Mechanically Gated Degradable Polymers

Article abstract of DOI:10.1021/jacs.9b13359

Degradable polymers are desirable for the replacement of conventional organic polymers that persist in the environment, but they often suffer from the unintentional scission of the degradable functionalities on the polymer backbone, which diminishes polymer properties during storage and regular use. Herein, we report a strategy that combats unintended degradation in polymers by combining two common degradation stimuli - mechanical and acid triggers - in an "AND gate" fashion. A cyclobutane (CB) mechanophore is used as a mechanical gate to regulate an acid-sensitive ketal that has been widely employed in acid degradable polymers. This gated ketal is further incorporated into the polymer backbone. In the presence of an acid trigger alone, the pristine polymer retains its backbone integrity, and delivering high mechanical forces alone by ultrasonication degrades the polymer to an apparent limiting molecular weight of 28 kDa. The sequential treatment of ultrasonication followed by acid, however, leads to a further 11-fold decrease in molecular weight to 2.5 kDa. Experimental and computational evidence further indicate that the ungated ketal possesses mechanical strength that is commensurate with the conventional polymer backbones. Single molecule force spectroscopy (SMFS) reveals that the force necessary to activate the CB molecular gate on the time scale of 100 ms is approximately 2 nN.

Full text of DOI:10.1021/jacs.9b13359

Subscriber access provided by BOSTON UNIV
Communication
Mechanically Gated Degradable Polymers
Yangju Lin, Tatiana B. Kouznetsova, and Stephen L. Craig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13359 • Publication Date (Web): 15 Jan 2020
Downloaded from pubs.acs.org on January 15, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Mechanically Gated Degradable Polymers
Yangju Lin, Tatiana B. Kouznetsova and Stephen L. Craig*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
Supporting Information Placeholder
degradation, while still responding to mild triggers for
degradation, would be advantageous.
ABSTRACT: Degradable polymers are desirable for the
replacement of conventional organic polymers that persist in
the environment, but they often suffer from the unintentional
scission of the degradable functionalities on the polymer
backbone, which diminishes polymer properties during
storage and regular use. Herein, we report a strategy that
combats unintended degradation in polymers by combining
two common degradation stimuli—mechanical and acid
triggers—in an “AND gate” fashion. A cyclobutane (CB)
mechanophore is used as a mechanical gate to regulate an acid-
sensitive ketal that has been widely employed in acid
degradable polymers. This gated ketal is further incorporated
into the polymer backbone. In the presence of acid trigger
alone, the pristine polymer retains its backbone integrity, and
delivering high mechanical forces alone by ultrasonication
degrades the polymer to an apparent limiting molecular weight
of 28 kDa. The sequential treatment of ultrasonication followed
by acid, however, leads to a further 11-fold decrease in
molecular weight to 2.5 kDa. Experimental and computational
evidence further indicate that the ungated ketal possesses
mechanical strength that is commensurate with the
conventional polymer backbones. Single molecule force
spectroscopy (SMFS) reveals that the force necessary to
activate the CB molecular gate on the timescale of 100 ms is
approximately 2 nN.
One strategy to achieving higher fidelity in triggered
degradation is to combine existing degradation methods in an
“AND gate” fashion (Figure 1), so that either stimulus alone
leads to less degradation than the two in combination. The
concept of gated function has been widely applied in regulable
molecular systems, including: photochemically controlled self-
healing and adhesion in polymers,21-22 photo-regulable
catalytic activity,23 paralysis in living organs,24 chemical or
mechanochemical reactions,25-27 and chemically controlled
photochromism.28
Degradable polymers, including biodegradable polymers1
and stimuli-degradable polymers,2-3 are highly desirable
targets for the purpose of alleviating plastic pollution that
results from poor recycling and improper disposal of typically
‘long-lived’ synthetic organic polymers.4-5 Typical degradable
polymers contain degradable functionalities (e.g. ester,6 azo,7-8
ketal,9, disulfide,10 diselenum11 and other cleavable
functionalities12) on the polymer backbone that cleave under
an external trigger, thus leading to the fragmentation of the
polymer main chain (Figure 1). By embedding appropriate
functionalities, polymers that degrade in response to heat,13-14
light,15 force,16 acid9 and redox species12 have been created.
