Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate

Article abstract of DOI:10.1021/jacs.9b08663

Stimuli-responsive polymers that release small molecules under mechanical stress are appealing targets for applications ranging from drug delivery to sensing. Here, we describe a modular mechanophore design platform for molecular release via a mechanically triggered cascade reaction. Mechanochemical activation of a furan-maleimide Diels-Alder adduct reveals a latent furfuryl carbonate that subsequently decomposes under mild conditions to release a covalently bound cargo molecule. The computationally guided design of a reactive secondary furfuryl carbonate enables the decomposition and release to proceed quickly at room temperature after unmasking via mechanical force. This general strategy is demonstrated using ultrasound-induced mechanical activation to release a fluorogenic coumarin payload from a polymer incorporating a chain-centered mechanophore.

Full text of DOI:10.1021/jacs.9b08663

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Communication
Mechanically Triggered Small Molecule
Release from a Masked Furfuryl Carbonate
Xiaoran Hu, Tian Zeng, Corey C Husic, and Maxwell J. Robb
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08663 • Publication Date (Web): 13 Sep 2019
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Mechanically Triggered Small Molecule Release from a Masked
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Xiaoran Hu, Tian Zeng, Corey C. Husic, Maxwell J. Robb*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United
States
Supporting Information Placeholder
Scheme 1. Mechanically Triggered Reaction Cascade Re-
sulting in Small Molecule Release.
ABSTRACT: Stimuli-responsive polymers that release small
molecules under mechanical stress are appealing targets for appli-
cations ranging from drug delivery to sensing. Here, we describe a
modular mechanophore design platform for molecular release via a
mechanically triggered cascade reaction. Mechanochemical activa-
tion of a furan–maleimide Diels–Alder adduct reveals a latent fur-
furyl carbonate that subsequently decomposes under mild condi-
tions to release a covalently bound cargo molecule. The computa-
tionally guided design of a reactive secondary furfuryl carbonate
enables the decomposition and release to proceed quickly at room
temperature after unmasking via mechanical force. This general
strategy is demonstrated using ultrasound-induced mechanical ac-
tivation to release a fluorogenic coumarin payload from a polymer
incorporating a chain-centered mechanophore.
Mechanical to chemical transduction is a powerful strategy for
achieving materials with stimuli-responsive properties. The emerg-
ing field of polymer mechanochemistry aims to harness mechanical
forces in polymers to promote productive chemical transformations
in stress-responsive molecules known as mechanophores.1 Me-
chanical force is delivered to mechanophores through covalently
attached polymer chains using a variety of techniques including so-
lution-phase ultrasonication,2 tension/compression in solid materi-
als,3 atomic force microscopy,4 laser-induced stress waves,5 and
high intensity focused ultrasound.6 Mechanically coupled chemical
activation has been demonstrated for covalent bond transfor-
mations to engender a wide range of functional responses including
changes in color or fluorescence,3a,7 chemiluminescence,8 switch-
ing of electrical conductivity,9 activation of catalysts,10 and gener-
ation of reactive functional groups.11
Cascade reactions initiated by external stimuli offer a unique ap-
proach for controlling molecular release. For example, retro-Diels–
Alder reactions have served as thermal triggers for the depolymer-
ization of self-immolative polymers. Boydston and coworkers re-
ported a 1,2-oxazine linker,17 while Gillies and coworkers reported
a furan–maleimide adduct that initiated a depolymerization reac-
tion at elevated temperatures by invoking the thermal decomposi-
tion of a furfuryl carbonate intermediate.18 The photogating con-
cept has also been used to control cascade reactions. Branda and
coworkers designed a diarylethene photoswitch that allowed elec-
tronic conjugation between a remote electron donating group and a
labile carbonate group to be modulated with light, resulting in car-
bonate fragmentation upon photochemical electrocyclization.19 We
recently extended the concept of mechanochemical gating20 to reg-
ulate a photochemical transformation in which a mechanically fa-
cilitated retro-Diels–Alder reaction unmasked a diarylethene pho-
toswitch.21
Polymers that release small molecules under stress are particu-
larly appealing targets for a number of applications including catal-
ysis, sensing, self-healing, and drug delivery.12 However, mech-
anophores capable of releasing functional small molecules are still
limited. An oxanorbornadiene mechanophore was demonstrated to
release a benzyl furfuryl ether molecule from polymeric materials
under compression,13 while a gem-dichlorocyclopropanated indene
mechanophore was shown to generate HCl.14 In addition, mecha-
nochemical chain scission of poly(o-phthalaldehyde) results in an
unzipping reaction above its ceiling temperature to regenerate mon-
omer.15 Metal ion release from the mechanical dissociation of fer-
rocene was also recently demonstrated.16 Nevertheless, a more
modular and general mechanophore design platform capable of the
triggered release of functional organic molecules would enable new
opportunities for polymer mechanochemistry.
