Acid-Triggered, Acid-Generating, and Self-Amplifying Degradable Polymers

Article abstract of DOI:10.1021/jacs.8b07705

We describe the 3-iodopropyl acetal moiety as a simple cleavable unit that undergoes acid catalyzed hydrolysis to liberate HI (pK_a-10) and acrolein stoichiometrically. Integrating this unit into linear and network polymers gives a class of macromolecules that undergo a new mechanism of degradation with an acid amplified, sigmoidal rate. This trigger-responsive self-amplified degradable polymer undergoes accelerated rate of degradation and agent release.

Full text of DOI:10.1021/jacs.8b07705

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Communication
Acid-Triggered, Acid-Generating, and Self-Amplifying Degradable Polymers
Kali A. Miller, Ephraim G. Morado, Shampa R. Samanta, Brittany A. Walker, Arif Z. Nelson, Samya
Sen, Dung T. Tran, Daniel J. Whitaker, Randy H. Ewoldt, Paul V. Braun, and Steven C. Zimmerman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07705 • Publication Date (Web): 30 Jan 2019
Downloaded from http://pubs.acs.org on January 31, 2019
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Acid-Triggered, Acid-Generating, and Self-Amplifying Degradable
Polymers
Kali A. Miller,†,∇,⊥ Ephraim G. Morado,†,⊥ Shampa R. Samanta,†,⊥ Brittany A. Walker,†,⊥ Arif Z. Nelson,§ Samya
Sen,§ Dung T. Tran,† Daniel J. Whitaker,† Randy H. Ewoldt,§,∥ Paul V. Braun,†,‡,∥,∇ and Steven C. Zimmerman*,†,∥
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†Department of Chemistry, ‡Department of Materials Science and Engineering, §Department of Mechanical Science and Engineer-
ing, ∥Materials Research Laboratory, ∇Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-
Champaign, Urbana, Illinois 61801, USA
Supporting Information
Indeed, a renewed interest in degradable polymers, espe-
cially for biomedical and engineering applications has led
to an extensive search for new mechanisms to breakdown
polymers.2 Most degradable polymers contain functional
groups along their main chain that cleave independently
by chemical or photochemical reaction, in which case, the
degradation rate remains more or less constant until the
trigger or cleavable functionality is consumed (Figure 1a).
The discovery of self-immolative polymers was particu-
larly exciting because one triggering event is sufficient to
activate an entire polymer chain to degrade.3,4 These sys-
tems are stable under ambient conditions until a reactive
unit at the polymer end is cleaved, triggering a cascade of
fragmentation reactions that proceed sequentially along
the polymer chain (Figure 1b).
ABSTRACT: We describe the 3-iodopropyl acetal moiety as a
simple cleavable unit that undergoes acid catalyzed hydroly-
sis to liberate HI (pKa ~ -10) and acrolein stoichiometrically.
Integrating this unit into linear and network polymers gives
a class of macromolecules that undergo a new mechanism of
degradation with an acid amplified, sigmoidal rate. This trig-
ger-responsive self-amplified degradable polymer undergoes
accelerated rate of degradation and agent release.
The simultaneous growth in waste plastics, 3D-printing,
and implantable biomaterials has challenged chemists to
develop new polymers able to meet the demands of real-
world applications. In particular, there is increasing de-
mand for smart polymers that change their shape or prop-
erties or degrade in response to environmental stimuli.1
Figure 1. Schematic representation of polymer degradation mechanisms: (a) Traditional cleavage of polymer chain, (b) Self-im-
molative polymer degradation. Loss of end-cap is followed by sequential loss of end units, (c) Trigger-responsive chain-shattering
polymer degradation mechanism, and (d) Amplified chain-shattering mechanism developed in the current work. Green linkages
are labile under reaction conditions, whereas red are stable.