These degradable polymers have proven to be useful in drug
17
delivery,3,
biomedical surgery,18 and designing transient
electronics.19-20 Despite exhibiting desirable degradability in
response to mild triggers (e.g., orthoester or ketal containing
polymers degrade in the presence of catalytic amount of acid),
the instability that originates from the same degradable
functionality increases the risk of diminished polymer
properties under storage or in regular service. Therefore,
polymers that are increasingly resistant to unintended
Figure
fragment into oligomers in response to, e.g.,
mechanical force or chemical trigger.
1
．
Typical
degradable
polymers
a
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
Mechanically gated degradable polymers retain
to yield P3. GPC analysis reveals that the retention time shifts
slightly from 13.38 min to 13.48 min, and multi-angle light
scattering shows a decrease in number average molecular
weight (Mn) to 120 kDa (Figure 2b), which is attributed to the
cleavage of the ketal (1H NMR, Figure 2c) without main chain
scission. Thus, the main chain of P1 is resistant to acidic
degradation.
most of all of their backbone in response to
either stimulus alone, whereas combined
exposure leads to a much greater extent of
fragmentation.
1
2
3
4
Scheme 1. Synthesis of mechanically gated
degradable polymers P1 and P2.
5
6
7
8
9
If, however, P1 (Mn = 154 kDa, Đ = 1.53, 34 mol% 4, 66 mol%
gDCC-COD) is first subjected to pulsed ultrasonication (1 mg
1
mL-1 in THF, 1s on/1s off, ice bath, N2) for 240 min, H NMR
indicates that the product P4 comprises pristine and activated
CB and gDCC mechanophores on the backbone (Figure 3a). The
1H NMR integrations show that 58% of CB and 85% of the gDCC
internal standard
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mechanical force is a common trigger for degrading polymer
molecular weight, and we were inspired by the recent use of a
cyclobutane as a mechanochemical gate for the tandem
activation
of
a
gem-dichlorocyclopropane
(gDCC)
mechanophore.29 The concept of mechanochemical gating was
further exploited by Robb and co-workers to regulate
photochromism30 and small molecule release,31 and Otsuka has
similarly used photochemistry to gate mechanochemical
27
reactivity.
In these latter examples, the “AND gating” is
Figure 2. a) Treatment of P1 polymer with TFA
cleaves the ketal functionality but preserves
the polymer backbone; b) Normalized GPC
traces of P1 and P3; c) 1H NMR spectrum of P1
and P3.
limited to a single event per chain. Here, we demonstrate that
a similar mechanochemical gating concept (Figure 1) is also a
viable strategy for degradable polymers. Broadly, we
envisioned polymers in which
a chemically triggered
degradable functionality is gated in a side-chain loop by a
mechanophore that is positioned along the polymer main
chain. Thus, application of the chemical trigger alone would not
lead to molecular weight degradation. On the other hand,
subjecting the polymer to high mechanical loads would open
the non-scissile gate, leading to many chemically degradable
functionalities
mechanochemical
along
the
main
allows
chain.
many
Because
degradable
gating
functionalities to be exposed per mechanical chain scission
event, the combination of mechanical and chemical triggers
would lead to greater degradation than either stimulus alone.
Our synthetic design is described in Scheme 1. Cyclic alkene
1 with acid-cleavable ketal group is subjected to photo [2+2]
cycloaddition with maleic anhydride to provide cyclobutane
(CB) containing molecule 2. Esterification of 2 yields diene 3,
and subsequent ring-closing metathesis gives polymerizable
macrocycle 4. Further entropy-driven ring-opening metathesis
polymerization (ED-ROMP)32 of 4 with gDCC-COD and epoxy-
COD co-monomers gives polymers P1 and P2, respectively.
These co-monomers were chosen for their respective
demonstrated
utility
as
internal
standards
of
mechanochemical activity (gDCC in P1)33-35 and as a means to
promote high forces of adhesion to cantilevers in single
molecule force spectroscopy (SMFS) studies (epoxide in P2).36
To verify that our design is resilient to acid alone, a THF
solution of P1 (Mn = 129 kDa, Đ = 1.49; 1.2 mg mL-1) was treated
with trifluoroacetic acid (TFA) at room temperature overnight
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
are activated under these conditions. Notably, activation of CB
produces E/Z alkenes in a ratio of ~ 2/1 that is substantially
higher than 1.14/1 observed previously with similar
1
2
a
cyclohexane-fused CB mechanophore.37 We hypothesize that
the increased E content from the ketal-fused CB here is due to
the more strained seven-member ring,38 relative to the
cyclohexyl ring reported previously, that is fused to the CB.