Here we report a mechanophore platform based on a furan–ma-
leimide Diels–Alder adduct that leverages the instability of a judi-
ciously designed furfuryl carbonate for small molecule release via
a mechanically gated reaction cascade. As illustrated in Scheme 1,
mechanochemical activation of the kinetically stable adduct results
in a retro-Diels–Alder reaction, revealing a metastable furfuryl car-
bonate that quickly decomposes in polar protic media to release
carbon dioxide and a covalently bound alcohol molecule. The sec-
ondary furfuryl carbonate structure is a key design feature that sig-
nificantly increases the rate of decomposition and small molecule
release, enabling the transformation to proceed spontaneously un-
der mild conditions, but only after the prerequisite mechanochem-
ical cycloelimination reaction. We describe the computationally
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supported design and reactivity of the furfuryl carbonate, and as a
from stabilization of the putative furfuryl cation intermediate sug-
gested by the mechanism in Scheme 1. We therefore identified the
general structure of furfuryl carbonate FC3 as a promising target
for mechanically triggered small molecule release from a furan–
maleimide Diels–Alder adduct using the 5-position of the furan for
polymer attachment. Additional DFT calculations using the simple
constrained geometries simulate external force (CoGEF) tech-
nique22 indicate that mechanical elongation of an appropriately
substituted furan–maleimide adduct generates the expected furfuryl
carbonate (Figure 1b, see the SI for details). The retro-Diels–Alder
reaction occurs with an estimated rupture force of 4.0 nN, which is
comparable to rupture forces calculated with the CoGEF method
for other active furan–maleimide mechanophores.23 While these
forces are typically overestimated compared to experiments,24 they
provide a useful framework for predicting relative mechanochemi-
cal activity.
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proof-of-concept, demonstrate the mechanically triggered release
of a model fluorogenic coumarin probe via ultrasound-induced
mechanochemical activation of a polymer chain-centered mech-
anophore.
We initially set out to investigate the effect of substitution on the
decomposition reaction of furfuryl carbonates. Activation energies
for the reaction of a series of three model furfuryl carbonates (FC1–
FC3) were calculated at the M06-2X/6-311+G** level of density
functional theory (DFT) to gauge the effect of substitution on the
rate of decomposition (Figure 1a, see the SI for details). The acti-
vation energy for the fragmentation of FC1, which is analogous to
Gillies’ design,18 was calculated to be 29.4 kcal/mol, suggesting
very slow reaction at room temperature. Addition of a methyl group
at the 5-position of the furan (FC2) reduces the reaction barrier to
25.8 kcal/mol, although this is still insufficient for rapid release. In
fact, model compounds with analogous structures to FC1 and FC2
were synthesized and the half-lives for decomposition at room tem-
perature were estimated to be on the order of several weeks (Fig-
ures S1 and S2). DFT calculations indicate that substitution with an
α-methyl group, however, results in a pronounced decrease in acti-
vation energy for FC3 (ΔG‡ = 22.0 kcal/mol) as might be expected
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We synthesized fluorogenic furfuryl carbonate model compound
1 with an analogous structure to computational model FC3 and in-
vestigated its reactivity experimentally (Figure 2). The coumarin
payload exhibits enhanced photoluminescence (PL) upon release,
allowing reaction progress to be tracked using fluorescence spec-
troscopy in addition to NMR spectroscopy. Furfuryl carbonate 1 is
relatively stable in chloroform and acetonitrile (Figures S3 and S4);
however, the addition of methanol to an acetonitrile solution of 1
leads to fast decomposition at room temperature and clean for-
mation of hydroxycoumarin 2 and furfuryl ether 3 (Figure 2a). The
generation of furfuryl ether 3 under these conditions is consistent
with a mechanism involving initial fragmentation of the carbonate