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More recently, the development of chain-shattering pol-
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Scheme 2
1
2
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8
ymers allows materials to spontaneously degrade along
the main chain with a triggering event occurring at each
monomer unit (Figure 1c).5 Both the self-immolative and
chain-shattering approaches do have limitations in degra-
dation rate and require a stoichiometric amount of the
triggering agent. We were interested in a less studied ap-
proach that can be referred to as an amplified chain-shat-
tering degradation. In this mechanism, a catalytic species
accelerates chain cleavage, which in turn generates a full
equivalent of the same agent, leading to an exponential
degradation cascade (Figure 1d).6 For example, polyesters
such as PLGA show mild autocatalysis because the liber-
ated carboxylic acids accelerate the hydrolysis.7
H
O
O
X
O
1) TMSBr, PhH
2)
O
O
O
HO
4
TsOH, PhH,
Dean-Stark; 54%
acetone
5
1
: X = Br
KI, rt; 86%
: X =
I
ADMET
acetone
O
O
O
O
9
O
O
O
O
n
K2OsO4
NMMO
H2O; 54%
n
OH
HO
10
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I
I
10
9
OH
OH
Herein, we describe a simple, yet powerful acetal unit
derived from 3-iodopropanal that undergoes acid cata-
lyzed, self-amplified cleavage and demonstrate how it can
be readily integrated into both degradable polymers and
hydrogels. Unlike polyesters, our designed system shows
strong autocatalysis and is more suitable to applications
where exponential rates are needed. The acetal unit and
acid trigger were chosen because pH gradients are ubiqui-
tous in the environment and within biological systems.
Furthermore, polymeric acetals (polyacetals) are well
studied, with tunable reactivities and properties.8 The
simplest, polyoxymethylene (POM) is a widely used engi-
neering thermoplastic, whereas more complex polyace-
tals are used in a range of applications from controlled re-
lease to drug delivery.
The acetal design was based on small molecules re-
ported by Ichimura and coworkers9 that produce p-tol-
uenesulfonic acid (pKa ≈ -2.8) in an amplified manner.
With this starting point, various monomeric units were
prepared and tested, ultimately leading to the 3-iodo-1,1-
dialkoxy moiety as having the most suitable properties. In
particular, this unit is easily prepared and has good stabil-
ity, but undergoes acid amplified degradation under
mildly acidic conditions. In this mechanism, the acetal
likely hydrolyzes to the hemiacetal and then further to the
aldehyde, which subsequently undergoes β-elimination to
generate stoichiometric amounts of hydroiodic acid with
pKa ≈ -10 and acrolein (Scheme 1). Each of the three steps
is catalyzed by acid.
Me
O
3
O
Me
3
HO
O
O
OH
O
O
I
I
2
3
HCl in place of TMSBr, the diol units in 2 obtained by dihy-
droxylation (see Supporting Information).
The ability of the 3-iodopropyl acetal unit to undergo
acid amplified cleavage was examined by monitoring the
hydrolysis of 3 using H NMR under different conditions.
A solution of 3 in D2O at pD = 5.5 at 70 ºC showed an in-
duction period of about 15-20 minutes at which time the
acetal underwent a rapidly accelerating degradation (Fig-
ure 2a). The reaction was largely complete after about 45
min. Consecutive 1H NMR spectra taken over 1 h were con-
sistent with the formation of hemiacetal 7, further hydrol-
ysis to aldehyde 8, which subsequently undergoes β-
elimination to generate hydroiodic acid (Figure 2b and
Figure S1). The stoichiometric generation of the strong
1
(a)
(c)
Scheme 1. Mechanism of 3‐iodopropyl acetal hydrolysis
with stoichiometric formation of HI and amplified cleav‐
age.
(b)
H2O, cat. H+
H2O, cat. H+
+
I-
H
H2O, cat. H+
step 1
H2O, cat. H+
step 2
cat. H+
step 3
O
I-
+
O
H+
+
HO
O
Me
3
O
3
R1O OR2
HO
H
O
OR2
H
O
I
H
Me
OH
3
I
6
O
H
7
8
R2OH
R1OH
I
I
I
6
Figure 2. (a) Percent conversion of 3 in D2O at initial pD = 5.5,
with [3] = 48 mM at 70 °C in presence (green diamonds) and
absence (blue circles) of 0.1 M acetate buffer. (b) Proposed
mechanism of acetal hydrolysis with stoichiometric formation
of HI and amplified cleavage. (c) Change in solution pH over
time of a solution, [3] = 48 mM in nanopure water. Blue points,
[H+]; green points pH. Triangle, 50 °C, circle 70 °C, square, 90
°C. Connected lines are added to guide the eye.
The key 3-iodopropyl acetals 1-3 used in this study are
shown in Scheme 2. The synthesis of iodo-acetal monomer
1 was achieved by treatment of acrolein with TMSBr and
acetalization with alcohol 4 to afford 5.10 Conversion of
bromo acetal 5 to the iodo acetal 1 proceeded in good
yield under standard Finkelstein conditions. Iodo acetals
2 and 3 were prepared in analogous fashion or by using
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acid HI can accelerate each of the previous steps and pro-
Using Grubb’s 1st generation catalyst, monomer 1 un-
derwent successful acyclic diene metathesis (ADMET)
polymerization providing polymer 9 with Mn ≈ 10,000.