Following initial C1-C2 bond scission, the greater ring strain in
the current design might promote the rate of C3-C4 bond
scission, so that it occurs more quickly relative to C1-C4 bond
rotation in the diradical intermediate. Such dynamic
competition has previously been implicated in determining the
product stereochemistry, with rapid C3-C4 scission facilitating
the formation of EE product.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Figure 3. a) Mechanical conversion of P1 into P4; H NMR
spectrum of P4 after 30 min sonication. The relative integration of
i(E) and i(Z) protons gives E:Z = 2:1; b) GPC traces of P4 as a
function of sonication time; c) Ring-opening percentage of CB and
gDCC over sonication time.
Figure 4. a) Schematic illustration of
generated fragments and furanone after TFA
treatment of P4 and its 1H NMR spectrum in
CDCl3. The molar ratio of furanone to E alkene
species is 1/2. b) Overlay of normalized GPC
traces of P4 polymer before (maroon) and after
(green) TFA treatment. Blue trace is PS
standard (Mn = 1000 Da). c) GPC overlay of
TFA
treated
P4
polymer
with
various
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
sonication times. The arrows indicate the
subsequent release of reserved length give a characteristic
plateau transition at f ~ 2000 pN, which is about 200 pN lower
than observed for a similar CB molecular gate fused to an eight-
membered ring.29 We attribute this minor difference in force to
the greater ring strain in the fused CB in the present bicyclic
design (see ESI, Section V.). Despite our best efforts, we were
unable to obtain a force-extension curve in which the polymer
completed the ring-opening transition. An analysis of the
polymer survival times in the plateau region (Figure 5b) is
consistent with an effective (but approximate) rate constant
for chain detachment of 16 s-1 at the plateau force of ca. 2000
pN. The competition with chain detachment limits the average
fractional extension observed to only ~1.5%, far less than the
34% extension expected from modeling (see Supporting
Information).
shift of polymer peak and increase of oligomer
peak over sonication time. d) Comparison of
Mn for P4 before (red dots) and after (green
dots) TFA treatment and high molecular weight
fragment P3’ (blue dots).
1
2
3
4
5
6
7
8
With increasing sonication time, GPC traces show
a
continuous shift to longer retention time (Figure 3b), as
expected for typical polymer chain scission under pulsed
ultrasonication. Meanwhile, 1H NMR indicates the activation of
both CB and gDCC mechanophores due to sonication, with
more ring opening observed for gDCC than CB (Figure 3c). The
greater activity of gDCC relative to CB is consistent with prior
reports on similar substrates.29 The activation of CB results in
unveiled ketals along the polymer backbone. To assess the
mechanical stability of the ketals, we followed the procedure of
previous studies that have shown that mechanically weak
bonds on polymer backbones lead to less activation of gDCC
internal standard per chain scission event.39-41 After 15 min
sonication, where the Mn reaches to half of initial value (from
154 kDa to 78 kDa, Figure 4d), the activation of gDCC reaches
53%. This gives 54% gDCC activation per average scission
event, which is comparable to previous results on C-C bond
containing polymers34 and suggests that the ketal is
mechanically robust relative to conventional hydrocarbon
polymers. This experimental result is supported
computationally by CoGEF42 calculations that show that it is the
C-O bond adjacent to the ester group, rather than the ketal, that
breaks at high extension (Figure S19).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we have demonstrated that gated backbones
provide access to polymers that are efficiently degraded by
combinations of triggers used commonly in polymer
degradation (here, mechanical force and acid), but that are
resistant to degradation from either trigger alone. If similar
concepts (e.g., combinations of degradable functionalities with
other photo/chemical gates) could be applied to scale, it might
lead to new degradable polymer systems that are increasingly
(if not perfectly) robust and more reliably maintain their
properties during regular service. Beyond degradability, we
also envision that the cleavable, gated ketal functionality
provides a mechanism to chemically regulate the stress-
relieving behavior (turning extensible mechanophores into
scissile mechanophores). We are currently applying this
concept to the study of stress-relief and fracture behavior in
mechanophore-enriched polymer networks.