group to form a furfuryl cation, which is subsequently attacked by
methanol followed by proton transfer. Figure 2b shows the decom-
position of furfuryl carbonate 1 in a 3:1 (v/v) mixture of acetoni-
trile-d3 and methanol monitored by 1H NMR spectroscopy. Signals
corresponding to 1 fully disappear in a few hours with the concom-
itant formation of two new sets of resonances that match the spectra
of the isolated hydroxycoumarin and furfuryl methyl ether prod-
ucts. The generation of hydroxycoumarin 2 from a room tempera-
ture solution of furfuryl carbonate 1 in MeCN:MeOH (3:1) was
also monitored over time using fluorescence spectroscopy (Figure
2c). Excitation at 330 nm revealed an emission peak around 380
nm that increased in intensity over time and matches the emission
spectrum of hydroxycoumarin 2 (Figure S5). Approximately 98%
of the theoretical yield of hydroxycoumarin 2 is released over about
6 h (Figure 2d). The conversion of furfuryl carbonate 1 and the gen-
eration of hydroxycoumarin 2 follow exponential decay under
these conditions with the reaction half-life estimated from NMR
measurements to be t1/2 = 79 min. We note that decomposition of
furfuryl carbonate 1 occurs even faster in a water/acetonitrile mix-
ture (t1/2 < 10 min), indicating the potential of this system for mo-
lecular release in aqueous environments (Figure S6).
Having identified a suitable furfuryl carbonate structure for
small molecule release we next set out to synthesize a furan–malei-
mide Diels–Alder adduct and incorporate it into a polymer to study
its mechanochemical behavior. Polymers containing a chain-cen-
tered mechanophore are mechanically activated in solution using
ultrasonication, which produces elongational forces that are max-
imized near the chain midpoint.2 Furan–maleimide adduct (±)-4
equipped with two α-bromoester initiating sites and a modular al-
cohol functional group for cargo attachment was prepared on gram
scale in four steps from commercially available reagents (Scheme
2, see the SI for details). Starting from a racemic mixture of α-
methylfurfuryl alcohol resulted in four diastereomeric Diels–Alder
adducts. Although both endo and exo isomers exhibited mechano-
chemical reactivity in an initial screening as expected from previ-
ous studies of furan–maleimide mechanophores,23 here we focus on
one particular endo racemate shown in Scheme 2. The absolute
configuration of the Diels–Alder adduct was confirmed by single
crystal X-ray diffraction. Precursor (±)-4 was converted to
Figure 1. Density functional theory (DFT) calculations of (a)
activation energies for carbonate fragmentation from a series of
furfuryl carbonates at the M06-2X/6-311+G** level of theory, and
(b) mechanical elongation of a truncated furan–maleimide Diels–
Alder adduct using the constrained geometries simulate external
force (CoGEF) method at the B3LYP/6-31G* level of theory.
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Figure 2. Characterization of the room temperature decomposition reaction of furfuryl carbonate 1. (a) Decomposition of 1 in 3:1
MeCN:MeOH generates fluorescent hydroxycoumarin 2 and furfuryl methyl ether 3 via a putative furfuryl cation intermediate. (b) 1H NMR
spectra (3:1 MeCN-d3:MeOH) demonstrating the clean conversion of 1 to products ([1]0 = 12 mM). (c) Photoluminescence spectra ([1]0 =
6.1 μM in 3:1 MeCN:MeOH, λex = 330 nm) monitoring the generation of hydroxycoumarin 2 over time. (d) Quantification of data from
panels b and c illustrating the time-dependent conversion of furfuryl carbonate 1 and the generation of hydroxycoumarin 2 as measured by
NMR and fluorescence spectroscopy, respectively.
mechanophore bis-initiator (±)-6 via installation of the fluorogenic
coumarin payload by reaction with the corresponding chlorofor-
mate, and then subsequently employed in the controlled radical
polymerization of methyl acrylate using Cu wire/Me6TREN in
DMSO to afford the chain-centered polymer PMA-1 (Mn = 100
kg/mol; Ð = 1.06). Chain-end functional control polymer PMA-
Scheme 2. Synthesis of Poly(Methyl Acrylate) (PMA) Containing a Chain-Centered Mechanophore Equipped with a Fluoro-
genic Coumarin Probe and a Chain-End Functional Control Polymer.