Upjohn-dihydroxylation was subsequently used to con-
vert 9 to 10 which significantly increased its water solu-
bility (Scheme 2). However, polymer 10 exhibits thermo-
responsiveness in pure aqueous solution with an LCST
above room temperature. Therefore, a 40% (v/v) CD3CN
in D2O (pD0 = 5.5) mixture was used for degradation stud-
1
2
3
4
5
6
7
8
duce the nonlinearity observed for the process. Consistent
with these observations, performing the same hydrolysis
reaction in the presence of 0.1 M acetate buffer dramati-
cally suppressed the hydrolysis rate as seen in Figure 2a.
The acid amplified degradation of 3 was further charac-
terized by measuring the pH over time. Thus, 48 mM aque-
ous solutions of 3 in nanopure water, which was slightly
acidic (pH = 5.5) due to dissolved atmospheric CO2, were
heated at three temperatures (50, 70, and 90 °C) and the
pH was measured at regular intervals (Figure 2c). The
proliferation of acid was almost instantaneous at 90 °C,
whereas an induction period of ca. 2 h and 5 min was ob-
served at 50 °C and 70 °C, respectively. The release of acid
at 50 °C could be made instantaneous by starting the reac-
tion in a pH 3 solution by adding p-toluenesulfonic acid
monohydrate. Both of the higher temperature reactions
rapidly leveled off at pH ≈ 1.5, with the final [H+] value be-
ing consistent with near quantitative conversion of 3 to HI.
Final support for the autocatalytic, acid amplification
mechanism comes from successfully fitting the degrada-
tion data of 3 at 70 ºC to an autocatalytic kinetic model
(Equation S1).11 In this model, rate constants k1 and k2 de-
scribe the non-autocatalytic hydrolysis step and autocata-
lytic HI-accelerated steps, respectively. As expected for an
autocatalytic reaction, k1 (1.9 x 10-4 min−1) ≪ k2c0 (3.0 x
10-2 min−1) (Table 1). Additional support for this model in-
volves a linear fit of the data over time using Equation S3
and shown in Figure S6.
1
ies, which were monitored by H NMR spectroscopy and
gel permeation chromatography (GPC).
9
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The hydrolysis of 10 was observed in NMR by watching
the disappearance of the acetal proton. A plot of normal-
ized acetal conversion vs. time showed a distinctive sig-
moidal shape that can be linearized (Figure 3a, Figure S7).
This data fits well to our autocatalytic model and the ex-
tracted values for 10 agree with those observed for the
degradation of 3 (Table 1). An autocatalytic, acid-ampli-
fied polymer degradation process should also be accom-
panied by a sigmoidal decrease in molar mass of 10. As
seen in Figure 3b, a solution of 10 heated to 70 °C was
monitored at regular time intervals using GPC. Due to self-
amplified degradation, there are only small changes in the
Table 1. Calculated rate constants for the non‐auto‐
catalytic and autocatalytic pathways of the degrada‐
tion of 3, 10, and 13 at various temperatures. Average
and standard deviation values are listed from three
measurements.
Figure 4. (a) Visual observation of the degradation of 13
compared to polyacrylamide control at 90 ºC. Pictures are of
the gel in a scintillation vial submerged in an oil bath. (b)
Storage modulus of 13 at 70 ºC, 13 with and without 0.1 M
acetate buffer at 90 ºC, and the polyacrylamide hydrogel at
90 ºC.
Temp (ºC)
k1 (103 min-1)
0.19 ± 0.26
0.16 ± 0.19
37 ± 6
k2 (M-1min-1)
6.2 ± 1.2
70
70
90
3
2.9 ± 0.6
10
13
7250 ± 3810
GPC traces at first, followed by a rapid increase in reten-
tion time, and then much smaller changes.
Upon successful demonstration of the acid triggered
self-amplified degradation behavior of the small molecule
and linear polymer, we were interested in developing a
degradable hydrogel containing the 3-iodopropyl acetal
moiety. Treatment of 1 with HCl and acetalization with
TMS-protected N-hydroxyethyl acrylamide gave 11,
which was converted to acrylamide crosslinker 12 con-
taining a central 3-iodopropyl acetal unit. Finally, de-
gradable hydrogel 13 was synthesized by free radical
polymerization using 3 mol% of 12 as the crosslinker and
the monomer acrylamide (AAm) with diethoxyacetophe-
none (DEAP) as the photo-initiator (Scheme 3 and S6). An
additional example of polyol hydrogel synthesis and visual
observation of its degradation can be found in the Supple-
mental Information.