The mechanically activated P4 was then treated with TFA. As
seen in Figure 4a, TFA treatment of P4 generates CB and gDCC
containing polymer P3’, along with activated gDCC
fragments/oligomers that are consistent with acid catalyzed
hydrolysis of the ketals. The 1H NMR spectrum of the P4 + TFA
products shows activated CB and gDCC proton signals and,
remarkably, signals from furanone. The formation of furanone
is attributed to quantitative conversion of the mechanically
1
generated Z alkene, as supported by H NMR integration. The
GPC of the P4 + TFA products is bimodal, with a higher
molecular weight (MW) peak (P3’) that is shifted to longer
retention times (lower MW) than untreated P4, and a new peak
at even longer (~17-19 min) retention times that corresponds
to low MW fragments and oligomers of ~1 kDa (Figure 4b). As
sonication time increases, the GPC peak of P3’ consistently
shifts to longer retention time and the relative RI intensity of
the oligomer region increases (Figure 4c). After 4 h of
mechanical treatment followed by acid degradation, the gated
system reaches an ultimate Mn of 2.5 kDa, in comparison to 28
kDa for the mechanical treatment alone and effectively no
backbone degradation for acid treatment alone. Interestingly,
the order of the combined treatment matters; reaction with
TFA followed by 4 h of mechanical treatment leads to Mn = 22
kDa (Figure S2), because treatment with TFA converts the CB
into a scissile “weak bond” whose activation now breaks the
polymer main chain. That scission event prevents the
activation of multiple CB mechanophores in the daughter
1
fragments, and the associated H NMR spectra are consistent
with a single CB activation per chain scission event (Figure S5).
Figure 5. a) Representative force-extension
curve of P2 polymer (pulling velocity: 300
The gated cyclic ketal provides additional extension of the
polymer upon mechanical activation of the CB gate, and so the
design is well suited for quantitative studies of kinetics using
previously reported SMFS techniques.43-44 A representative
force-extension curve of P2 (48 mol% 4, 52 mol% epoxy-COD)
is shown in Figure 5a. The mechanical activation of CB and
nm/s).
b)
Probability
distribution
of
survival time at transition force (green
histogram)
and
corresponding
one-phase
fitting (blue dotted line, k = 16 s-1). Note
that very short survival times might be easily
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
missed by visual inspection, artificially
13.
Peterson, G. I.; Church, D. C.; Yakelis, N. A.; Boydston, A. J.
limiting the population of the lowest bin.
1,2-Oxazine Linker as a Thermal Trigger for Self-Immolative
Polymers. Polymer 2014, 55, 5980-5985.
1
2
3
4
5
6
7
8
14.
Yardley, R. E.; Kenaree, A. R.; Gillies, E. R. Triggering
ASSOCIATED CONTENT
Depolymerization: Progress and Opportunities for Self-Immolative
Supporting Information. Synthetic procedures, sonication
details, SMFS analysis and additional SMFS curves, CoGEF
modeling. The Supporting Information is available free of
charge on the ACS Publications website.
Polymers. Macromolecules 2019, 52, 6342-6360.
15.
Ayer, M. A.; Schrettl, S.; Balog, S.; Simon, Y. C.; Weder, C.
Light-Responsive Azo-Containing Organogels. Soft Matter 2017,
13, 4017-4023.
16.
Diesendruck, C. E.; Peterson, G. I.; Kulik, H. J.; Kaitz, J. A.;
Mar, B. D.; May, P. A.; White, S. R.; Martinez, T. J.; Boydston, A. J.;
Moore, J. S. Mechanically Triggered Heterolytic Unzipping of a Low-
Ceiling-Temperature Polymer. Nat. Chem. 2014, 6, 623-628.
AUTHOR INFORMATION
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Corresponding Author
17.
Li, Y.; Maciel, D.; Rodrigues, J.; Shi, X.; Tomas, H.
*stephen.craig@duke.edu
Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery.
Chem. Rev. 2015, 115, 8564-8608.
18.
Notes
Cai, Z.; Wan, Y.; Becker, M. L.; Long, Y. Z.; Dean, D.
Fumarate)-Based Materials: Synthesis,
The authors declare no competing financial interest.
Poly(Propylene
Functionalization, Properties, Device Fabrication and Biomedical
Applications. Biomaterials 2019, 208, 45-71.
ACKNOWLEDGMENT
This manuscript is based on work based upon work supported
by the National Science Foundation under Grant No. CHE-
1808518. Y. L. is grateful to the Duke University Department of
Chemistry for a Burroughs Wellcome Graduate Fellowship. We
thank Dr. Peter Silinski for mass spectrometry analysis.
19.
Hernandez, H. L.; Kang, S. K.; Lee, O. P.; Hwang, S. W.;
Kaitz, J. A.; Inci, B.; Park, C. W.; Chung, S.; Sottos, N. R.; Moore, J. S.;
Rogers, J. A.; White, S. R. Triggered Transience of Metastable
Poly(Phthalaldehyde) for Transient Electronics. Adv. Mater. 2014,
26, 7637-7642.