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control (Mn = 86 kg/mol; Ð = 1.14) was synthesized similarly start-
ing from (±)-5 containing a single α-bromoester initiating group
(see the SI for details).
the time-dependent PL data to a first-order rate expression, the ex-
tent of release is projected to plateau at a maximum value of ap-
proximately 87% (Figure S8). The reduced efficiency compared to
the small molecule decomposition study likely stems from the in-
herent competition between mechanophore activation and nonspe-
cific chain scission, resulting in part from a distribution in the po-
sition of mechanophores in the polymer backbones.26 The fluores-
cence data presented in Figure 3 was acquired after incubating each
aliquot at room temperature for approximately 20 h to ensure com-
plete decomposition of the mechanically generated furfuryl car-
bonate. However, PL measurements taken immediately after sam-
ple removal from the sonicated solution exhibit appreciable fluo-
rescence, indicating that a significant degree of release occurs
quickly even at lower temperatures (Figure S9). Importantly, chain-
end functional control polymer PMA-control subjected to the
same ultrasonication conditions exhibits negligible changes in flu-
orescence compared to PMA-1 (Figure 3b). These results indicate
that ultrasound-induced release of hydroxycoumarin 2 from PMA-
1 is indeed a mechanically triggered cascade reaction process.
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Mechanically triggered molecular release from PMA-1 was
evaluated using pulsed ultrasonication (1s on/2s off, 0 °C, 20 kHz,
8.2 W/cm2) in the same polar protic solvent mixture employed in
the small molecule model studies (3:1 MeCN:MeOH). Aliquots
were periodically removed from the sonicated polymer solution
and measured with gel permeation chromatography (GPC) to de-
termine changes in molecular weight and fluorescence spectros-
copy to monitor the generation of hydroxycoumarin 2 (Figure 3).
The Mn decreased steadily over 150 min of ultrasonication, with the
GPC chromatograms exhibiting characteristic features of midchain
scission (Figure 3a and Figure S7). Photoluminescence measure-
ments also showed a predictable increase in intensity indicating the
successful release of hydroxycoumarin 2, reaching approximately
64% of the theoretical yield after 150 min (Figure 3a). By fitting
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In summary, we have demonstrated a mechanophore platform
for release of small molecules via a mechanically triggered cascade
reaction. The strategy relies on the mechanochemically activated
retro-Diels–Alder reaction of a furan–maleimide adduct, which re-
veals a latent furfuryl carbonate that subsequently decomposes in
polar protic solvents to release a covalently bound cargo molecule.
The computationally guided design of a reactive α-methylfurfuryl
carbonate enabled small molecule release via a well-defined de-
composition reaction that proceeds efficiently under mild condi-
tions. Ultrasound-induced mechanical activation of a chain-cen-
tered furan–maleimide mechanophore loaded with a fluorogenic
coumarin probe illustrates the power of this approach for a wide
range of mechanically triggered cascade reactions. We anticipate
that this general strategy will be useful for the mechanically trig-
gered release of functional molecules in drug delivery, stress sens-
ing, depolymerization, and other applications.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental details, synthetic procedures, DFT calculations, GPC
chromatograms, fluorescence data, NMR spectra, and crystallo-
graphic data (PDF).
AUTHOR INFORMATION
Corresponding Author
mrobb@caltech.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Figure 3. Characterization of mechanically triggered small mole-
cule release. (a) Time-dependent evolution of number-average mo-
lecular weight (Mn) monitored by GPC-MALLS and release of hy-
droxycoumarin 2 monitored using fluorescence spectroscopy for
PMA-1 subjected to ultrasound-induced mechanochemical activa-
tion (2 mg/mL polymer in 3:1 MeCN:MeOH). λex = 330 nm. (b)
Fluorescence spectra of PMA-1 and PMA-control before and after
ultrasonication for 150 min. The inset shows photographs of soni-
cated solutions excited with 365 nm UV light after 6x dilution and
addition of 5% water.25 Error bars represent standard deviation
from three replicate experiments.
Financial support from Caltech and the Dow Next Generation Ed-
ucator Fund is gratefully acknowledged. We thank the Center for
Catalysis and Chemical Synthesis of the Beckman Institute at Cal-
tech for access to equipment and Larry Henling for assistance with
X-ray crystallography.
REFERENCES
(1) (a) Beyer, M. K.; Clausen-Schaumann, H. Mechanochemistry:ꢀ The
Mechanical Activation of Covalent Bonds. Chem. Rev. 2005, 105, 2921–
2948. (b) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N.
4
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in
Y.; Weng, W.; Boulatov, R. Mechanochromism and Mechanical-Force-
Triggered Cross-Linking from a Single Reactive Moiety Incorporated into
Polymer Chains. Angew. Chem. Int. Ed. 2016, 55, 3040–3044.
(12) (a) Swager, T. M. Sensor Technologies Empowered by Materials and
Molecular Innovations. Angew. Chem. Int. Ed. 2018, 57, 4248–4257. (b)
Roth, M. E.; Green, O.; Gnaim, S.; Shabat, D. Dendritic, Oligomeric, and
Polymeric Self-Immolative Molecular Amplification. Chem. Rev. 2016,
116, 1309–1352. (c) White, S. R.; Sottos, N. R.; Geubelle, P. H.; Moore, J.
S.; Kessler, M. R.; Sriram, S. R.; Brown, E. N.; Viswanathan, S. Autonomic
healing of polymer composites. Nature 2001, 409, 794–797.
(13) Larsen, M. B.; Boydston, A. J. “Flex-Activated” Mechanophores: Us-
ing Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am.
Chem. Soc. 2013, 135, 8189–8192. (31) Larsen, M. B.; Boydston, A. J. Suc-
cessive Mechanochemical Activation and Small Molecule Release in an
Elastomeric Material. J. Am. Chem. Soc. 2014, 136, 1276–1279.
(14) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.;
Sottos, N. R.; White, S. R.; Braun, P. V.; Moore, J. S. Proton-Coupled
Mechanochemical Transduction: A Mechanogenerated Acid. J. Am. Chem.
Soc. 2012, 134, 12446–12449.
(15) (a) Diesendruck, C. E.; Peterson, G. I.; Kulik, H. J.; Kaitz, J. A.; Mar,
B. D.; May, P. A.; White, S. R.; Martínez, T. J.; Boydston, A. J.; Moore, J.
S. Mechanically triggered heterolytic unzipping of a low-ceiling-tempera-
ture polymer. Nat. Chem. 2014, 6, 623. (b) Peterson, G. I.; Boydston, A. J.
Kinetic Analysis of Mechanochemical Chain Scission of Linear
Poly(phthalaldehyde). Macromol. Rapid Commun. 2014, 35, 1611–1614.
(16) (a) Di Giannantonio, M.; Ayer, M. A.; Verde-Sesto, E.; Lattuada, M.;
Weder, C.; Fromm, K. M. Triggered Metal Ion Release and Oxidation: Fer-
rocene as a Mechanophore in Polymers. Angew. Chem. Int. Ed. 2018, 57,
11445–11450. (b) Sha, Y.; Zhang, Y.; Xu, E.; Wang, Z.; Zhu, T.; Craig, S.
L.; Tang, C. Quantitative and Mechanistic Mechanochemistry in Ferrocene
Dissociation. ACS Macro Lett. 2018, 7, 1174–1179.
(17) Peterson, G. I.; Church, D. C.; Yakelis, N. A.; Boydston, A. J. 1,2-
oxazine linker as a thermal trigger for self-immolative polymers. Polymer
2014, 55, 5980–5985.
(18) Fan, B.; Trant, J. F.; Hemery, G.; Sandre, O.; Gillies, E. R. Thermo-
responsive self-immolative nanoassemblies: direct and indirect triggering.
Chem. Commun. 2017, 53, 12068–12071.
(19) 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. 2015, 51, 7039–
7042.
(20) Wang, J.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L. Mechanical
gating of a mechanochemical reaction cascade. Nat. Commun. 2016, 7,
13433.
(21) Hu, X.; McFadden, M. E.; Barber, R. W.; Robb, M. J. Mechanochem-
ical Regulation of a Photochemical Reaction. J. Am. Chem. Soc. 2018, 140,
14073–14077.
(22) (a) Beyer, M. K. The mechanical strength of a covalent bond calcu-
lated by density functional theory. J. Chem. Phys. 2000, 112, 7307–7312.
(b) Kryger, M. J.; Munaretto, A. M.; Moore, J. S. Structure–Mechanochem-
ical Activity Relationships for Cyclobutane Mechanophores. J. Am. Chem.
Soc. 2011, 133, 18992–18998.
(23) Stevenson, R.; De Bo, G. Controlling Reactivity by Geometry in
Retro-Diels–Alder Reactions under Tension. J. Am. Chem. Soc. 2017, 139,
16768–16771.
(24) Stauch, T.; Dreuw, A. Advances in Quantum Mechanochemistry:
Electronic Structure Methods and Force Analysis. Chem. Rev. 2016, 116,
14137–14180.
(25) Cohen, B.; Huppert, D. Excited State Proton-Transfer Reactions of
Coumarin 4 in Protic Solvents. J. Phys. Chem. A 2001, 105, 7157–7164.
(26) Kean, Z. S.; Gossweiler, G. R.; Kouznetsova, T. B.; Hewage, G. B.;
Craig, S. L. A Coumarin Dimer Probe of Mechanochemical Scission Effi-
ciency in the Sonochemical Activation of Chain-Centered Mechanophore
Polymers. Chem. Commun. 2015, 51, 9157–9160.
Polymeric Materials. Chem. Rev. 2009, 109, 5755–5798. (c) Li, J.; Naga-
mani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive to
Productive. Acc. Chem. Res. 2015, 48, 2181–2190.
(2) Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. Ul-
trasound-Induced Site-Specific Cleavage of Azo-Functionalized Poly(eth-
ylene glycol). Macromolecules 2005, 38, 8975–8978.
(3) (a) Davis, D. A.; Hamilton, A.; Yang, J.; Cremar, L. D.; Van Gough,
D.; Potisek, S. L.; Ong, M. T.; Braun, P. V.; Martínez, T. J.; White, S. R.;
Moore, J. S.; Sottos, N. R. Force-induced activation of covalent bonds in
mechanoresponsive polymeric materials. Nature 2009, 459, 68–72. (b)
Gossweiler, G. R.; Hewage, G. B.; Soriano, G.; Wang, Q.; Welshofer, G.
W.; Zhao, X.; Craig, S. L. Mechanochemical Activation of Covalent Bonds
in Polymers with Full and Repeatable Macroscopic Shape Recovery. ACS
Macro Lett. 2014, 3, 216–219.
(4) (a) Wu, D.; Lenhardt, J. M.; Black, A. L.; Akhremitchev, B. B.; Craig,
S. L. Molecular Stress Relief through a Force-Induced Irreversible Exten-
sion in Polymer Contour Length. J. Am. Chem. Soc. 2010, 132, 15936–
15938. (b) Sulkanen, A. R.; Sung, J.; Robb, M. J.; Moore, J. S.; Sottos, N.
R.; Liu, G. Spatially Selective and Density-Controlled Activation of Inter-
facial Mechanophores. J. Am. Chem. Soc. 2019, 141, 4080–4085.
(5) (a) Grady, M. E.; Beiermann, B. A.; Moore, J. S.; Sottos, N. R. Shock-
wave Loading of Mechanochemically Active Polymer Coatings. ACS Appl.
Mater. Interfaces 2014, 6, 5350–5355. (b) Sung, J.; Robb, M. J.; White, S.
R.; Moore, J. S.; Sottos, N. R. Interfacial Mechanophore Activation Using
Laser-Induced Stress Waves. J. Am. Chem. Soc. 2018, 140, 5000–5003.
(6) Kim, G.; Lau, V. M.; Halmes, A. J.; Oelze, M. L.; Moore, J. S.; Li, K.
C. High-intensity focused ultrasound-induced mechanochemical transduc-
tion in synthetic elastomers. Proc. Natl. Acad. Sci. 2019, 116, 10214.
(7) (a) Imato, K.; Irie, A.; Kosuge, T.; Ohishi, T.; Nishihara, M.; Takahara,
A.; Otsuka, H. Mechanophores with a Reversible Radical System and
Freezing-Induced Mechanochemistry in Polymer Solutions and Gels. An-
gew. Chem. Int. Ed. 2015, 54, 6168–6172. (b) Wang, Z.; Ma, Z.; Wang, Y.;
Xu, Z.; Luo, Y.; Wei, Y.; Jia, X. A Novel Mechanochromic and Photo-
chromic Polymer Film: When Rhodamine Joins Polyurethane. Adv. Mater.
2015, 27, 6469–6474. (c) Göstl, R.; Sijbesma, R. P. π-extended anthracenes
as sensitive probes for mechanical stress. Chem Sci 2016, 7, 370–375. (d)
Robb, M. J.; Kim, T. A.; Halmes, A. J.; White, S. R.; Sottos, N. R.; Moore,
J. S. Regioisomer-Specific Mechanochromism of Naphthopyran in Poly-
meric Materials. J. Am. Chem. Soc. 2016, 138, 12328–12331. (e) McFad-
den, M. E.; Robb, M. J. Force-Dependent Multicolor Mechanochromism
from a Single Mechanophore. J. Am. Chem. Soc. 2019, 141, 11388–11392.
(8) Chen, Y.; Spiering, A. J. H.; Karthikeyan, S.; Peters, G. W. M.; Meijer,
E. W.; Sijbesma, R. P. Mechanically induced chemiluminescence from pol-
ymers incorporating a 1,2-dioxetane unit in the main chain. Nat. Chem.
2012, 4, 559–562.
(9) (a) Chen, Z.; Mercer, J. A. M.; Zhu, X.; Romaniuk, J. A. H.; Pfattner,
R.; Cegelski, L.; Martinez, T. J.; Burns, N. Z.; Xia, Y. Mechanochemical
unzipping of insulating polyladderene to semiconducting polyacetylene.
Science 2017, 357, 475. (b) Yang, J.; Horst, M.; Romaniuk, J. A. H.; Jin,
Z.; Cegelski, L.; Xia, Y. Benzoladderene Mechanophores: Synthesis,
Polymerization, and Mechanochemical Transformation. J. Am. Chem. Soc.
2019, 141, 6479–6483.
(10) (a) Piermattei, A.; Karthikeyan, S.; Sijbesma, R. P. Activating cata-
lysts with mechanical force. Nat. Chem. 2009, 1, 133. (b) Michael, P.;
Binder, W. H. A Mechanochemically Triggered “Click” Catalyst. Angew.
Chem. Int. Ed. 2015, 13918–13922.
(11) (a) Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.;
Baudry, J.; Wilson, S. R. Biasing reaction pathways with mechanical force.
Nature 2007, 446, 423–427. (b) Ramirez, A. L. B.; Kean, Z. S.; Orlicki, J.
A.; Champhekar, M.; Elsakr, S. M.; Krause, W. E.; Craig, S. L. Mechano-
chemical strengthening of a synthetic polymer in response to typically de-
structive shear forces. Nat. Chem. 2013, 5, 757–761. (c) Robb, M. J.;
Moore, J. S. A Retro-Staudinger Cycloaddition: Mechanochemical Cy-
cloelimination of a β-Lactam Mechanophore. J. Am. Chem. Soc. 2015, 137,
10946–10949. (d) Wang, J.; Piskun, I.; Craig, S. L. Mechanochemical
Strengthening of a Multi-mechanophore Benzocyclobutene Polymer. ACS
Macro Lett. 2015, 4, 834–837. (e) Zhang, H.; Gao, F.; Cao, X.; Li, Y.; Xu,
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