Figure 3. (a) Monitoring the disappearance of acetal func-
tionality of 10 by 1H NMR as a 3 mM solution in D2O/CD3CN
at 70 ºC. Dashed line is fit of the data to Equation S4 and dot-
ted line is provided as a guide for the eye. (b) GPC traces of
the degradation of 10 in a 0.3 M solution in H2O/CH3CN over
time at 70 ºC.
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Detailed experimental procedures, NMR spectra, addi-
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Scheme 3. Synthesis of degradable hydrogel 13.
tional characterization and kinetic data, kinetic model-
ing details, and synthesis and degradation of a PEG-
based hydrogel (PDF)
O
O
H
O
1) 1M HCl-Et2O
O
O
N
H
N
H
H
2)
N
TMSO
X 11 : X = Cl
12 : X = I
AUTHOR INFORMATION
O
TMSOTf
NaI
Corresponding Author
AAm
hv
*sczimmer@illinois.edu
CONH2
O
H2NOC
O
ORCID
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O
O
Kali A. Miller: 0000-0003-3632-0615
Randy H. Ewoldt: 0000-0003-2720-9712
Paul V. Braun: 0000-0003-4079-8160
Steven C. Zimmerman: 0000-0002-5333-3437
N
N
H
H
CONH2
H2NOC
I
13
Author Contributions
⊥K.A.M., E.G.M, S.R.S., and B.A.W contributed equally.
Hydrogel 13 was studied and compared to gels pre-
pared with a nondegradable crosslinker (N,N'-meth-
ylenebisacrylamide) in the same mole ratio (Scheme S7).
Visual observation of hydrogel degradation over time
shows that 13 has a delay period of ~30 min and then de-
grades rapidly to give a solution, whereas the polyacryla-
mide control did not show any sign of degradation (Figure
4a). The degradation process was also characterized using
rheology. The storage modulus was measured, and mini-
mal degradation was seen from the polyacrylamide con-
trol (PAAm) at 90 ºC, 13 at 70 ºC, and 13 at 90 ºC in 0.1 M
acetate buffer. However, upon heating to 90 ºC, 13 under-
goes the rapid degradation that is characteristic of auto-
catalytic reactions (Figure 4b). This degradation profile
was quantified using the autocatalytic rate equations de-
scribed above and in the Supporting Information, includ-
ing an interrelation between elastic modulus and concen-
tration to compare the apparent chemical rate constants
(Figure S8). The increase of k1 and k2 for 13 can be at-
tributed to increased hydrolysis and amplification rates at
higher temperatures (Table 1).
In conclusion, we demonstrated a novel class of trigger-
responsive self-amplified-degradable materials. The spe-
cific moiety developed here, the 3-iodopropyl acetal
group, produces two products stoichiometrically: (1) hy-
droiodic acid, a very strong acid that accelerates further
degradation, and (2) acrolein, a potent biocide and mer-
captan scavenger. We anticipate that this acid amplifying
motif could serve as a unique method for the controlled
delivery of protic acid for various biological and chemical
applications. These materials may also serve as benign
carriers that undergo amplified release of biocidal acro-
lein in acidic solution. Investigations in these directions
are currently in progress in our laboratory. We are further
developing polymers for the self-amplified release of
other reagents as well as other architectures with differ-
ent rates and byproducts to expand the toolbox for poten-
tial applications.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge support by the
Dow Chemical Company (design and synthesis), the Na-
tional Science Foundation under award NSF CHE-
1709718 (synthesis and degradation studies), the De-
partment of Defense/US Army under Award Number
W911NF-17-1-0351 (hydrogel fabrication), and the
U.S. Department of Energy, Office of Basic Energy Sci-
ences, Division of Materials Sciences and Engineering
under Award Number DE-FG02-07ER46471 (modeling
efforts). K.A.S. acknowledges the National Science
Foundation for support (DGE-1746047). We thank
Shuqi Lai, Eric S. Epstein, Kaitlyn Curtis, Hsuan-Chin
Wang, and Yugang Bai for technical support and insight-
ful discussions.
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ASSOCIATED CONTENT
Supporting Information
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on the ACS Publications website.
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