reactions).49 Hawker and
(
Gutekunst expanded upon this concept with macrocyclic
monomers containing specific amino-acid sequences that could
44
be degraded under transesterification conditions. Gutekunst
and coworkers also prepared modular monomers (e.g., 4) which
gave polymers with acid-sensitive acetals in each repeat unit.46
A common strategy to impart degradability to a polymer is
to incorporate degradable linkages into the polymer backbone.
ADMET polymerization has been utilized to prepare degradable
1
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RESEARCH ARTICLE
with other linkers failed. We imagined that we might be able to
further improve the polymerization performance and expand the
diversity of SBMs by switching to monomers, based on D-xylose,
with different linkers that could enable the modulation of polymer
degradability (Figure 1D).
Herein, we report the living polymerization of new SBMs.
The switch to D-xylose-based monomers enhanced the
polymerization efficiency and enabled the implementation of N-,
C- and O-based linkers in the monomer. We, for the first time,
were able to obtain controlled living polymerizations with
monomers containing O linkers. The linker was also found to play
a critical role in tuning the degradability of the resulting polymers
and the identity of the degradation products: the later we exploited
to trigger the secondary release of a reporter molecule after
polymer degradation.
Results and Discussion
Monomers M1-4 (Figure 2) were prepared from the
pyranose form of D-xylose (see Figure S1 in the Supporting
Information, SI, for synthetic details). We first explored the
polymerization of M1 (N-TPS linker) with G3 catalyst. After
optimizing the polymerization conditions (see Table S1 in the SI),
we found that the polymerization was well controlled up to M/I of
1
25 (Figure 3A), with number average molecular weight (M
values ranging 10.6 – 38.7 kDa and molecular weight dispersity
) values ranging 1.11 – 1.40 (Table 1, entries 1 – 5). With our
previous D-glucose-based monomer with a N-TPS linker (which
has an additional CH OAc group), we could only maintain control
n
)
(Ð
M
2
of the polymerization up to M/I of 50 due to incomplete conversion
and long reaction times (at M/I of 75 and 100, monomer
conversions reached 87% in 12
h and 77% in 15 h,
respectively).45 Thus the reduced steric bulk on the sugar ring
appeared to significantly enhance the polymerization efficiency
(full conversion within 4 h). We conducted a 1H NMR kinetics
study and found first order conversion of monomer (see Figure
S2 in the SI), suggesting monomer reacting with the catalyst is
rate determining, which is in accord with the previously observed
reactivity of D-glucose-based monomers.
Figure 1. (A) General reaction scheme for the cascade metathesis
polymerization of monomers with terminal alkyne and cyclohexene units. (B)
Proposed polymerization mechanism. (C) Previous work: representative
monomers for cascade metathesis polymerization. (D) In this work: new sugar-
based monomers with N, C, and O linkers prepared from D-xylose. Mes =
mesityl. TBDMS = tert-butyldimethylsilyl. Ts = tosyl.
We recently reported the cascade metathesis
polymerization of sugar-based monomers (SBMs) to yield fully
degradable polymers containing acid-sensitive hemiaminal
4
5
ethers. Specifically, we prepared SBMs from D-galactose and D-
glucose with the alkyne attached at the anomeric carbon via a N-
2
,4,6-triisopropylbenzenesulfonyl (N-TPS) linker (e.g., 5). While
we could achieve high molecular weight polymers in a controlled
and living manner, compared to other cascade polymerizations,
the polymerization of these monomers was relatively slow. For
example, at room temperature (RT), our best monomer (5)
reached full conversion in 7 h with a monomer to initiator ratio
4
5
(
M/I) of 100, compared to 30 min for 4 (M/I of 200 and similar
4
6
concentration), and 1 min for 1 (M/I of 100 and slightly higher
4
7
concentration). We attributed the slower polymerization rates to
the more substituted (sterically crowded) sugar ring. Also, the
scope for the SBMs was rather limited because we could only use
N-based linkers (at the X position, see Figure 1): polymerizations
Figure 2. (A) Chemical structures and stereochemistry (α:β) for monomers used
in this study. (B) Cascade polymerization of D-xylose-based monomers.