20.
Tan, M. J.; Owh, C.; Chee, P. L.; Kyaw, A. K. K.; Kai, D.; Loh,
X. J. Biodegradable Electronics: Cornerstone for Sustainable
Electronics and Transient Applications. Journal of Materials
Chemistry C 2016, 4, 5531-5558.
REFERENCES
1.
Leja, K.; Lewandowicz, G. Polymer Biodegradation and
Biodegradable Polymers - a Review. Pol J Environ Stud 2010, 19,
21.
Fuhrmann, A.; Gostl, R.; Wendt, R.; Kotteritzsch, J.; Hager,
255-266.
2.
M. D.; Schubert, U. S.; Brademann-Jock, K.; Thunemann, A. F.;
Nochel, U.; Behl, M.; Hecht, S. Conditional Repair by Locally
Switching the Thermal Healing Capability of Dynamic Covalent
Polymers with Light. Nat. Commun. 2016, 7, 13623.
Zhang, Q.; Ko, N. R.; Oh, J. K. Recent Advances in Stimuli-
Responsive Degradable Block Copolymer Micelles: Synthesis and
Controlled Drug Delivery Applications. Chem Commun (Camb)
2012, 48, 7542-7552.
22.
Asadirad, A. M.; Boutault, S.; Erno, Z.; Branda, N. R.
3.
Bawa, K. K.; Oh, J. K. Stimulus-Responsive Degradable
Controlling a Polymer Adhesive Using Light and a Molecular
Polylactide-Based Block Copolymer Nanoassemblies for
Controlled/Enhanced Drug Delivery. Mol. Pharm. 2017, 14, 2460-
2474.
Switch. J. Am. Chem. Soc. 2014, 136, 3024-3027.
23.
Kaur, B.; Raza, R.; Stashick, M. J.; Branda, N. R. Using Light
to Control the Inhibition of Karstedt's Catalyst. Organic Chemistry
Frontiers 2019, 6, 1253-1256.
4.
Siracusa, V.; Rocculi, P.; Romani, S.; Rosa, M. D.
Biodegradable Polymers for Food Packaging: A Review. Trends
Food Sci. Technol. 2008, 19, 634-643.
24.
Al-Atar, U.; Fernandes, R.; Johnsen, B.; Baillie, D.; Branda,
N. R. A Photocontrolled Molecular Switch Regulates Paralysis in a
5.
Schneiderman, D. K.; Hillmyer, M. A. 50th Anniversary
Living Organism. J. Am. Chem. Soc. 2009, 131, 15966-15967.
Perspective: There Is a Great Future in Sustainable Polymers.
25.
Erno, Z.; Asadirad, A. M.; Lemieux, V.; Branda, N. R. Using
Macromolecules 2017, 50, 3733-3749.
Light and a Molecular Switch to 'Lock' and 'Unlock' the Diels-Alder
6.
Kricheldorf, H. R. Syntheses of Biodegradable and
Reaction. Org Biomol Chem 2012, 10, 2787-2792.
Biocompatible Polymers by Means of Bismuth Catalysts. Chem. Rev.
2009, 109, 5579-5594.
26.
Warford, C. C.; Carling, C. J.; Branda, N. R. From Slow to
Fast--the User Controls the Rate of the Release of Molecules from
Masked Forms Using a Photoswitch and Different Types of Light.
Chem Commun (Camb) 2015, 51, 7039-7042.
7.
Kenley, R. A.; Manser, G. E. Degradable Polymers -
Incorporating a Difunctional Azo Compound into a Polymer
Network to Produce Thermally Degradable Polyurethanes.
Macromolecules 1985, 18, 127-131.
27.
Kida, J.; Imato, K.; Goseki, R.; Aoki, D.; Morimoto, M.;
Otsuka, H. The Photoregulation of a Mechanochemical Polymer
8.
Mutlu, H.; Geiselhart, C. M.; Barner-Kowollik, C. Untapped
Scission. Nat. Commun. 2018, 9, 3504.
28.
'Chemically-Gated' Photoresponsive Compound as
Detector for Organophosphorus Nerve Agents. Chem Commun
Potential for Debonding on Demand: The Wonderful World of Azo-
Nourmohammadian, F.; Wu, T.; Branda, N. R.
A
Compounds. Materials Horizons 2018, 5, 162-183.
a
Visible
9.