2
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RESEARCH ARTICLE
S1 in the SI for optimization), we found the polymerization of M3
Table 1. Polymerization Results for SBMs (MX).
to be controlled up to M/I of 125 (Figure 3C), with M
n
values
conc. temp. time conv.
entry MX M/I
yield
(%) (kDa)
M
n
ranging 8.9 – 32.2 kDa and Ð values ranging 1.09 – 1.29 (Table
Ð [
d]
M
[
a]
[b]
[c]
[d]
M
(M)
(˚C)
(h)
(%)
1
, entries 10 – 14). Addition of a second methyl group (M4) led to
a rather significant decrease in polymerization performance.
However, by increasing the concentration and further increasing
the temperature, we could achieve controlled polymerizations up
1
2
3
4
5
6
7
8
9
M1
M1
M1
30
50
75
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
10
10
10
10
10
10
10
10
10
RT
RT
RT
RT
RT
30
30
30
30
30
1
2
99
87
68
85
89
87
76
84
86
84
88
86
82
86
84
62
65
87
86
84
10.6
1.11
1.17
1.21
1.32
1.40
1.10
1.20
1.34
1.39
1.09
1.10
1.12
1.24
1.29
1.15
1.19
1.22
1.28
1.27
>99
>99
>99
>99
>99
>99
>99
96
18.4
25.8
31.5
38.7
11.5
17.8
29.1
33.2
8.9
n
to M/I of 60 (Figure 3D), with M values ranging 7.7 – 25.9 kDa
3
and Ð values ranging 1.15 – 1.28 (Table 1, entries 15 – 19). For
M
both of these monomers, kinetics studies supported first order
monomer conversion (see Table S2 in the SI) albeit with slower
rates (than M1 and M2), presumably due to the added steric
hinderance of the methyl groups, which would slow catalyst
approach to the alkyne. Likewise, the polymerization of M4 (with
a dimethyl group) was the slowest by at least one order of
magnitude.
M1 100
M1 125
4
5.5
1
M2
M2
M2
30
50
75
2
3
M2 100
4
1
0
1
2
3
4
5
6
7
8
9
M3
M3
M3
30
50
75
0.05
0.05
0.05
0.33
0.5
0.75
1
>99
>99
>99
97
1
1
1
1
1
1
1
1
1
14.4
21.3
29.0
32.2
7.7
M3 100 0.05
M3 125 0.05
1.33
0.67
0.92
1.25
1.5
2.5
>99
>99
>99
99
M4
M4
M4
M4
M4
20
30
40
50
60
0.3
0.3
0.3
0.3
0.3
11.2
18.6
22.4
25.9
98
>99
[
˚
a] Monomer concentration. [b] RT = room temperature, which averaged ca. 21
C. [c] Conversion: determined by crude H NMR analysis. [d] Determined by
1
size exclusion chromatography (SEC), in THF, calibrated by polystyrene
standards.
We next turned our attention to monomers with C-based and
O linkers. Using the same optimized polymerization conditions,
the polymerization of M2 (C-(CO
up to M/I of 100 (Figure 3B), with M
kDa and Ð values ranging 1.10 – 1.39 (Table 1, entries 6 – 9).
2
Me)
2
linker) was well controlled
n
values ranging 11.5 – 33.2
M
These results are comparable to our previous results with
monomers utilizing di-substituted carbon linkers,49 albeit with
longer polymerization times. Again, 1H NMR kinetics studies
revealed first order consumption of monomer (see Figure S2 in
the SI). Unfortunately, initial attempts to polymerize monomers
with O linkers were not as successful. As mentioned above,
polymerization of 3 (Figure 1C), which has a simple propargyl
group (no additional substituents), was only achieved with dilute
Figure 3. Controlled cascade metathesis polymerization of D-xylose-based
monomers. (A) Linear plots of M versus M/I × conversion for M1, (B) M2, (C)
n
M
3
,
a
n
d
(
D
)
M
4
.
B
l
a
c
k
c
i
r
c
l
e
s
r
e
p
r
e
s
e
n
t
M
n
v
a
l
u
e
s
.
B
l
u
e
s
q
u
a
r
e
s
r
e
p
r
e
s
e
n
t
Ð
M
values. Dashed lines are for visual aid only.
To determine the influence of linker type (e.g., N, C, O) on
each polymer’s degradability and the resulting degradation
products, we conducted 1H NMR studies with each polymer in
conditions and gave low molecular weight polymers with broad
dispersity (>1.5).48,49 Similarly, polymerization of the D-xylose-
3
acidic conditions. Specifically, polymers were dissolved in CD CN
with 2% v/v MeOH, HCl was added, and the degradation was
monitored over time. With an HCl concentration of 5×10-5 M, P1
underwent complete degradation to D1 (Figure 4A, degradation
products confirmed by NMR and HRMS analysis, see the SI for
details) within ca. 4 min (Figure 4B). Attempts to further decrease
the acid resulted in the incomplete degradation of the polymer
analogue of this monomer (see SM1 in the SI) was unsuccessful
(
see Table S1, entry 10 and 11 in the SI). Fortunately, addition of
a methyl group adjacent to the alkyne (M3) enabled successful
polymerization, presumably by sterically shielding the
5
0
propagating carbene and slowing decomposition pathways. By
decreasing the concentration and increasing the temperature,
compared to the optimized conditions for M1 and M2 (see Table
(
degradation leveled off around 40%). D1 is structurally
3
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RESEARCH ARTICLE
neutral, the observation of the % degradation leveling off (at the
lower acid concentrations) suggests consumption of acid via an
unknown mechanism. Based on these results, we rank the acidic
degradability of polymers as follows: P1 > P3 > P4 > P2. While
D1 and D3 (which contain aromatic pyrrole and furan moieties,
respectively) were quite stable (under the degradation conditions),
we observed an interesting transformation in which D4 further
degraded to D4’ via subsequent intermolecular and
intramolecular alcohol additions at higher HCl concentrations
-2
(
e.g., 1×10 M, see Figure S30 in the SI for more details). Overall,
these studies demonstrate the highly degradable nature of D-
xylose-based polymers under mildly acidic conditions. Notably,
P1 and P2 showed no degradation over 7 d in solution without
acid, whereas P3 and P4 showed some slow degradation,
reaching ca. 15 and 9% degradation in 7 d without acid,
respectively (see Figure S3).
Figure 4. (A) Acidic degradation of polymers and the resulting degradation
products. (B) Plot of degradation versus time for P1
concentrations are indicated in the legend. Other conditions: polymers at 0.02
M in CD CN with 2% v/v MeOH. Solid and dashed lines are for visual aid only.
– P4. The HCl
3
analogous to the pyrrole-based degradation products observed
for our previous D-glucose/galactose-based polymers.45 P2 did
Figure 5. (A) Synthetic scheme for the preparation of P2-b-P1. (B) SEC traces
for P2 (via an aliquot just before addition of M1) and P2-b-P1. Peaks normalized
to the maximum peak height. (C) SEC traces at various time points during the
acidic degradation of P2-b-P1 in THF (HCl concentration of 1.3 M). Peaks
normalized to an internal standard (ca. 900 kDa polystyrene, PS).
not degrade over ca. 8 h with an HCl concentration 5×10-5 M.
Relatively slow degradation was observed at a much higher HCl
concentration (1×10-1 M), reaching full degradation in 11 h (to
non-specific degradation products). P3 underwent nearly
instantaneous degradation to a furan-based product (D3) with an
HCl concentration of 1×10-4 M (degradation leveled off around
Next, we wanted to explore the feasibility of preparing a
block copolymer (from two different SBMs) and achieve
sequential degradation of blocks with very different degradation
6
0% with an HCl concentration of 5×10-5 M). Finally, P4 also
underwent nearly instantaneous degradation (to D4) with an HCl
concentration of 1×10-4 M (although degradation leveled off
around 40% with an HCl concentration of 5×10-5 M). As the
degradation with catalytic amounts of acid should be proton
45
profiles. In our previous report, we could not demonstrate
sequential degradation because polymers from D-glucose and D-
galactose showed similar degradation rates due to their structural
4
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RESEARCH ARTICLE
Figure 6. (A) Scheme for the degradation of a polymer and release of molecular cargo. (B) Synthesis and degradation of P5 and P6 with release of PNP. Blue
letters represent protons assigned in the 1H NMR spectrum. (C) Stacked 1H NMR spectrum of P6 undergoing acidic degradation (1×10 M HCl concentration in
-3
-
3
3 3
CD CN with 2% v/v MeOH). (D) Change in UV-vis absorbance during the acidic degradation of P6 (1×10 M HCl concentration in CH CN with 2% v/v MeOH). The
inset plot shows the PNP calibration curve (absorbance at 320 nm) used to determine the concentration of released PNP. (E) Plot of the percentage of PNP released
1
from P6 over time for H NMR and UV-vis experiments.
similarity. We began by first polymerizing M2, and then adding M1
to the P2 block (with a living chain end, M : 7.2 kDa and Đ : 1.12)
to form P2-b-P1 (Figure 5A). Comparison of the SEC traces from
copolymer synthesis (see Figure S4 and S5 in the SI, which show
the overlapped SEC traces of the P2 blocks, from synthesis and
degradation, and the loss of all P1 signals after 5 min by H NMR
n
M
1
the block copolymer and first block revealed a clear shift in the
spectroscopy, respectively). After 24 h, the P2 block too was
almost completely degraded to small molecules, with only a little
oligomeric material remaining. Therefore, sequential degradation
of a block copolymer was achieved. This result highlights further
highlights the advantage of broadening the monomer scope, and
thereby, being able to tune polymer degradability.
In most cases, the degradation of D-xylose-based polymers
yielded well-defined small molecules such as pyrroles (D1),
furans (D3) and even spirocyclic compounds (D4’). This inspired
us to explore the feasibility of designing a functional degradation
SEC peak to shorter retention times (M
without residual P2 block or excessive tailing, and maintaining a
of 1.18. This result supports the living nature of the cascade
n
: 22.2 kDa, Figure 5B),
Đ
M
metathesis polymerization. With this block copolymer on hand, we
began to explore its acidic degradation. The polymer was
dissolved in THF, HCl was added (final concentration of 1.3 M),
and the degradation was monitored by SEC (Figure 5C). After 5
min, the P1 block was completely degraded, leaving only the P2
n
block having the same M as the P2 intermediate in the block
5
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RESEARCH ARTICLE
compound and proceeding backward by retrosynthetic analysis to
a new monomer. Furan-maleimide Diels-Alder adducts have been
shown to function as thermal or mechanochemical triggers for
initiating depolymerization or releasing small molecules,
respectively.51,52 In these examples, the generation of a furfuryl
carbonate intermediate, which undergoes further decomposition
on D-xylose with different linkers, to produce new fully degradable
polymers. Polymerizations were well-controlled and high
molecular weights were obtained (M up to ca. 39 kDa) with
n
generally narrow dispersity (1.09−1.40). The living nature of the
polymerization was supported by the preparation of a block
copolymer from SBMs with two different linker types (N- and C-
based linkers in M1 and M2, respectively). The resulting block
2
via CO loss and production of a carbocation intermediate, was
the key to the desired reactivity. With this specific reactivity in
mind, we designed a furfuryl carbonate degradation product (an
analogue to D3) which would enable the release of covalently
bound molecular cargo, after the acidic degradation of the
polymer. Polymers that release cargo upon degradation (Figure
copolymer contained a first block with hemi-aminal ether
functional groups and a second block with ether functional groups.
The significantly slower degradation of the ether functionalities
(compared to the hemi-aminal ethers) enabled sequential
degradation of the block copolymer under acidic conditions. The
linker also influenced the resulting degradation products. We took
advantage of the reactivity of furan-based degradation products
to prepare polymers which undergo initial acidic degradation,
followed by secondary release of molecular cargo. We envision
these polymers may have potential use in the various arenas
which require degradable polymers or small molecule release
capabilities (e.g., drug delivery, sensors, etc.).
6
A) are relevant to various applications including sensing, self-
healing, and drug delivery.16,53-56 We designed two new
monomers, M5 and M6 (see Figure S6 in the SI for synthetic
details), such that their polymers (P5 and P6) would generate D5
and D6, which would subsequently release p-nitrophenol (PNP)
as a model cargo molecule (Figure 6B), which could be easily
monitored by UV-vis and NMR analysis. Each monomer
underwent efficient polymerization at a M/I of 30 (0.05 M
monomer concentration at RT), giving polymers with M
.6 kDa (1.17) and 9.7 kDa (1.12) for P5 and P6, respectively.
We first studied the degradation and PNP release for P5.
n M
(Ð ) of
8
Supporting Information: Supplemental figures, experimental details, and
characterization of monomers, polymers, and degradation products are
included in the SI.
Based on density functional theory (DFT) calculations and
experimentally measured half-lives of model compounds
52
conducted by Robb and coworkers, we expected that PNP
release would be considerably slow for this polymer. Indeed, we
observed rapid degradation of the polymer to D5 upon addition of
Acknowledgements
HCl at RT (1×10-3 M HCl concentration in CD
CN with 2% v/v
3
We acknowledge Hojoon Song (SNU) for help with monomer
scaleup. The authors also thank the Korean NRF for the following
funding: Creative research initiative and Young Investigator Grant
MeOH), however, only 13% of PNP released over 31 h via
methanolysis (see Figure S7 in the SI). Robb and coworkers also
found that addition of an α-methyl group was found to lower the
activation barrier of furfuryl carbonate decomposition and enable
release to occur at relatively fast rates at RT, presumably due to
higher stabilization of the furfuryl cationic intermediate at the
secondary carbon (see Figure S8 in the SI).52 Therefore, we
expected P6 to exhibit much faster release of PNP. Subjecting P6
to the same acidic degradation conditions, we observed, with both
(
NRF-2018R1C1B6003054).
Keywords: polymerization • metathesis • cascade • degradation
• sugars
[1]
R. H. Grubbs in Handbook of Metathesis, Vols. 1, 2; Wiley-VCH:
Weinheim, 2003.
1
H NMR (Figure 6C and 6E) and UV-vis (Figure 6D and 6E)
[
2]
O. M. Ogba, N. C. Warner, D. J. O’Leary, R. H. Grubbs. Chem. Soc.
Rev. 2018, 47, 4510-4544.
experiments, that rapid and complete degradation of the polymer
to D6 initially occurred in less than 2 min, followed by the fast
secondary release of PNP (>90% in less than 2 h). Formation of
the degradation product D6’ (via trapping the cationic
intermediate with MeOH, see Figure S8 in the SI) supports that
the PNP was released via the furfuryl intermediate, rather than
simple methanolysis, which is a much slower process. Notably,
P6 showed better stability in solution without acid than P3 (over
[
[
[
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4]
5]
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1
0 d, see Figure S9 in the SI), as we observed no polymer
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Entry for the Table of Contents
Degradable sugar-based polymers are prepared with cascade metathesis polymerizations in a controlled and living manner. The
resulting polymers are fully degradable and degradation profiles can be modified by using different monomer linkers. Polymers can
also be designed such that their degradation products undergo secondary reactions to release small molecules.
8
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