Paramonov, S. E.; Bachelder, E. M.; Beaudette, T. T.;
Standley, S. M.; Lee, C. C.; Dashe, J.; Frechet, J. M. Fully Acid-
Degradable Biocompatible Polyacetal Microparticles for Drug
Delivery. Bioconjug Chem 2008, 19, 911-919.
(Camb) 2011, 47, 10954-10956.
29.
Wang, J.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L.
Mechanical Gating of a Mechanochemical Reaction Cascade. Nat.
10.
Tachibana, Y.; Baba, T.; Kasuya, K.-i. Environmental
Commun. 2016, 7, 13433.
Biodegradation Control of Polymers by Cleavage of Disulfide
30.
Hu, X.; McFadden, M. E.; Barber, R. W.; Robb, M. J.
Bonds. Polym. Degrad. Stab. 2017, 137, 67-74.
Mechanochemical Regulation of a Photochemical Reaction. J. Am.
11.
Xia, J.; Li, T.; Lu, C.; Xu, H. Selenium-Containing Polymers:
Chem. Soc. 2018, 140, 14073-14077.
Perspectives toward Diverse Applications in Both Adaptive and
31.
Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically
Biomedical Materials. Macromolecules 2018, 51, 7435-7455.
Triggered Small Molecule Release from a Masked Furfuryl
12.
Song, C.-C.; Du, F.-S.; Li, Z.-C. Oxidation-Responsive
Carbonate. J. Am. Chem. Soc. 2019, 141, 15018-15023.
Polymers for Biomedical Applications. J. Mater. Chem. B 2014, 2,
32.
Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Template-
3413-3426.
Directed Ring-Closing Metathesis: Synthesis and Polymerization of
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Unsaturated Crown Ether Analogs. Angew Chem Int Ed Engl 1997,
36, 1101-1103.
43.
Gossweiler, G. R.; Kouznetsova, T. B.; Craig, S. L. Force-
Rate Characterization of Two Spiropyran-Based Molecular Force
Probes. J. Am. Chem. Soc. 2015, 137, 6148-6151.
1
2
3
4
33.
Lenhardt, J. M.; Black, A. L.; Craig, S. L. Gem-
Dichlorocyclopropanes as Abundant and Efficient Mechanophores
in Polybutadiene Copolymers under Mechanical Stress. J. Am.
Chem. Soc. 2009, 131, 10818-10819.
44.
Barbee, M. H.; Kouznetsova, T.; Barrett, S. L.; Gossweiler,
G. R.; Lin, Y.; Rastogi, S. K.; Brittain, W. J.; Craig, S. L. Substituent
Effects and Mechanism in a Mechanochemical Reaction. J. Am.
Chem. Soc. 2018, 140, 12746-12750.
5
34.
Lenhardt, J. M.; Ramirez, A. L. B.; Lee, B.; Kouznetsova, T.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
36.
Klukovich, H. M.; Kouznetsova, T. B.; Kean, Z. S.; Lenhardt,
J. M.; Craig, S. L. A Backbone Lever-Arm Effect Enhances Polymer
Mechanochemistry. Nat. Chem. 2013, 5, 110-114.
37.
Kean, Z. S.; Niu, Z.; Hewage, G. B.; Rheingold, A. L.; Craig,
S. L. Stress-Responsive Polymers Containing Cyclobutane Core
Mechanophores: Reactivity and Mechanistic Insights. J. Am. Chem.
Soc. 2013, 135, 13598-13604.
38.
Neary, W. J.; Kennemur, J. G. Polypentenamer
Renaissance: Challenges and Opportunities. ACS Macro. Lett. 2018,
8, 46-56.
39.
Lee, B.; Niu, Z.; Wang, J.; Slebodnick, C.; Craig, S. L.
Relative Mechanical Strengths of Weak Bonds in Sonochemical
Polymer Mechanochemistry. J. Am. Chem. Soc. 2015, 137, 10826-
10832.
40.
Sha, Y.; Zhang, Y. D.; Xu, E. H.; Wang, Z.; Zhu, T. Y.; Craig,
S. L.; Tang, C. B. Quantitative and Mechanistic Mechanochemistry
in Ferrocene Dissociation. ACS Macro. Lett. 2018, 7, 1174-1179.
41.
Wang, Z.; Craig, S. L. Stereochemical Effects on the
Mechanochemical Scission of Furan-Maleimide Diels-Alder
Adducts. Chem Commun (Camb) 2019, 55, 12263-12266.
42.
Beyer, M. K. The Mechanical Strength of a Covalent Bond
Calculated by Density Functional Theory. J. Chem. Phys. 2000, 112,
7307-7312.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
TOC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment