Mechanically Triggered Release of Functionally Diverse Molecular Payloads from Masked 2-Furylcarbinol DerivativesClick to copy article linkArticle link copied!
- Xiaoran HuXiaoran HuDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United StatesMore by Xiaoran Hu
- Tian ZengTian ZengDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United StatesMore by Tian Zeng
- Corey C. HusicCorey C. HusicDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United StatesMore by Corey C. Husic
- Maxwell J. Robb*Maxwell J. Robb*Email for M.J.R.: [email protected]Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United StatesMore by Maxwell J. Robb
Abstract
Polymers that release functional small molecules in response to mechanical force are appealing targets for drug delivery, sensing, catalysis, and many other applications. Mechanically sensitive molecules called mechanophores are uniquely suited to enable molecular release with excellent selectivity and control, but mechanophore designs capable of releasing cargo with diverse chemical functionality are limited. Here, we describe a general and highly modular mechanophore platform based on masked 2-furylcarbinol derivatives that spontaneously decompose under mild conditions upon liberation via a mechanically triggered reaction, resulting in the release of a covalently installed molecular payload. We identify key structure–property relationships for the reactivity of 2-furylcarbinol derivatives that enable the mechanically triggered release of functionally diverse molecular cargo with release kinetics being tunable over several orders of magnitude. In particular, the incorporation of an electron-donating phenoxy group on the furan ring in combination with an α-methyl substituent dramatically lowers the activation barrier for fragmentation, providing a highly active substrate for molecular release. Moreover, we find that phenoxy substitution enhances the thermal stability of the mechanophore without adversely affecting its mechanochemical reactivity. The generality and efficacy of this molecular design platform are demonstrated using ultrasound-induced mechanical force to trigger the efficient release of a broad scope of cargo molecules, including those bearing alcohol, phenol, alkylamine, arylamine, carboxylic acid, and sulfonic acid functional groups.
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Synopsis
Polymers that release small molecules under mechanical force are desirable targets for a wide range of applications. We report a highly effective platform for mechanically triggered molecular release.
Introduction
Scheme 1
Results and Discussion
Figure 1
Figure 1. Substituent effects on the reactivity of 2-furylcarbinol derivatives. (a) Structures of model furfuryl carbonates (X = O) and furfuryl carbamates (X = NH) with varying substitution patterns, and (b) corresponding activation energies for fragmentation of the α-C–O bond calculated at the M06-2X/6-311+G** level of density functional theory.
Figure 2
Figure 2. Characterization of the decomposition reactions of model furfuryl carbamates 1 and 2. (a) Decomposition of 1 in MeCN/MeOH (3:1) at room temperature generates fluorescent aminocoumarin 3 and furfuryl methyl ether 4 via a putative furfuryl cation intermediate; (b) partial 1H NMR spectra (400 MHz, CDCl3) demonstrating the clean conversion of 1 to products ([1]0 = 19 μM); (c) time course experiments following the conversion of furfuryl carbamates 1 and 2 by NMR spectroscopy (in 3:1 MeCN-d3/MeOH; [1]0 = 14 mM; [2]0 = 14 mM) and the generation of aminocoumarin 3 by photoluminescence spectroscopy (3:1 MeCN/MeOH; λex = 365 nm; λem = 424 nm; [1]0, [2]0 = 7.6 μM).
Scheme 2
Scheme 3
aĐ = 1.03–1.06 for all polymers.
Figure 3
Figure 3. Mechanically triggered release of (a) hydroxycoumarin and (b) aminocoumarin from polymers as a function of mechanophore substitution. Polymer solutions (2 mg/mL in 3:1 MeCN/MeOH) were sonicated for 60 min (“on” time), warmed to room temperature, and the release of coumarin cargo from the mechanically liberated 2-furylcarbinol derivatives was monitored by photoluminescence spectroscopy. PL parameters: λex = 330 nm, λem = 378 nm (hydroxycoumarin); λex = 365 nm, λem = 424 nm (aminocoumarin). The initial PL intensity was subtracted from each measurement and the data were normalized to the plateau value. For PMA-3(NH), the data were normalized assuming 36% mechanophore activation; the black dashed line represents a first-order reaction with a half-life of 240 days.
Scheme 4
aValues of percent release and half-lives are averages from two replicate experiments. Percent release is reported relative to the initial mechanophore concentration and does not account for incomplete mechanophore conversion after 60 min of ultrasonication. The values of percent release were determined by HPLC.
bHalf-life for cargo release was measured by photoluminescence spectroscopy.
cHalf-life for cargo release was measured by HPLC.
Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.1c00460.
Experimental details, synthetic procedures, DFT calculations, fluorescence and HPLC data, and NMR spectra (PDF)
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Acknowledgments
This research was supported by Caltech and the Arnold and Mabel Beckman Foundation through a Beckman Young Investigator Award. We thank the Center for Catalysis and Chemical Synthesis of the Beckman Institute at Caltech and the CCE Multiuser Mass Spectrometry Laboratory for access to equipment.
References
This article references 46 other publications.
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- 6Küng, R.; Pausch, T.; Rasch, D.; Göstl, R.; Schmidt, B. M. Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage. Angew. Chem., Int. Ed. 2021, 60, 13626– 13630, DOI: 10.1002/anie.202102383Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCktrvI&md5=76865e50e6afbd97ed3335d210bc894dMechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular CageKueng, Robin; Pausch, Tobias; Rasch, Dustin; Goestl, Robert; Schmidt, Bernd M.Angewandte Chemie, International Edition (2021), 60 (24), 13626-13630CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Supramol. coordination cages show a wide range of useful properties including, but not limited to, complex mol. machine-like operations, confined space catalysis, and rich host-guest chemistries. Here we report the uptake and release of non-covalently encapsulated, pharmaceutically-active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)-decorated bipyridine ligands are used to assemble an octahedral PdII6(TPT)4 cage. The supramol. container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aq. soln. entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.
- 7White, 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, DOI: 10.1038/35057232Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFCjsbg%253D&md5=6c89d4c4b2c83453a81f2a0a99854c4eAutonomic healing of polymer compositesWhite, S. R.; Sottos, N. R.; Geubelle, P. H.; Moore, J. S.; Kessler, M. R.; Sriram, S. R.; Brown, E. N.; Viswanathan, S.Nature (London, United Kingdom) (2001), 409 (6822), 794-797CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mech. degrdn. of fiber-reinforced polymer composites; in microelectronic polymeric components it can also lead to elec. failure. Microcracking induced by thermal and mech. fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Expts. exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here, a structural polymeric material with the ability to autonomically heal cracks is reported. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymn. of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. The fracture expts. yield as much as 75% recovery in toughness, and the approach may be applicable to other brittle materials systems (including ceramics and glasses).
- 8Toohey, K. S.; Sottos, N. R.; Lewis, J. A.; Moore, J. S.; White, S. R. Self-healing materials with microvascular networks. Nat. Mater. 2007, 6, 581– 585, DOI: 10.1038/nmat1934Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVShu7s%253D&md5=8df7bc545204a8fa59eed8e088a6577cSelf-healing materials with microvascular networksToohey, Kathleen S.; Sottos, Nancy R.; Lewis, Jennifer A.; Moore, Jeffrey S.; White, Scott R.Nature Materials (2007), 6 (8), 581-585CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Self-healing polymers composed of microencapsulated healing agents exhibit remarkable mech. performance and regenerative ability, but are limited to autonomic repair of a single damage event in a given location. Self-healing is triggered by crack-induced rupture of the embedded capsules; thus, once a localized region is depleted of healing agent, further repair is precluded. Re-mendable polymers can achieve multiple healing cycles, but require external intervention in the form of heat treatment and applied pressure. Here, we report a self-healing system capable of autonomously repairing repeated damage events. Our bio-inspired coating-substrate design delivers healing agent to cracks in a polymer coating via a three-dimensional microvascular network embedded in the substrate. Crack damage in the epoxy coating is healed repeatedly. This approach opens new avenues for continuous delivery of healing agents for self-repair as well as other active species for addnl. functionality.
- 9Li, J.; Nagamani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive to Productive. Acc. Chem. Res. 2015, 48, 2181– 2190, DOI: 10.1021/acs.accounts.5b00184Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyqs7%252FO&md5=f79b0417f88f2a70997f583ba4f190cdPolymer Mechanochemistry: From Destructive to ProductiveLi, Jun; Nagamani, Chikkannagari; Moore, Jeffrey S.Accounts of Chemical Research (2015), 48 (8), 2181-2190CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. When one brings "polymeric materials" and "mech. action" into the same conversation, the topic of this discussion might naturally focus on everyday circumstances such as failure of fibers, fatigue of composites, abrasion of coatings, etc. This intuitive viewpoint reflects the historic consensus in both academia and industry that mech. induced chem. changes are destructive, leading to polymer degrdn. that limits materials lifetime on both macroscopic and mol. levels. In the 1930s, Staudinger obsd. mech. degrdn. of polymers, and Melville later discovered that polymer chain scission caused the degrdn. Inspired by these historical observations, we sought to redirect the destructive mech. energy to a productive form that enables mechanoresponsive functions. In this Account, we provide a personal perspective on the origin, barriers, developments, and key advancements of polymer mechanochem. We revisit the seminal events that offered mol.-level insights into the mechanochem. behavior of polymers and influenced our thinking. We also highlight the milestones achieved by our group along with the contributions from key comrades at the frontier of this field. We present a workflow for the design, evaluation, and development of new "mechanophores", a term that has come to mean a mol. unit that chem. responds in a selective manner to a mech. perturbation. We discuss the significance of computation in identifying pairs of points on the mechanophore that promote stretch-induced activation. Attaching polymer chains to the mechanophore at the most sensitive pair and locating the mechanophore near the center of a linear polymer are thought to maximize the efficiency of mech.-to-chem. energy transduction. We also emphasize the importance of control expts. to validate mechanochem. transformations, both in soln. and in the solid state, to differentiate "mech." from "thermal" activation. This Account offers our first-hand perspective of the change-in-thinking in polymer mechanochem. from "destructive" to "productive" and looks at future advances that will stimulate this growing field.
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- 11Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials. Chem. Rev. 2009, 109, 5755– 5798, DOI: 10.1021/cr9001353Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvK&md5=bae0e40d8fd4637ff652dba4c4dbbe40Mechanically-Induced Chemical Changes in Polymeric MaterialsCaruso, Mary M.; Davis, Douglas A.; Shen, Qilong; Odom, Susan A.; Sottos, Nancy R.; White, Scott R.; Moore, Jeffrey S.Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5755-5798CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the chem. changes that accompany polymeric materials subjected to mech. stimuli. The review is organized by the length scale over which the chem. change takes place.
- 12Kim, G.; Lau, V. M.; Halmes, A. J.; Oelze, M. L.; Moore, J. S.; Li, K. C. High-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 10214– 10222, DOI: 10.1073/pnas.1901047116Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFOkurs%253D&md5=a1fdcf4a548eeb200ef6c5418b7a744eHigh-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomersKim, Gun; Lau, Vivian M.; Halmes, Abigail J.; Oelze, Michael L.; Moore, Jeffrey S.; Li, King C.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (21), 10214-10222CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)While study in the field of polymer mechanochem. has yielded mechanophores that perform various chem. reactions in response to mech. stimuli, there is not yet a triggering method compatible with biol. systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mech.-to-chem. transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochem. reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradn. evidence of the mechanochem. transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradn. successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradn. provides spatiotemporal control of the mechanochem. activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.
- 13Akbulatov, S.; Boulatov, R. Experimental polymer mechanochemistry and its interpretational frameworks. ChemPhysChem 2017, 18, 1422– 1450, DOI: 10.1002/cphc.201601354Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFShsrY%253D&md5=3b477b6950260ed6aab21b3168ae0f4aExperimental Polymer Mechanochemistry and its Interpretational FrameworksAkbulatov, Sergey; Boulatov, RomanChemPhysChem (2017), 18 (11), 1422-1450CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Polymer mechanochem. is an emerging field at the interface of chem., materials science, physics and engineering. It aims at understanding and exploiting unique reactivities of polymer chains confined to highly non-equil. stretched geometries by interactions with their surroundings. Macromol. chains or their segments become stretched in bulk polymers under mech. loads or when polymer solns. are sonicated or flow rapidly through abrupt contractions. An increasing amt. of empirical data suggests that mechanochem. phenomena are widespread wherever polymers are used. In the past decade, empirical mechanochem. has progressed enormously, from studying fragmentations of commodity polymers by simple backbone homolysis to demonstrations of self-strengthening and stress-reporting materials and mechanochem. cascades using purposefully designed monomers. This progress has not yet been matched by the development of conceptual frameworks within which to rationalize, systematize and generalize empirical mechanochem. observations. As a result, mechanistic and/or quant. understanding of mechanochem. phenomena remains, with few exceptions, tentative. In this review, we aim at systematizing reported macroscopic manifestations of polymer mechanochem., and critically assessing the interpretational framework that underlies their mol. rationalizations from a phys. chemist's perspective. We propose a hierarchy of mechanochem. phenomena which may guide the development of multiscale models of mechanochem. reactivity to match the breadth and utility of the Eyring equation of chem. kinetics. We discuss the limitations of the approaches to quantifying and validating mechanochem. reactivity, with particular focus on sonicated polymer solns., in order to identify outstanding questions that need to be solved for polymer mechanochem. to become a rigorous, quant. field. We conclude by proposing 7 problems whose soln. may have a disproportionate impact on the development of polymer mechanochem.
- 14Diesendruck, 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, DOI: 10.1021/ja305645xGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVKlu7g%253D&md5=d5f3da927570764cb6015e3738d3e338Proton-Coupled Mechanochemical Transduction: A Mechanogenerated AcidDiesendruck, Charles E.; Steinberg, Brian D.; Sugai, Naoto; Silberstein, Meredith N.; Sottos, Nancy R.; White, Scott R.; Braun, Paul V.; Moore, Jeffrey S.Journal of the American Chemical Society (2012), 134 (30), 12446-12449CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel mechanophore with acid-releasing capability is designed to produce a simple catalyst for chem. change in materials under mech. stress. The mechanophore, based on a gem-dichlorocyclopropanated indene, is synthesized and used as a cross-linker in poly(Me acrylate). Force-dependent rearrangement is demonstrated for cross-linked mechanophore samples loaded in compression, while the control shows no significant response. The availability of the released acid is confirmed by exposing a piece of insol. compressed polymer to a pH indicator soln. The development of this new mechanophore is the first step toward force-induced remodeling of stressed polymeric materials utilizing acid-catalyzed crosslinking reactions.
- 15Lin, Y.; Kouznetsova, T. B.; Craig, S. L. A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials. J. Am. Chem. Soc. 2020, 142, 99– 103, DOI: 10.1021/jacs.9b12861Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVyitLrI&md5=b7a6c0decebe1477b3dddd5dd1861b57A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric MaterialsLin, Yangju; Kouznetsova, Tatiana B.; Craig, Stephen L.Journal of the American Chemical Society (2020), 142 (1), 99-103CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mech. coupled proton transduction offers potential for stress-responsive polymeric materials whose properties can be switched via acid-triggered coloration, polymn./crosslinking, or degrdn. The utility of currently available mechanoacids, however, is limited by modest force-free stability or a scissile response that caps mechanoacid generation at one proton per strained polymer chain. Here, the authors report a new mechanoacid based on 2-methoxy-substituted gem-dichlorocyclopropane (MeO-gDCC). Pulsed ultrasonication leads to the mechanochem. ring opening of the MeO-gDCC and the subsequent elimination of either HCl or MeCl, with ∼0.58 equiv of HCl released per mechanophore activation and ∼67 protons per chain scission event. Single-mol. force spectroscopy reveals that the methoxy substituent lowers the force required for rapid (kopen ∼102 s-1) ring opening to ca. 900 pN, vs 1300 pN required for the parent gDCC. The utility of the mechanoacid is demonstrated in silicone elastomers, where its mech. activation leads to a strain-triggered color change prior to fracture of the elastomer. The post activation kinetics of coloration are used to demonstrate a new concept in mechanochromism, namely, a spectroscopic indicator of not only whether and where a mech. event has occurred but when it occurred.
- 16Larsen, M. B.; Boydston, A. J. Flex-Activated” Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am. Chem. Soc. 2013, 135, 8189– 8192, DOI: 10.1021/ja403757pGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFyisb4%253D&md5=e4d08119d68aaa100452814ef1a1ad58"Flex-Activated" Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending ActivationLarsen, Michael B.; Boydston, Andrew J.Journal of the American Chemical Society (2013), 135 (22), 8189-8192CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We describe studies in mechanochem. transduction that probe the activation of bonds orthogonal to an elongated polymer main chain. Compression of mechanophore-crosslinked materials resulted in the release of small mols. via cleavage of covalent bonds that were not integral components of the elongated polymer segments. The reactivity is proposed to arise from the distribution of force through the crosslinking units of the polymer network and subsequent bond bending motions that are consistent with the geometric changes in the overall reaction. This departure from contemporary polymer mechanochem., in which activation is achieved primarily by force-induced bond elongation, is a first step toward mechanophores capable of releasing side-chain functionalities without inherently compromising the overall macromol. architecture.
- 17Larsen, M. B.; Boydston, A. J. Successive Mechanochemical Activation and Small Molecule Release in an Elastomeric Material. J. Am. Chem. Soc. 2014, 136, 1276– 1279, DOI: 10.1021/ja411891xGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotVequw%253D%253D&md5=756d3c176befc893e78bfbb236786abdSuccessive Mechanochemical Activation and Small Molecule Release in an Elastomeric MaterialLarsen, Michael B.; Boydston, Andrew J.Journal of the American Chemical Society (2014), 136 (4), 1276-1279CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The authors have developed a mechanochem. responsive material capable of successively releasing small org. mols. from a cross-linked network upon repeated compressions. The use of a flex activated mechanophore that does not lead to main chain scission and an elastomeric polyurethane enabled consecutive compressions with incremental increases in the % mechanophore activation. Addnl., the authors examd. the effect of multiple applications of compressive stress on both mechanophore activity and the mech. behavior of the elastomeric matrix in which the mechanophore is embedded.
- 18Shen, H.; Larsen, M. B.; Roessler, A.; Zimmerman, P.; Boydston, A. J. Mechanochemical Release of N-heterocyclic Carbenes from Flex-Activated Mechanophores. Angew. Chem., Int. Ed. 2021, 60, 13559, DOI: 10.1002/anie.202100576Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCrtLnJ&md5=8cd573f15cde8622c004c3ff28898fa7Mechanochemical Release of N-Heterocyclic Carbenes from Flex-Activated MechanophoresShen, Hang; Larsen, Michael B.; Roessler, Allison G.; Zimmerman, Paul M.; Boydston, Andrew J.Angewandte Chemie, International Edition (2021), 60 (24), 13559-13563CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have discovered a new flex-activated mechanophore that releases an N-heterocyclic carbene (NHC) under mech. load. The mechanophore design is based upon NHC-carbodiimide (NHC-CDI) adducts and demonstrates an important first step toward flex-activated designs capable of further downstream reactivities. Since the flex-activation is non-destructive to the main polymer chains, the material can be subjected to multiple compression cycles to achieve iterative increases in the activation percentage of mechanophores. Two different NHC structures were demonstrated, signifying the potential modularity of the mechanophore design.
- 19Diesendruck, 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-temperature polymer. Nat. Chem. 2014, 6, 623– 628, DOI: 10.1038/nchem.1938Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvFSjtrk%253D&md5=4134bc74bd65deca7c5ce7a6388ab7d1Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymerDiesendruck, Charles E.; Peterson, Gregory I.; Kulik, Heather J.; Kaitz, Joshua A.; Mar, Brendan D.; May, Preston A.; White, Scott R.; Martinez, Todd J.; Boydston, Andrew J.; Moore, Jeffrey S.Nature Chemistry (2014), 6 (7), 623-628CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Biol. systems rely on recyclable materials resources such as amino acids, carbohydrates and nucleic acids. When biomaterials are damaged as a result of aging or stress, tissues undergo repair by a depolymn.-repolymn. sequence of remodelling. Integration of this concept into synthetic materials systems may lead to devices with extended lifetimes. Here, we show that a metastable polymer, end-capped poly(o-phthalaldehyde), undergoes mech. initiated depolymn. to revert the material to monomers. Trapping expts. and steered mol. dynamics simulations are consistent with a heterolytic scission mechanism. The obtained monomer was repolymd. by a chem. initiator, effectively completing a depolymn.-repolymn. cycle. By emulating remodelling of biomaterials, this model system suggests the possibility of smart materials where aging or mech. damage triggers depolymn., and orthogonal conditions regenerate the polymer when and where necessary.
- 20Peterson, G. I.; Boydston, A. J. Kinetic Analysis of Mechanochemical Chain Scission of Linear Poly(phthalaldehyde). Macromol. Rapid Commun. 2014, 35, 1611– 1614, DOI: 10.1002/marc.201400271Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisbnP&md5=ad8179456e878f6800b0ffbf6b264720Kinetic Analysis of Mechanochemical Chain Scission of Linear Poly(phthalaldehyde)Peterson, Gregory I.; Boydston, Andrew J.Macromolecular Rapid Communications (2014), 35 (18), 1611-1614CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)The kinetics of mechanochem. chain scission of poly(phthalaldehyde) (PPA) are investigated. Ultrasound-induced cavitation is capable of causing chain scission in the PPA backbone that ultimately leads to rapid depolymn. of each resulting polymer fragment when above the polymer's ceiling temp. (Tc). An interesting feature of the mechanochem. breakdown of PPA is that "half-chain" daughter fragments are not obsd., since the depolymn. is rapid following chain scission. These features facilitate the detn. of rate consts. of activation for multiple mol. wts. from a single sonication expt. Addnl., the degrdn. kinetics are modified with chain-end trapping agents through variation of the nature and amt. of small mol. nucleophile or electrophile.
- 21Wiita, A. P.; Ainavarapu, S. R. K.; Huang, H. H.; Fernandez, J. M. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 7222– 7227, DOI: 10.1073/pnas.0511035103Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslOktb0%253D&md5=b1894f1e85ea785b5d56d45114e6a0e1Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniquesWiita, Arun P.; Ainavarapu, Rama Koti; Huang, Hector H.; Fernandez, Julio M.Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (19), 7222-7227CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The mechanism by which mech. force regulates the kinetics of a chem. reaction is unknown. Here, we use single-mol. force-clamp spectroscopy and protein engineering to study the effect of force on the kinetics of thiol/disulfide exchange. Redn. of disulfide bonds through the thiol/disulfide exchange chem. reaction is crucial in regulating protein function and is known to occur in mech. stressed proteins. We apply a const. stretching force to single engineered disulfide bonds and measure their rate of redn. by DTT. Although the redn. rate is linearly dependent on the concn. of DTT, it is exponentially dependent on the applied force, increasing 10-fold over a 300-pN range. This result predicts that the disulfide bond lengthens by 0.34 Å at the transition state of the thiol/disulfide exchange reaction. Our work at the single bond level directly demonstrates that thiol/disulfide exchange in proteins is a force-dependent chem. reaction. Our findings suggest that mech. force plays a role in disulfide redn. in vivo, a property that has never been explored by traditional biochem. Furthermore, our work also indicates that the kinetics of any chem. reaction that results in bond lengthening will be force-dependent.
- 22Dopieralski, P.; Ribas-Arino, J.; Anjukandi, P.; Krupicka, M.; Marx, D. Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution. Nat. Chem. 2017, 9, 164– 170, DOI: 10.1038/nchem.2632Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCgtbjJ&md5=7d7aada474084ac849905dec4cf01337Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solutionDopieralski, Przemyslaw; Ribas-Arino, Jordi; Anjukandi, Padmesh; Krupicka, Martin; Marx, DominikNature Chemistry (2017), 9 (2), 164-170CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)The redn. of disulfides has a broad importance in chem., biochem. and materials science, particularly those methods that use mechanochem. activation. Here the authors show, using isotensional simulations, that strikingly different mechanisms govern disulfide cleavage depending on the external force. Desolvation and resolvation processes are crucial, as they have a direct impact on activation free energies. The preferred pathway at moderate forces, a bimol. SN2 attack of OH- at sulfur, competes with unimol. C-S bond rupture at ∼2 nN, and the latter even becomes barrierless at greater applied forces. Also, study unveils a surprisingly rich reactivity scenario that also includes the transformation of concerted SN2 reactions into pure bond-breaking processes at specific forces. Given that these forces are easily reached in expts., these insights will fundamentally change understanding of mechanochem. activation in general, which is now expected to be considerably more intricate than previously thought.
- 23Shi, Z.; Song, Q.; Göstl, R.; Herrmann, A. Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug release. Chem. Sci. 2021, 12, 1668, DOI: 10.1039/D0SC06054BGoogle Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1SgsL3N&md5=ce3ffb162231ee37b948794e44139ea9Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug releaseShi, Zhiyuan; Song, Qingchuan; Goestl, Robert; Herrmann, AndreasChemical Science (2021), 12 (5), 1668-1674CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Drug delivery systems responsive to physicochem. stimuli allow spatiotemporal control over drug activity to overcome limitations of systemic drug administration. Alongside, the non-invasive real-time tracking of drug release and uptake remains challenging as pharmacophore and reporter function are rarely unified within one mol. Here, we present an ultrasound-responsive release system based on the mechanochem. induced 5-exo-trig cyclization upon scission of disulfides bearing cargo mols. attached via β-carbonate linker within the center of a water sol. polymer. In this bifunctional theranostic approach, we release one reporter mol. per drug mol. to quant. track drug release and distribution within the cell in real-time. We use N-butyl-4-hydroxy-1,8-naphthalimide and umbelliferone as fluorescent reporter mols. to accompany the release of camptothecin and gemcitabine as clin. employed anticancer agents. The generality of this approach paves the way for the theranostic release of a variety of probes and drugs by ultrasound.
- 24Shi, Z. Ultrasound-mediated activation of drugs. Ph.D. Dissertation, RWTH Aachen University, Aachen, Germany, 2021. https://publications.rwth-aachen.de/record/814605 (accessed 2021-05-07).Google ScholarThere is no corresponding record for this reference.
- 25Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate. J. Am. Chem. Soc. 2019, 141, 15018– 15023, DOI: 10.1021/jacs.9b08663Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslKisbjI&md5=5b335054eb92d57bf90338ab96dbb10aMechanically Triggered Small Molecule Release from a Masked Furfuryl CarbonateHu, Xiaoran; Zeng, Tian; Husic, Corey C.; Robb, Maxwell J.Journal of the American Chemical Society (2019), 141 (38), 15018-15023CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Stimuli-responsive polymers that release small mols. under mech. stress are appealing targets for applications ranging from drug delivery to sensing. Here, we describe a modular mechanophore design platform for mol. release via a mech. triggered cascade reaction. Mechanochem. activation of a furan-maleimide Diels-Alder adduct reveals a latent furfuryl carbonate that subsequently decomps. under mild conditions to release a covalently bound cargo mol. The computationally guided design of a reactive secondary furfuryl carbonate enables the decompn. and release to proceed quickly at room temp. after unmasking via mech. force. This general strategy is demonstrated using ultrasound-induced mech. activation to release a fluorogenic coumarin payload from a polymer incorporating a chain-centered mechanophore.
- 26Hay, M. P.; Sykes, B. M.; Denny, W. A.; O’Connor, C. J. Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs. J. Chem. Soc., Perkin Trans. 1 1999, (19), 2759– 2770, DOI: 10.1039/a904067fGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtVGmt7s%253D&md5=ca10f19fbbdaa8ec6ccd4390be961515Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugsHay, Michael P.; Sykes, Bridget M.; Denny, William A.; O'Connor, Charmian J.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1999), (19), 2759-2770CODEN: JCPRB4; ISSN:0300-922X. (Royal Society of Chemistry)4-Nitrobenzyl carbamates are of interest as triggers for bioreductive drugs, particularly in conjunction with the E. coli B nitroreductase, which efficiently reduces them to the corresponding hydroxylamines. These then fragment to release highly toxic amine-based toxins. While many 4-nitrobenzyl carbamate derivs. have been evaluated as bioreductive drugs, there has been no systematic study of substituent effects on the rate of this fragmentation (which should be as fast as possible following redn.). We therefore prepd. a series of 2-, 3- and α-substituted 4-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]phenylacetamides as model compds. to study these effects. The majority of the carbamates were prepd. by in situ formation of the chloroformate of the appropriate 4-nitrobenzyl alc. and reaction with Me 4-(methylamino)phenylacetate, followed by ester hydrolysis and 1,1'-carbonyldiimidazole (CDI) mediated coupling with N,N-dimethylaminoethylamine. The hydroxylamines were generated by 60Co γ-ray irradn. of the nitro compds. in aq. phosphate-buffered propan-2-ol. The reactions were analyzed by reverse-phase HPLC to det. the max. half-life (Mt1/2) of the hydroxylamines generated, and the extent of release of amine from these after 10 half-lives (t∞). The parent (unsubstituted) hydroxylaminobenzyl carbamate had a Mt1/2 of 16 min under these conditions, while that of the corresponding α-Me analog was 9.5 min. Electron-donating substituents on the benzyl ring also accelerated fragmentation, with the data being fitted to the equation log(Mt1/2) = 0.57σ + 1.30, where σ represents σp for 2-substituents and σm for 3-substituents. The acceleration of fragmentation of the hydroxylamines with increasing substituent electron-donation is consistent with the proposed mechanism, and is presumably due to stabilization of the developing pos. charge on the benzylic carbon. The extent of release of amine (t∞) also increased with increasing substituent electron-donation. These data suggest that the std. 4-nitrobenzyl carbamate trigger for nitroreductase enzyme (NTR) prodrugs can likely be improved on, by increasing the rate of fragmentation by the use of α-Me and/or electron-donating benzyl substituents.
- 27Mosey, R. A.; Floreancig, P. E. Versatile approach to α-alkoxy carbamate synthesis and stimulus-responsive alcohol release. Org. Biomol. Chem. 2012, 10, 7980– 7985, DOI: 10.1039/c2ob26571kGoogle Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2htb3O&md5=5907239a71b4ba0b2a9aee0c61dad003Versatile approach to α-alkoxy carbamate synthesis and stimulus-responsive alcohol releaseMosey, R. Adam; Floreancig, Paul E.Organic & Biomolecular Chemistry (2012), 10 (39), 7980-7985CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A series of α-alkoxy carbamates that cleave under mild conditions to release alcs. has been synthesized through a multicomponent process. The relationship between structural features in these compds. and the rate of alc. release in the presence of basic hydrogen peroxide has been studied. The prepn. of carbamates that cleave under other conditions has been demonstrated. The prepn. of α-alkoxy carbamates involved a sequence of nitrile hydrozirconation, acylation, and alc. addn. E.g., hydrozirconation of Me3CCN with Cp2Zr(H)Cl, followed by reaction with chloroformate I and addn. of neopentyl alc. gave α-alkoxy carbamate (II). Treatment of the latter with urea.H2O2 led to release of neopentyl alc.
- 28Wang, J.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L. Mechanical gating of a mechanochemical reaction cascade. Nat. Commun. 2016, 7, 13433, DOI: 10.1038/ncomms13433Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVygu7zM&md5=b5927e373fa2420dde7cdacf687a21baMechanical gating of a mechanochemical reaction cascadeWang, Junpeng; Kouznetsova, Tatiana B.; Boulatov, Roman; Craig, Stephen L.Nature Communications (2016), 7 (), 13433pp.CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Covalent polymer mechanochem. offers promising opportunities for the control and engineering of reactivity. To date, covalent mechanochem. has largely been limited to individual reactions, but it also presents potential for intricate reaction systems and feedback loops. Here we report a mol. architecture, in which a cyclobutane mechanophore functions as a gate to regulate the activation of a second mechanophore, dichlorocyclopropane, resulting in a mechanochem. cascade reaction. Single-mol. force spectroscopy, pulsed ultrasonication expts. and DFT-level calcns. support gating and indicate that extra force of >0.5 nN needs to be applied to a polymer of gated gDCC than of free gDCC for the mechanochem. isomerization gDCC to proceed at equal rate. The gating concept provides a mechanism by which to regulate stress-responsive behaviors, such as load-strengthening and mechanochromism, in future materials designs.
- 29Hu, X.; McFadden, M. E.; Barber, R. W.; Robb, M. J. Mechanochemical Regulation of a Photochemical Reaction. J. Am. Chem. Soc. 2018, 140, 14073– 14077, DOI: 10.1021/jacs.8b09628Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFeqsLbO&md5=2af17aef65e04a91bc27e984a0a9f5fdMechanochemical Regulation of a Photochemical ReactionHu, Xiaoran; McFadden, Molly E.; Barber, Ross W.; Robb, Maxwell J.Journal of the American Chemical Society (2018), 140 (43), 14073-14077CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We introduce the concept of mechanochem. gated photoswitching. Mech. regulation of a photochem. reaction is exemplified using a newly designed mechanophore based on a cyclopentadiene-maleimide Diels-Alder adduct. Ultrasound-induced mech. activation of the photochem. inert mechanophore in polymers generates a diarylethene photoswitch via a retro-[4 + 2] cycloaddn. reaction that photoisomerizes between colorless and colored states upon exposure to UV and visible light. Control expts. demonstrate the thermal stability of the cyclopentadiene-maleimide adduct and confirm the mech. origin of the "unlocked" photochromic reactivity. This technol. holds promise for applications such as lithog. and stress-sensing, enabling the mech. history of polymeric materials to be recorded and read on-demand.
- 30Fan, 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, DOI: 10.1039/C7CC06410AGoogle Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aksb3I&md5=6de1e6447f10d080a568a34f0f01db2aThermo-responsive self-immolative nanoassemblies: direct and indirect triggeringFan, Bo; Trant, John F.; Hemery, Gauvin; Sandre, Olivier; Gillies, Elizabeth R.Chemical Communications (Cambridge, United Kingdom) (2017), 53 (89), 12068-12071CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A thermo-responsive end-cap based on a retro-Diels-Alder and subsequent furan elimination reaction was developed. It was used to cap poly(Et glyoxylate), allowing end-to-end depolymn. upon thermal triggering. Using block copolymers, thermo-responsive micelles and vesicles were prepd. and shown to disassemble upon heating. Thermal degrdn. could also be triggered indirectly by magnetic field hyperthermia after incorporation of iron oxide nanoparticles into the assemblies.
- 31Schmid, K. M.; Jensen, L.; Phillips, S. T. A Self-Immolative Spacer That Enables Tunable Controlled Release of Phenols under Neutral Conditions. J. Org. Chem. 2012, 77, 4363– 4374, DOI: 10.1021/jo300400qGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xltl2hu70%253D&md5=b0bb0447e0dccf2d26bb12b2c08ed596A Self-Immolative Spacer That Enables Tunable Controlled Release of Phenols under Neutral ConditionsSchmid, Kyle M.; Jensen, Lasse; Phillips, Scott T.Journal of Organic Chemistry (2012), 77 (9), 4363-4374CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A current challenge in the area of responsive materials is the design of reagents and polymers that provide controlled release of phenols in environments that are less polar than water. In these contexts, a mol. strategy that enables release of nearly any phenol with predictable and tunable rates and without complication from background hydrolysis would substantially increase the precision with which materials can be designed to respond to a particular signal. This Article addresses this problem at the fundamental level by describing the design, synthesis, and phys.-org. characterization of two small mol. self-immolative spacers that are capable of releasing phenols in org. and mixed org.-aq. solns. The rate of release from these small mol. model systems is predictable and tunable, such that nearly any type of phenol, regardless of pKa value, can be released in neutral solns. without complications from nonspecific background release due to hydrolysis. Furthermore, the release properties of the spacers can be predicted from bond length and conformation data (obtained from crystal structures). On the basis of these results, it should now be possible to incorporate these design elements into materials to enable precise response properties in environments that are not 100% aq.
- 32Nichol, M. F.; Clark, K. D.; Dolinski, N. D.; Read de Alaniz, J. Multi-stimuli responsive trigger for temporally controlled depolymerization of self-immolative polymers. Polym. Chem. 2019, 10, 4914– 4919, DOI: 10.1039/C9PY00301KGoogle Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFKisr3E&md5=26c59341e6cb081ab852a96cc7efc58bMulti-stimuli responsive trigger for temporally controlled depolymerization of self-immolative polymersNichol, Meghan F.; Clark, Kyle D.; Dolinski, Neil D.; Read de Alaniz, JavierPolymer Chemistry (2019), 10 (36), 4914-4919CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)For many decades, stimuli-responsive materials have been studied and utilized in various fields, ranging from chem. sensors to controlled drug release. Among these responsive materials are self-immolative polymers (SIPs) that allow for end-to-end depolymn. and the ability to release a desired cargo on demand or amplify analyte detection. However, in typical SIP systems, the triggering event leads to a relatively uncontrolled degrdn. process. Herein we present a multi-stimuli trigger that utilizes the combination of heat and acid to impart control over the trigger event and thus the degrdn. process. By controlling this reaction, we achieve temporal control over the trigger cleavage and subsequent depolymn. and release of cargo from the SIP.
- 33Alouane, A.; Labruère, R.; Le Saux, T.; Schmidt, F.; Jullien, L. Self-Immolative Spacers: Kinetic Aspects, Structure-Property Relationships, and Applications. Angew. Chem., Int. Ed. 2015, 54, 7492– 7509, DOI: 10.1002/anie.201500088Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXps1eguro%253D&md5=fe98dd1aff7066a9a58073ee3c57f688Self-immolative spacers: kinetic aspects, structure-property relationships, and applicationsAlouane, Ahmed; Labruere, Raphael; Le Saux, Thomas; Schmidt, Frederic; Jullien, LudovicAngewandte Chemie, International Edition (2015), 54 (26), 7492-7509CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chem. bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller mols. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chem., anal. chem., and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic expts. and fully exploit the rich perspectives of self-immolative spacers.
- 34Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. Ultrasound-Induced Site-Specific Cleavage of Azo-Functionalized Poly(ethylene glycol). Macromolecules 2005, 38, 8975– 8978, DOI: 10.1021/ma051394nGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVeht73P&md5=4251e187f5a324bd20b2de4aff6f4dc2Ultrasound-induced site-specific cleavage of azo-functionalized poly(ethylene glycol)Berkowski, Kimberly L.; Potisek, Stephanie L.; Hickenboth, Charles R.; Moore, Jeffrey S.Macromolecules (2005), 38 (22), 8975-8978CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Ultrasound-induced site-specific cleavage of a polymer was accomplished by incorporating a single weak, azo linkage into the backbone of poly(ethylene glycol). The ultrasonic fragmentation of azo-functionalized polymers differs from the previously reported degrdn. of homopolymers or block copolymers in two important ways. First, the rate of ultrasonic cleavage is appreciably faster in the azo-centered polymers due to the weak bond in the polymer backbone. In addn., the azo-functionalized polymer cleaves with a high degree of bond specificity, resulting in one type of chain end and fragments of low polydispersity. Ultrasound-induced site-specific cleavage of polymers could be extended as an alternative to thermal or photoinduced reactions.
- 35Nguyen, N. H.; Rosen, B. M.; Lligadas, G.; Percec, V. Surface-Dependent Kinetics of Cu(0)-Wire-Catalyzed Single-Electron Transfer Living Radical Polymerization of Methyl Acrylate in DMSO at 25 °C. Macromolecules 2009, 42, 2379– 2386, DOI: 10.1021/ma8028562Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjt1Gqtbc%253D&md5=921611687412818360b4dd32ef292a95Surface-Dependent Kinetics of Cu(0)-Wire-Catalyzed Single-Electron Transfer Living Radical Polymerization of Methyl Acrylate in DMSO at 25 °CNguyen, Nga H.; Rosen, Brad M.; Lligadas, Gerard; Percec, VirgilMacromolecules (Washington, DC, United States) (2009), 42 (7), 2379-2386CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The effect of Cu(0) wire dimensions on the Cu(0) wire/Me6-TREN-catalyzed heterogeneous single-electron transfer living radical polymn. (SET-LRP) of Me acrylate (MA) initiated with Me 2-bromopropionate (MBP) in DMSO at 25 °C was analyzed by kinetic expts. These kinetic results were compared with those of Cu(0) powder/Me6-TREN-catalyzed SET-LRP. Both wire and powder produce perfect SET-LRP with a first-order rate of polymn. in growing species up to 100% conversion. Nevertheless, Cu(0) wire expts. demonstrated SET-LRP with greater perfection, allowing for the accurate detn. of the external rate order (vis-a-vis surface area) for heterogeneous Cu(0) catalyst and accurate prediction of kpapp from wire dimension. Cu(0) wire also exhibited a significantly greater control of mol. wt. distribution than Cu(0) powder. The combined advantages of easier catalyst prepn., handling, predictability, tunability, simple recovery/recycling, and enhanced control of mol. wt. distribution make Cu(0)-wire-catalyzed SET-LRP the ideal methodol. for the synthesis of tailored polyacrylates.
- 36Beyer, M. K. The mechanical strength of a covalent bond calculated by density functional theory. J. Chem. Phys. 2000, 112, 7307– 7312, DOI: 10.1063/1.481330Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXis1ansr0%253D&md5=1586bc3690c4f8fafcb64cb264a7b88bThe mechanical strength of a covalent bond calculated by density functional theoryBeyer, Martin K.Journal of Chemical Physics (2000), 112 (17), 7307-7312CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The rupture forces of covalent bonds in a polymer as a function of bond lifetime are calcd. with an Arrhenius kinetics model based on high-level d. functional theory calcns. Relaxed potential energy surface scans of small model mols. yield potential functions that account for the deformations and hybridizations caused by the application of force. Morse potentials chosen to exhibit the same well depth and max. force are used as an analytic representation of an individual bond in an infinitely long one-dimensional polymer. Application of force deforms the potential, and the activation energy for the bond rupture event together with the frequency of an optical phonon in the one-dimensional polymer are the two Arrhenius parameters. Rupture forces of the bonds C-C, C-N, C-O, Si-C, Si-N, Si-O, and Si-Si are reported as a function of the lifetime of the bond.
- 37Klein, I. M.; Husic, C. C.; Kovács, D. P.; Choquette, N. J.; Robb, M. J. Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry. J. Am. Chem. Soc. 2020, 142, 16364– 16381, DOI: 10.1021/jacs.0c06868Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslKgur3N&md5=c9c569611172a826776b8419c2843058Validation of the CoGEF method as a predictive tool for polymer mechanochemistryKlein, Isabel M.; Husic, Corey C.; Kovacs, David P.; Choquette, Nicolas J.; Robb, Maxwell J.Journal of the American Chemical Society (2020), 142 (38), 16364-16381CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The development of force-responsive mols. called mechanophores is a central component of the field of polymer mechanochem. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to mol. release and self-healing materials. Nevertheless, an insufficient understanding of structure-activity relationships limits exptl. development, and thus computation is necessary to guide the structural design of mechanophores. The constrained geometries simulate external force (CoGEF) method is a highly accessible and straightforward computational technique that simulates the effect of mech. force on a mol. and enables the prediction of mechanochem. reactivity. Here, we use the CoGEF method to systematically evaluate every covalent mechanophore reported to date and compare the predicted mechanochem. reactivity to exptl. results. Mols. that are mechanochem. inactive are also studied as neg. controls. In general, mechanochem. reactions predicted with the CoGEF method at the common B3LYP/6-31G* level of d. functional theory are in excellent agreement with reactivity detd. exptl. Moreover, bond rupture forces obtained from CoGEF calcns. are compared to exptl. measured forces and demonstrated to be reliable indicators of mechanochem. activity. This investigation validates the CoGEF method as a powerful tool for predicting mechanochem. reactivity, enabling its widespread adoption to support the developing field of polymer mechanochem. Secondarily, this study provides a contemporary catalog of over 100 mechanophores developed to date.
- 38Konda, S. S. M.; Brantley, J. N.; Varghese, B. T.; Wiggins, K. M.; Bielawski, C. W.; Makarov, D. E. Molecular Catch Bonds and the Anti-Hammond Effect in Polymer Mechanochemistry. J. Am. Chem. Soc. 2013, 135, 12722– 12729, DOI: 10.1021/ja4051108Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SlsbzN&md5=3521e7dfc2772f1f3388186ddff3b9a7Molecular Catch Bonds and the Anti-Hammond Effect in Polymer MechanochemistryKonda, Sai Sriharsha M.; Brantley, Johnathan N.; Varghese, Bibin T.; Wiggins, Kelly M.; Bielawski, Christopher W.; Makarov, Dmitrii E.Journal of the American Chemical Society (2013), 135 (34), 12722-12729CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)While the field of polymer mechanochem. has traditionally focused on the use of mech. forces to accelerate chem. processes, theor. considerations predict an underexplored alternative: the suppression of reactivity through mech. perturbation. Here, we use electronic structure calcns. to analyze the mech. reactivity of six mechanophores, or chem. functionalities that respond to mech. stress in a controlled manner. Our computational results indicate that appropriately directed tensile forces could attenuate (as opposed to facilitate) mechanochem. phenomena. Accompanying exptl. studies supported the theor. predictions and demonstrated that relatively simple computational models may be used to design new classes of mech. responsive materials. In addn., our computational studies and theor. considerations revealed the prevalence of the anti-Hammond (as opposed to Hammond) effect (i.e., the increased structural dissimilarity between the reactant and transition state upon lowering of the reaction barrier) in the mech. activation of polyat. mols.
- 39Robb, M. J.; Kim, T. A.; Halmes, A. J.; White, S. R.; Sottos, N. R.; Moore, J. S. Regioisomer-Specific Mechanochromism of Naphthopyran in Polymeric Materials. J. Am. Chem. Soc. 2016, 138, 12328– 12331, DOI: 10.1021/jacs.6b07610Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyht7fN&md5=05af4225a1f310ab4f7dafe1791bd508Regioisomer-Specific Mechanochromism of Naphthopyran in Polymeric MaterialsRobb, Maxwell J.; Kim, Tae Ann; Halmes, Abigail J.; White, Scott R.; Sottos, Nancy R.; Moore, Jeffrey S.Journal of the American Chemical Society (2016), 138 (38), 12328-12331CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Transformation of naphthopyran into a colored merocyanine species in polymeric materials is achieved using mech. force. We demonstrate that the mechanochem. reactivity of naphthopyran is critically dependent on the regiochem., with only one particular substitution pattern leading to successful mechanochem. activation. Two alternative regioisomers with different polymer attachment points are demonstrated to be mechanochem. inactive. This trend in reactivity is accurately predicted by DFT calcns., reinforcing predictive capabilities in mechanochem. systems. We rationalize the reactivity differences between naphthopyran regioisomers in terms of the alignment of the target C-O pyran bond with the direction of the applied mech. force and its effect on mechanochem. transduction along the reaction coordinate.
- 40Stevenson, R.; De Bo, G. Controlling Reactivity by Geometry in Retro-Diels-Alder Reactions under Tension. J. Am. Chem. Soc. 2017, 139, 16768– 16771, DOI: 10.1021/jacs.7b08895Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCiur3J&md5=14b87c5c0efbac3c19dbc3e9058baa42Controlling Reactivity by Geometry in Retro-Diels-Alder Reactions under TensionStevenson, Richard; De Bo, GuillaumeJournal of the American Chemical Society (2017), 139 (46), 16768-16771CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mech. force, with its ability to distort, bend, and stretch chem. bonds, is unique in the way it activates chem. reactions. In polymer mechanochem., the force is transduced in a directional fashion, and the efficiency of activation depends on how well the force is transduced from the polymer to the scissile bond in the mechanophore (i.e., mechanochem. coupling). We have studied the effects of regio- and stereochem. on the rate of force-accelerated retro-Diels-Alder reactions of furan/maleimide adducts. Four adducts, presenting an endo or exo configuration and proximal or distal geometry, were activated in soln. by ultrasound-generated elongational forces. A combination of structural (1H NMR) and computational (CoGEF) analyses allowed us to interrogate the mechanochem. activation of these adducts. We found that, unlike its thermal counterpart where the reactivity is dictated by the stereochem., the mech. reactivity is mainly dependent on the regiochem. Remarkably, the thermally active distal-exo adduct becomes inert under tension due to poor mechanochem. coupling.
- 41Boutelle, R. C.; Northrop, B. H. Substituent Effects on the Reversibility of Furan-Maleimide Cycloadditions. J. Org. Chem. 2011, 76, 7994– 8002, DOI: 10.1021/jo201606zGoogle Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOmsbvP&md5=cc7c272bf128aeeb80d220810aef7956Substituent Effects on the Reversibility of Furan-Maleimide CycloadditionsBoutelle, Robert C.; Northrop, Brian H.Journal of Organic Chemistry (2011), 76 (19), 7994-8002CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The effects of furan and maleimide substitution on the dynamic reversibility of their Diels-Alder reactivity have been investigated computationally and by 1H NMR spectroscopy. Furan and furan derivs. bearing methoxy, Me, or formyl groups at their 2- or 3-positions were investigated with maleimide and maleimide derivs. bearing N-Me, N-allyl, and N-Ph substituents. Computational predictions indicate that electronic and regiochem. effects of furan substitution significantly influence their Diels-Alder reactivity with maleimide, with reaction free energies of exo adduct formation ranging from ΔG = -9.4 to 0.9 kcal/mol and transition state barriers to exo adduct formation ranging from ΔG‡ = 18.9 to 25.6 kcal/mol. Much less variation was obsd. for the reactivity of N-substituted maleimide derivs. and furan, with reaction and transition state free energies each falling within a range of 1.1 kcal/mol. Dynamic exchange expts. monitored by 1H NMR spectroscopy support computational predictions. The results indicate the reactivity and reversibility of furan-maleimide cycloaddns. can be tuned significantly through the addn. of appropriate substituents and have implications in the use of furan and maleimide derivs. in the construction of thermally responsive org. materials.
- 42Foster, R. W.; Benhamou, L.; Porter, M. J.; Bučar, D.-K.; Hailes, H. C.; Tame, C. J.; Sheppard, T. D. Irreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-Cantharimides. Chem. - Eur. J. 2015, 21, 6107– 6114, DOI: 10.1002/chem.201406286Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvF2ls7g%253D&md5=555455dd7c3d4c40d74c87a3f5d8fe7eIrreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-CantharimidesFoster, Robert W.; Benhamou, Laure; Porter, Michael J.; Bucar, Dejan-Kresimir; Hailes, Helen C.; Tame, Christopher J.; Sheppard, Tom D.Chemistry - A European Journal (2015), 21 (16), 6107-6114CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The [4+2] cycloaddn. of 3-alkoxyfurans with N-substituted maleimides provides the first general route for prepg. endo-cantharimides [e.g., 3-methoxy-2-(2-phenylethyl)furan + N-methylmaleimide → I (89% yield, 80:20 endo/exo)]. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substituted furans including alkyl, arom., and heteroarom. groups. The cycloaddn. products were converted into a range of cantharimide products with promising lead-like properties for medicinal chem. programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivs. under mild conditions. DFT calcns. have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels-Alder reaction.
- 43Kryger, M. J.; Munaretto, A. M.; Moore, J. S. Structure-Mechanochemical Activity Relationships for Cyclobutane Mechanophores. J. Am. Chem. Soc. 2011, 133, 18992– 18998, DOI: 10.1021/ja2086728Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyjsr7F&md5=252f8108c6f1317a91e0c2865b64d23aStructure-Mechanochemical Activity Relationships for Cyclobutane MechanophoresKryger, Matthew J.; Munaretto, Alexander M.; Moore, Jeffrey S.Journal of the American Chemical Society (2011), 133 (46), 18992-18998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Ultrasound activation of mechanophores embedded in polymer backbones was extensively studied of late as a method for realizing chem. reactions using force. To date, however, there were few attempts at systematically investigating the effects of mechanophore structure upon rates of activation by an acoustic field. Herein, we develop a method for comparing the relative reactivities of various cyclobutane mechanophores. Through the synthesis and ultrasonic irradn. of a mol. wt. series of poly(Me acrylate) polymers in which each macromol. has a single chain-centered mechanophore, we find measurable and statistically significant shifts in mol. wt. thresholds for mechanochem. activation that depend on the structure of the mechanophore. We also show that calcns. based on the constrained geometries simulate external force method reliably predict the trends in mechanophore reactivity. These straightforward calcns. and the exptl. methods described herein may be useful in guiding the design and the development of new mechanophores for targeted applications.
- 44May, P. A.; Munaretto, N. F.; Hamoy, M. B.; Robb, M. J.; Moore, J. S. Is Molecular Weight or Degree of Polymerization a Better Descriptor of Ultrasound-Induced Mechanochemical Transduction?. ACS Macro Lett. 2016, 5, 177– 180, DOI: 10.1021/acsmacrolett.5b00855Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKmsrY%253D&md5=609f5da3274065405bfc464702d997a4Is Molecular Weight or Degree of Polymerization a Better Descriptor of Ultrasound-Induced Mechanochemical Transduction?May, Preston A.; Munaretto, Nicholas F.; Hamoy, Michael B.; Robb, Maxwell J.; Moore, Jeffrey S.ACS Macro Letters (2016), 5 (2), 177-180CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)A detailed understanding of the fundamental processes that govern mech. transduction in covalent polymer mechanochem. is essential to advance innovation in this field. In contrast to progress in the development of new mechanophores, the influence of polymer structure and compn. on mechanochem. activity has received relatively little attention. In order to address this gap in knowledge, a continuous flow system with synchronous UV-vis absorption capabilities was designed to quantify the ultrasound-induced mech. activation of a spiropyran mechanophore in real-time. Measurements of reaction kinetics with polymer tethers of varying repeating unit structure demonstrate that d.p. is the key descriptor of mechanochem. activity, independent of mol. wt. and pendant group constitution. These results have important implications for the rationalization of mechanochem. properties and the design of new mechanochem. active polymer systems.
- 45Schaefer, M.; Icli, B.; Weder, C.; Lattuada, M.; Kilbinger, A. F. M.; Simon, Y. C. The Role of Mass and Length in the Sonochemistry of Polymers. Macromolecules 2016, 49, 1630– 1636, DOI: 10.1021/acs.macromol.5b02362Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWksrg%253D&md5=1543fe09e55603f3e3815156dc053c91The Role of Mass and Length in the Sonochemistry of PolymersSchaefer, Mark; Icli, Burcak; Weder, Christoph; Lattuada, Marco; Kilbinger, Andreas F. M.; Simon, Yoan C.Macromolecules (Washington, DC, United States) (2016), 49 (5), 1630-1636CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The ultrasound-induced cleavage of macromols. has become a routine expt. in the emerging field of polymer mechanochem. To date, it has not been conclusively proven whether the mol. wt. of a polymer or its contour length is the detg. factor for chain scission upon ultrasonication. Here we report comparative expts. that confirm unequivocally that the contour length is the decisive parameter. We utilized postpolymn. modifications of specifically designed precursor polymers to create polymers with identical chain length but different mol. mass. To demonstrate the universality of the findings, two different polymer backbones were utilized-poly(styrene) and poly(norbornene imide alkyne)-whose mol. wts. were altered by bromination and removal of pendant triisopropylsilyl protecting groups, resp. Solns. of the resp. polymer pairs were subjected to pulsed ultrasound at 20 kHz and 10.4 W/cm2 in order to investigate the chain scission trends. The effects of cleavage and sonochem. treatments were monitored by size exclusion chromatog. In both series, exptl. data and calcns. show that the mol. wt. redn. upon sonication is the same for polymers with the same contour length.
- 46Lenhardt, J. M.; Black Ramirez, A. L.; Lee, B.; Kouznetsova, T. B.; Craig, S. L. Mechanistic Insights into the Sonochemical Activation of Multimechanophore Cyclopropanated Polybutadiene Polymers. Macromolecules 2015, 48, 6396– 6403, DOI: 10.1021/acs.macromol.5b01677Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVyntbrO&md5=25afd446a21a52da702b3b9e56343f63Mechanistic Insights into the Sonochemical Activation of Multimechanophore Cyclopropanated Polybutadiene PolymersLenhardt, Jeremy M.; Black Ramirez, Ashley L.; Lee, Bobin; Kouznetsova, Tatiana B.; Craig, Stephen L.Macromolecules (Washington, DC, United States) (2015), 48 (18), 6396-6403CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Structure-activity relationships in the mechanochem. of gem-dichlorocyclopropane (gDCC)-based polymer solns. triggered by pulsed ultrasound are reported. Insights into the flow-induced mechanochem. transformations of gDCC mechanophores into the corresponding 2,3-dichloroalkenes are obtained by monitoring the mechanochem. as a function of initial polymer mol. wt. and sonication conditions. The competition between gDCC activation and polymer chain scission is invariant to sonication power, temp., polymer concn., and solvent but is sensitive to initial polymer mol. wt. The results have practical implications for the use of polymer sonochem. as a tool for quantifying the relative mech. strength of scissile polymers and conceptual implications for thinking about the nature of the force distributions experienced during sonochem. expts.
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Abstract
Scheme 1
Scheme 1. Mechanically Triggered Molecular Release via a Retro-Diels–Alder/Fragmentation CascadeFigure 1
Figure 1. Substituent effects on the reactivity of 2-furylcarbinol derivatives. (a) Structures of model furfuryl carbonates (X = O) and furfuryl carbamates (X = NH) with varying substitution patterns, and (b) corresponding activation energies for fragmentation of the α-C–O bond calculated at the M06-2X/6-311+G** level of density functional theory.
Figure 2
Figure 2. Characterization of the decomposition reactions of model furfuryl carbamates 1 and 2. (a) Decomposition of 1 in MeCN/MeOH (3:1) at room temperature generates fluorescent aminocoumarin 3 and furfuryl methyl ether 4 via a putative furfuryl cation intermediate; (b) partial 1H NMR spectra (400 MHz, CDCl3) demonstrating the clean conversion of 1 to products ([1]0 = 19 μM); (c) time course experiments following the conversion of furfuryl carbamates 1 and 2 by NMR spectroscopy (in 3:1 MeCN-d3/MeOH; [1]0 = 14 mM; [2]0 = 14 mM) and the generation of aminocoumarin 3 by photoluminescence spectroscopy (3:1 MeCN/MeOH; λex = 365 nm; λem = 424 nm; [1]0, [2]0 = 7.6 μM).
Scheme 2
Scheme 2. Synthesis of Poly(methyl acrylate) (PMA) Polymers Containing a Chain-Centered Mechanophore with α-Methyl/Phenoxy Substitution and a Fluorogenic Coumarin PayloadScheme 3
Scheme 3. Ultrasound-Induced Mechanical Activation of Substituted Mechanophores and Release of Fluorescent Hydroxycoumarin or Aminocoumarin CargoaaĐ = 1.03–1.06 for all polymers.
Figure 3
Figure 3. Mechanically triggered release of (a) hydroxycoumarin and (b) aminocoumarin from polymers as a function of mechanophore substitution. Polymer solutions (2 mg/mL in 3:1 MeCN/MeOH) were sonicated for 60 min (“on” time), warmed to room temperature, and the release of coumarin cargo from the mechanically liberated 2-furylcarbinol derivatives was monitored by photoluminescence spectroscopy. PL parameters: λex = 330 nm, λem = 378 nm (hydroxycoumarin); λex = 365 nm, λem = 424 nm (aminocoumarin). The initial PL intensity was subtracted from each measurement and the data were normalized to the plateau value. For PMA-3(NH), the data were normalized assuming 36% mechanophore activation; the black dashed line represents a first-order reaction with a half-life of 240 days.
Scheme 4
Scheme 4. Scope of Mechanically Triggered Cargo Release from the Second-Generation Mechanophore with α-Methyl/Phenoxy SubstitutionaaValues of percent release and half-lives are averages from two replicate experiments. Percent release is reported relative to the initial mechanophore concentration and does not account for incomplete mechanophore conversion after 60 min of ultrasonication. The values of percent release were determined by HPLC.
bHalf-life for cargo release was measured by photoluminescence spectroscopy.
cHalf-life for cargo release was measured by HPLC.
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- 3Patrick, J. F.; Robb, M. J.; Sottos, N. R.; Moore, J. S.; White, S. R. Polymers with autonomous life-cycle control. Nature 2016, 540, 363– 370, DOI: 10.1038/nature210023https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVyru77L&md5=03ce64d6f8646df67e490b5d2af7c20fPolymers with autonomous life-cycle controlPatrick, Jason F.; Robb, Maxwell J.; Sottos, Nancy R.; Moore, Jeffrey S.; White, Scott R.Nature (London, United Kingdom) (2016), 540 (7633), 363-370CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. The lifetime of man-made materials is controlled largely by the wear and tear of everyday use, environmental stress, and unexpected damage, which ultimately lead to failure and disposal. Smart materials that mimic the ability of living systems to autonomously protect, report, heal and even regenerate in response to damage could increase the lifetime, safety and sustainability of many manufd. items. There are several approaches to achieving these functions using polymer-based materials, but making them work in highly variable, real-world situations is proving challenging.
- 4Lee, K. Y.; Peters, M. C.; Mooney, D. J. Controlled Drug Delivery from Polymers by Mechanical Signals. Adv. Mater. 2001, 13, 837– 839, DOI: 10.1002/1521-4095(200106)13:11<837::AID-ADMA837>3.0.CO;2-D4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksFKqsbY%253D&md5=45ecda5bf5ffb38aa80d0bb1b1e60d34Controlled drug delivery from polymers by mechanical signalsLee, Kuen Yong; Peters, Martin C.; Mooney, David J.Advanced Materials (Weinheim, Germany) (2001), 13 (11), 837-839CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH)It was hypothesized that the interaction of drug mols. with the polymers used for controlled drug delivery might play a crit. role in mediating drug delivery in response to mech. signals. To test this hypothesis, three different model drugs were incorporated into alginate hydrogels, i.e., trypan blue, methylene blue, and vascular endothelial growth factor (VEGF). The effect of mech. signals on drug release from polymers was examd. using these model drugs. Mech. signals were not able to significantly alter the cumulative release of trypan blue, possibly due to the relatively rapid depletion from alginate hydrogel blue to its low mol. wt. and the lack of the interaction with the hydrogel. Due to the stronger interaction with alginate, the release rate and the overall cumulative release of methylene blue was more dependent on mech. signaling than those of trypan blue. The release rate of VEGF under mech. signaling increased up to six times higher than that of control gels. Mech. signals can actively trigger the release of interactive drugs, e.g., peptides or proteins, from polymers in a controlled manner over time, suggesting a means to design advanced materials suitable for general drug-delivery applications and tissue engineering applications.
- 5Huo, S.; Zhao, P.; Shi, Z.; Zou, M.; Yang, X.; Warszawik, E.; Loznik, M.; Göstl, R.; Herrmann, A. Mechanochemical bond scission for the activation of drugs. Nat. Chem. 2021, 13, 131– 139, DOI: 10.1038/s41557-020-00624-85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjtVWqtbo%253D&md5=6510a298ed7765c6bc8709c91cf34aa9Mechanochemical bond scission for the activation of drugsHuo, Shuaidong; Zhao, Pengkun; Shi, Zhiyuan; Zou, Miancheng; Yang, Xintong; Warszawik, Eliza; Loznik, Mark; Gostl, Robert; Herrmann, AndreasNature Chemistry (2021), 13 (2), 131-139CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Pharmaceutical drug therapy is often hindered by issues caused by poor drug selectivity, including unwanted side effects and drug resistance. Spatial and temporal control over drug activation in response to stimuli is a promising strategy to attenuate and circumvent these problems. Here we use ultrasound to activate drugs from inactive macromols. or nano-assemblies through the controlled scission of mechanochem. labile covalent bonds and weak non-covalent bonds. We show that a polymer with a disulfide motif at the center of the main chain releases an alkaloid-based anticancer drug from its β-carbonate linker by a force-induced intramol. 5-exo-trig cyclization. Second, aminoglycoside antibiotics complexed by a multi-aptamer RNA structure are activated by the mechanochem. opening and scission of the nucleic acid backbone. Lastly, nanoparticle-polymer and nanoparticle-nanoparticle assemblies held together by hydrogen bonds between the peptide antibiotic vancomycin and its complementary peptide target are activated by force-induced scission of hydrogen bonds. This work demonstrates the potential of ultrasound to activate mechanoresponsive prodrug systems. [graphic not available: see fulltext].
- 6Küng, R.; Pausch, T.; Rasch, D.; Göstl, R.; Schmidt, B. M. Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage. Angew. Chem., Int. Ed. 2021, 60, 13626– 13630, DOI: 10.1002/anie.2021023836https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCktrvI&md5=76865e50e6afbd97ed3335d210bc894dMechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular CageKueng, Robin; Pausch, Tobias; Rasch, Dustin; Goestl, Robert; Schmidt, Bernd M.Angewandte Chemie, International Edition (2021), 60 (24), 13626-13630CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Supramol. coordination cages show a wide range of useful properties including, but not limited to, complex mol. machine-like operations, confined space catalysis, and rich host-guest chemistries. Here we report the uptake and release of non-covalently encapsulated, pharmaceutically-active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)-decorated bipyridine ligands are used to assemble an octahedral PdII6(TPT)4 cage. The supramol. container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aq. soln. entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.
- 7White, 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, DOI: 10.1038/350572327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFCjsbg%253D&md5=6c89d4c4b2c83453a81f2a0a99854c4eAutonomic healing of polymer compositesWhite, S. R.; Sottos, N. R.; Geubelle, P. H.; Moore, J. S.; Kessler, M. R.; Sriram, S. R.; Brown, E. N.; Viswanathan, S.Nature (London, United Kingdom) (2001), 409 (6822), 794-797CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mech. degrdn. of fiber-reinforced polymer composites; in microelectronic polymeric components it can also lead to elec. failure. Microcracking induced by thermal and mech. fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Expts. exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here, a structural polymeric material with the ability to autonomically heal cracks is reported. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymn. of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. The fracture expts. yield as much as 75% recovery in toughness, and the approach may be applicable to other brittle materials systems (including ceramics and glasses).
- 8Toohey, K. S.; Sottos, N. R.; Lewis, J. A.; Moore, J. S.; White, S. R. Self-healing materials with microvascular networks. Nat. Mater. 2007, 6, 581– 585, DOI: 10.1038/nmat19348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVShu7s%253D&md5=8df7bc545204a8fa59eed8e088a6577cSelf-healing materials with microvascular networksToohey, Kathleen S.; Sottos, Nancy R.; Lewis, Jennifer A.; Moore, Jeffrey S.; White, Scott R.Nature Materials (2007), 6 (8), 581-585CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Self-healing polymers composed of microencapsulated healing agents exhibit remarkable mech. performance and regenerative ability, but are limited to autonomic repair of a single damage event in a given location. Self-healing is triggered by crack-induced rupture of the embedded capsules; thus, once a localized region is depleted of healing agent, further repair is precluded. Re-mendable polymers can achieve multiple healing cycles, but require external intervention in the form of heat treatment and applied pressure. Here, we report a self-healing system capable of autonomously repairing repeated damage events. Our bio-inspired coating-substrate design delivers healing agent to cracks in a polymer coating via a three-dimensional microvascular network embedded in the substrate. Crack damage in the epoxy coating is healed repeatedly. This approach opens new avenues for continuous delivery of healing agents for self-repair as well as other active species for addnl. functionality.
- 9Li, J.; Nagamani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive to Productive. Acc. Chem. Res. 2015, 48, 2181– 2190, DOI: 10.1021/acs.accounts.5b001849https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyqs7%252FO&md5=f79b0417f88f2a70997f583ba4f190cdPolymer Mechanochemistry: From Destructive to ProductiveLi, Jun; Nagamani, Chikkannagari; Moore, Jeffrey S.Accounts of Chemical Research (2015), 48 (8), 2181-2190CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. When one brings "polymeric materials" and "mech. action" into the same conversation, the topic of this discussion might naturally focus on everyday circumstances such as failure of fibers, fatigue of composites, abrasion of coatings, etc. This intuitive viewpoint reflects the historic consensus in both academia and industry that mech. induced chem. changes are destructive, leading to polymer degrdn. that limits materials lifetime on both macroscopic and mol. levels. In the 1930s, Staudinger obsd. mech. degrdn. of polymers, and Melville later discovered that polymer chain scission caused the degrdn. Inspired by these historical observations, we sought to redirect the destructive mech. energy to a productive form that enables mechanoresponsive functions. In this Account, we provide a personal perspective on the origin, barriers, developments, and key advancements of polymer mechanochem. We revisit the seminal events that offered mol.-level insights into the mechanochem. behavior of polymers and influenced our thinking. We also highlight the milestones achieved by our group along with the contributions from key comrades at the frontier of this field. We present a workflow for the design, evaluation, and development of new "mechanophores", a term that has come to mean a mol. unit that chem. responds in a selective manner to a mech. perturbation. We discuss the significance of computation in identifying pairs of points on the mechanophore that promote stretch-induced activation. Attaching polymer chains to the mechanophore at the most sensitive pair and locating the mechanophore near the center of a linear polymer are thought to maximize the efficiency of mech.-to-chem. energy transduction. We also emphasize the importance of control expts. to validate mechanochem. transformations, both in soln. and in the solid state, to differentiate "mech." from "thermal" activation. This Account offers our first-hand perspective of the change-in-thinking in polymer mechanochem. from "destructive" to "productive" and looks at future advances that will stimulate this growing field.
- 10Beyer, M. K.; Clausen-Schaumann, H. Mechanochemistry: The Mechanical Activation of Covalent Bonds. Chem. Rev. 2005, 105, 2921– 2948, DOI: 10.1021/cr030697h10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmtlSntLw%253D&md5=2d29a87023af58392e0b9c98297ef313Mechanochemistry: The Mechanical Activation of Covalent BondsBeyer, Martin K.; Clausen-Schaumann, HaukeChemical Reviews (Washington, DC, United States) (2005), 105 (8), 2921-2948CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review of the classical works in mechanochem. The key mechanochem. phenomena are into perspective with recent results from at. force microscopy and quantum mol. dynamics simulations. Mechanochem. is an established field in material science and solid-state chem. The review is restricted mostly to those mechanochem. phenomena, where identifiable strong, covalent chem. bonds are activated by the presence of an external mech. force.
- 11Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials. Chem. Rev. 2009, 109, 5755– 5798, DOI: 10.1021/cr900135311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvK&md5=bae0e40d8fd4637ff652dba4c4dbbe40Mechanically-Induced Chemical Changes in Polymeric MaterialsCaruso, Mary M.; Davis, Douglas A.; Shen, Qilong; Odom, Susan A.; Sottos, Nancy R.; White, Scott R.; Moore, Jeffrey S.Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5755-5798CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the chem. changes that accompany polymeric materials subjected to mech. stimuli. The review is organized by the length scale over which the chem. change takes place.
- 12Kim, G.; Lau, V. M.; Halmes, A. J.; Oelze, M. L.; Moore, J. S.; Li, K. C. High-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 10214– 10222, DOI: 10.1073/pnas.190104711612https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFOkurs%253D&md5=a1fdcf4a548eeb200ef6c5418b7a744eHigh-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomersKim, Gun; Lau, Vivian M.; Halmes, Abigail J.; Oelze, Michael L.; Moore, Jeffrey S.; Li, King C.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (21), 10214-10222CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)While study in the field of polymer mechanochem. has yielded mechanophores that perform various chem. reactions in response to mech. stimuli, there is not yet a triggering method compatible with biol. systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mech.-to-chem. transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochem. reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradn. evidence of the mechanochem. transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradn. successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradn. provides spatiotemporal control of the mechanochem. activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.
- 13Akbulatov, S.; Boulatov, R. Experimental polymer mechanochemistry and its interpretational frameworks. ChemPhysChem 2017, 18, 1422– 1450, DOI: 10.1002/cphc.20160135413https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFShsrY%253D&md5=3b477b6950260ed6aab21b3168ae0f4aExperimental Polymer Mechanochemistry and its Interpretational FrameworksAkbulatov, Sergey; Boulatov, RomanChemPhysChem (2017), 18 (11), 1422-1450CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Polymer mechanochem. is an emerging field at the interface of chem., materials science, physics and engineering. It aims at understanding and exploiting unique reactivities of polymer chains confined to highly non-equil. stretched geometries by interactions with their surroundings. Macromol. chains or their segments become stretched in bulk polymers under mech. loads or when polymer solns. are sonicated or flow rapidly through abrupt contractions. An increasing amt. of empirical data suggests that mechanochem. phenomena are widespread wherever polymers are used. In the past decade, empirical mechanochem. has progressed enormously, from studying fragmentations of commodity polymers by simple backbone homolysis to demonstrations of self-strengthening and stress-reporting materials and mechanochem. cascades using purposefully designed monomers. This progress has not yet been matched by the development of conceptual frameworks within which to rationalize, systematize and generalize empirical mechanochem. observations. As a result, mechanistic and/or quant. understanding of mechanochem. phenomena remains, with few exceptions, tentative. In this review, we aim at systematizing reported macroscopic manifestations of polymer mechanochem., and critically assessing the interpretational framework that underlies their mol. rationalizations from a phys. chemist's perspective. We propose a hierarchy of mechanochem. phenomena which may guide the development of multiscale models of mechanochem. reactivity to match the breadth and utility of the Eyring equation of chem. kinetics. We discuss the limitations of the approaches to quantifying and validating mechanochem. reactivity, with particular focus on sonicated polymer solns., in order to identify outstanding questions that need to be solved for polymer mechanochem. to become a rigorous, quant. field. We conclude by proposing 7 problems whose soln. may have a disproportionate impact on the development of polymer mechanochem.
- 14Diesendruck, 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, DOI: 10.1021/ja305645x14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVKlu7g%253D&md5=d5f3da927570764cb6015e3738d3e338Proton-Coupled Mechanochemical Transduction: A Mechanogenerated AcidDiesendruck, Charles E.; Steinberg, Brian D.; Sugai, Naoto; Silberstein, Meredith N.; Sottos, Nancy R.; White, Scott R.; Braun, Paul V.; Moore, Jeffrey S.Journal of the American Chemical Society (2012), 134 (30), 12446-12449CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel mechanophore with acid-releasing capability is designed to produce a simple catalyst for chem. change in materials under mech. stress. The mechanophore, based on a gem-dichlorocyclopropanated indene, is synthesized and used as a cross-linker in poly(Me acrylate). Force-dependent rearrangement is demonstrated for cross-linked mechanophore samples loaded in compression, while the control shows no significant response. The availability of the released acid is confirmed by exposing a piece of insol. compressed polymer to a pH indicator soln. The development of this new mechanophore is the first step toward force-induced remodeling of stressed polymeric materials utilizing acid-catalyzed crosslinking reactions.
- 15Lin, Y.; Kouznetsova, T. B.; Craig, S. L. A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials. J. Am. Chem. Soc. 2020, 142, 99– 103, DOI: 10.1021/jacs.9b1286115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVyitLrI&md5=b7a6c0decebe1477b3dddd5dd1861b57A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric MaterialsLin, Yangju; Kouznetsova, Tatiana B.; Craig, Stephen L.Journal of the American Chemical Society (2020), 142 (1), 99-103CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mech. coupled proton transduction offers potential for stress-responsive polymeric materials whose properties can be switched via acid-triggered coloration, polymn./crosslinking, or degrdn. The utility of currently available mechanoacids, however, is limited by modest force-free stability or a scissile response that caps mechanoacid generation at one proton per strained polymer chain. Here, the authors report a new mechanoacid based on 2-methoxy-substituted gem-dichlorocyclopropane (MeO-gDCC). Pulsed ultrasonication leads to the mechanochem. ring opening of the MeO-gDCC and the subsequent elimination of either HCl or MeCl, with ∼0.58 equiv of HCl released per mechanophore activation and ∼67 protons per chain scission event. Single-mol. force spectroscopy reveals that the methoxy substituent lowers the force required for rapid (kopen ∼102 s-1) ring opening to ca. 900 pN, vs 1300 pN required for the parent gDCC. The utility of the mechanoacid is demonstrated in silicone elastomers, where its mech. activation leads to a strain-triggered color change prior to fracture of the elastomer. The post activation kinetics of coloration are used to demonstrate a new concept in mechanochromism, namely, a spectroscopic indicator of not only whether and where a mech. event has occurred but when it occurred.
- 16Larsen, M. B.; Boydston, A. J. Flex-Activated” Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am. Chem. Soc. 2013, 135, 8189– 8192, DOI: 10.1021/ja403757p16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFyisb4%253D&md5=e4d08119d68aaa100452814ef1a1ad58"Flex-Activated" Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending ActivationLarsen, Michael B.; Boydston, Andrew J.Journal of the American Chemical Society (2013), 135 (22), 8189-8192CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We describe studies in mechanochem. transduction that probe the activation of bonds orthogonal to an elongated polymer main chain. Compression of mechanophore-crosslinked materials resulted in the release of small mols. via cleavage of covalent bonds that were not integral components of the elongated polymer segments. The reactivity is proposed to arise from the distribution of force through the crosslinking units of the polymer network and subsequent bond bending motions that are consistent with the geometric changes in the overall reaction. This departure from contemporary polymer mechanochem., in which activation is achieved primarily by force-induced bond elongation, is a first step toward mechanophores capable of releasing side-chain functionalities without inherently compromising the overall macromol. architecture.
- 17Larsen, M. B.; Boydston, A. J. Successive Mechanochemical Activation and Small Molecule Release in an Elastomeric Material. J. Am. Chem. Soc. 2014, 136, 1276– 1279, DOI: 10.1021/ja411891x17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotVequw%253D%253D&md5=756d3c176befc893e78bfbb236786abdSuccessive Mechanochemical Activation and Small Molecule Release in an Elastomeric MaterialLarsen, Michael B.; Boydston, Andrew J.Journal of the American Chemical Society (2014), 136 (4), 1276-1279CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The authors have developed a mechanochem. responsive material capable of successively releasing small org. mols. from a cross-linked network upon repeated compressions. The use of a flex activated mechanophore that does not lead to main chain scission and an elastomeric polyurethane enabled consecutive compressions with incremental increases in the % mechanophore activation. Addnl., the authors examd. the effect of multiple applications of compressive stress on both mechanophore activity and the mech. behavior of the elastomeric matrix in which the mechanophore is embedded.
- 18Shen, H.; Larsen, M. B.; Roessler, A.; Zimmerman, P.; Boydston, A. J. Mechanochemical Release of N-heterocyclic Carbenes from Flex-Activated Mechanophores. Angew. Chem., Int. Ed. 2021, 60, 13559, DOI: 10.1002/anie.20210057618https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCrtLnJ&md5=8cd573f15cde8622c004c3ff28898fa7Mechanochemical Release of N-Heterocyclic Carbenes from Flex-Activated MechanophoresShen, Hang; Larsen, Michael B.; Roessler, Allison G.; Zimmerman, Paul M.; Boydston, Andrew J.Angewandte Chemie, International Edition (2021), 60 (24), 13559-13563CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have discovered a new flex-activated mechanophore that releases an N-heterocyclic carbene (NHC) under mech. load. The mechanophore design is based upon NHC-carbodiimide (NHC-CDI) adducts and demonstrates an important first step toward flex-activated designs capable of further downstream reactivities. Since the flex-activation is non-destructive to the main polymer chains, the material can be subjected to multiple compression cycles to achieve iterative increases in the activation percentage of mechanophores. Two different NHC structures were demonstrated, signifying the potential modularity of the mechanophore design.
- 19Diesendruck, 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-temperature polymer. Nat. Chem. 2014, 6, 623– 628, DOI: 10.1038/nchem.193819https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvFSjtrk%253D&md5=4134bc74bd65deca7c5ce7a6388ab7d1Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymerDiesendruck, Charles E.; Peterson, Gregory I.; Kulik, Heather J.; Kaitz, Joshua A.; Mar, Brendan D.; May, Preston A.; White, Scott R.; Martinez, Todd J.; Boydston, Andrew J.; Moore, Jeffrey S.Nature Chemistry (2014), 6 (7), 623-628CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Biol. systems rely on recyclable materials resources such as amino acids, carbohydrates and nucleic acids. When biomaterials are damaged as a result of aging or stress, tissues undergo repair by a depolymn.-repolymn. sequence of remodelling. Integration of this concept into synthetic materials systems may lead to devices with extended lifetimes. Here, we show that a metastable polymer, end-capped poly(o-phthalaldehyde), undergoes mech. initiated depolymn. to revert the material to monomers. Trapping expts. and steered mol. dynamics simulations are consistent with a heterolytic scission mechanism. The obtained monomer was repolymd. by a chem. initiator, effectively completing a depolymn.-repolymn. cycle. By emulating remodelling of biomaterials, this model system suggests the possibility of smart materials where aging or mech. damage triggers depolymn., and orthogonal conditions regenerate the polymer when and where necessary.
- 20Peterson, G. I.; Boydston, A. J. Kinetic Analysis of Mechanochemical Chain Scission of Linear Poly(phthalaldehyde). Macromol. Rapid Commun. 2014, 35, 1611– 1614, DOI: 10.1002/marc.20140027120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisbnP&md5=ad8179456e878f6800b0ffbf6b264720Kinetic Analysis of Mechanochemical Chain Scission of Linear Poly(phthalaldehyde)Peterson, Gregory I.; Boydston, Andrew J.Macromolecular Rapid Communications (2014), 35 (18), 1611-1614CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)The kinetics of mechanochem. chain scission of poly(phthalaldehyde) (PPA) are investigated. Ultrasound-induced cavitation is capable of causing chain scission in the PPA backbone that ultimately leads to rapid depolymn. of each resulting polymer fragment when above the polymer's ceiling temp. (Tc). An interesting feature of the mechanochem. breakdown of PPA is that "half-chain" daughter fragments are not obsd., since the depolymn. is rapid following chain scission. These features facilitate the detn. of rate consts. of activation for multiple mol. wts. from a single sonication expt. Addnl., the degrdn. kinetics are modified with chain-end trapping agents through variation of the nature and amt. of small mol. nucleophile or electrophile.
- 21Wiita, A. P.; Ainavarapu, S. R. K.; Huang, H. H.; Fernandez, J. M. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 7222– 7227, DOI: 10.1073/pnas.051103510321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslOktb0%253D&md5=b1894f1e85ea785b5d56d45114e6a0e1Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniquesWiita, Arun P.; Ainavarapu, Rama Koti; Huang, Hector H.; Fernandez, Julio M.Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (19), 7222-7227CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The mechanism by which mech. force regulates the kinetics of a chem. reaction is unknown. Here, we use single-mol. force-clamp spectroscopy and protein engineering to study the effect of force on the kinetics of thiol/disulfide exchange. Redn. of disulfide bonds through the thiol/disulfide exchange chem. reaction is crucial in regulating protein function and is known to occur in mech. stressed proteins. We apply a const. stretching force to single engineered disulfide bonds and measure their rate of redn. by DTT. Although the redn. rate is linearly dependent on the concn. of DTT, it is exponentially dependent on the applied force, increasing 10-fold over a 300-pN range. This result predicts that the disulfide bond lengthens by 0.34 Å at the transition state of the thiol/disulfide exchange reaction. Our work at the single bond level directly demonstrates that thiol/disulfide exchange in proteins is a force-dependent chem. reaction. Our findings suggest that mech. force plays a role in disulfide redn. in vivo, a property that has never been explored by traditional biochem. Furthermore, our work also indicates that the kinetics of any chem. reaction that results in bond lengthening will be force-dependent.
- 22Dopieralski, P.; Ribas-Arino, J.; Anjukandi, P.; Krupicka, M.; Marx, D. Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution. Nat. Chem. 2017, 9, 164– 170, DOI: 10.1038/nchem.263222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCgtbjJ&md5=7d7aada474084ac849905dec4cf01337Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solutionDopieralski, Przemyslaw; Ribas-Arino, Jordi; Anjukandi, Padmesh; Krupicka, Martin; Marx, DominikNature Chemistry (2017), 9 (2), 164-170CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)The redn. of disulfides has a broad importance in chem., biochem. and materials science, particularly those methods that use mechanochem. activation. Here the authors show, using isotensional simulations, that strikingly different mechanisms govern disulfide cleavage depending on the external force. Desolvation and resolvation processes are crucial, as they have a direct impact on activation free energies. The preferred pathway at moderate forces, a bimol. SN2 attack of OH- at sulfur, competes with unimol. C-S bond rupture at ∼2 nN, and the latter even becomes barrierless at greater applied forces. Also, study unveils a surprisingly rich reactivity scenario that also includes the transformation of concerted SN2 reactions into pure bond-breaking processes at specific forces. Given that these forces are easily reached in expts., these insights will fundamentally change understanding of mechanochem. activation in general, which is now expected to be considerably more intricate than previously thought.
- 23Shi, Z.; Song, Q.; Göstl, R.; Herrmann, A. Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug release. Chem. Sci. 2021, 12, 1668, DOI: 10.1039/D0SC06054B23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1SgsL3N&md5=ce3ffb162231ee37b948794e44139ea9Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug releaseShi, Zhiyuan; Song, Qingchuan; Goestl, Robert; Herrmann, AndreasChemical Science (2021), 12 (5), 1668-1674CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Drug delivery systems responsive to physicochem. stimuli allow spatiotemporal control over drug activity to overcome limitations of systemic drug administration. Alongside, the non-invasive real-time tracking of drug release and uptake remains challenging as pharmacophore and reporter function are rarely unified within one mol. Here, we present an ultrasound-responsive release system based on the mechanochem. induced 5-exo-trig cyclization upon scission of disulfides bearing cargo mols. attached via β-carbonate linker within the center of a water sol. polymer. In this bifunctional theranostic approach, we release one reporter mol. per drug mol. to quant. track drug release and distribution within the cell in real-time. We use N-butyl-4-hydroxy-1,8-naphthalimide and umbelliferone as fluorescent reporter mols. to accompany the release of camptothecin and gemcitabine as clin. employed anticancer agents. The generality of this approach paves the way for the theranostic release of a variety of probes and drugs by ultrasound.
- 24Shi, Z. Ultrasound-mediated activation of drugs. Ph.D. Dissertation, RWTH Aachen University, Aachen, Germany, 2021. https://publications.rwth-aachen.de/record/814605 (accessed 2021-05-07).There is no corresponding record for this reference.
- 25Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate. J. Am. Chem. Soc. 2019, 141, 15018– 15023, DOI: 10.1021/jacs.9b0866325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslKisbjI&md5=5b335054eb92d57bf90338ab96dbb10aMechanically Triggered Small Molecule Release from a Masked Furfuryl CarbonateHu, Xiaoran; Zeng, Tian; Husic, Corey C.; Robb, Maxwell J.Journal of the American Chemical Society (2019), 141 (38), 15018-15023CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Stimuli-responsive polymers that release small mols. under mech. stress are appealing targets for applications ranging from drug delivery to sensing. Here, we describe a modular mechanophore design platform for mol. release via a mech. triggered cascade reaction. Mechanochem. activation of a furan-maleimide Diels-Alder adduct reveals a latent furfuryl carbonate that subsequently decomps. under mild conditions to release a covalently bound cargo mol. The computationally guided design of a reactive secondary furfuryl carbonate enables the decompn. and release to proceed quickly at room temp. after unmasking via mech. force. This general strategy is demonstrated using ultrasound-induced mech. activation to release a fluorogenic coumarin payload from a polymer incorporating a chain-centered mechanophore.
- 26Hay, M. P.; Sykes, B. M.; Denny, W. A.; O’Connor, C. J. Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs. J. Chem. Soc., Perkin Trans. 1 1999, (19), 2759– 2770, DOI: 10.1039/a904067f26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtVGmt7s%253D&md5=ca10f19fbbdaa8ec6ccd4390be961515Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugsHay, Michael P.; Sykes, Bridget M.; Denny, William A.; O'Connor, Charmian J.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1999), (19), 2759-2770CODEN: JCPRB4; ISSN:0300-922X. (Royal Society of Chemistry)4-Nitrobenzyl carbamates are of interest as triggers for bioreductive drugs, particularly in conjunction with the E. coli B nitroreductase, which efficiently reduces them to the corresponding hydroxylamines. These then fragment to release highly toxic amine-based toxins. While many 4-nitrobenzyl carbamate derivs. have been evaluated as bioreductive drugs, there has been no systematic study of substituent effects on the rate of this fragmentation (which should be as fast as possible following redn.). We therefore prepd. a series of 2-, 3- and α-substituted 4-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]phenylacetamides as model compds. to study these effects. The majority of the carbamates were prepd. by in situ formation of the chloroformate of the appropriate 4-nitrobenzyl alc. and reaction with Me 4-(methylamino)phenylacetate, followed by ester hydrolysis and 1,1'-carbonyldiimidazole (CDI) mediated coupling with N,N-dimethylaminoethylamine. The hydroxylamines were generated by 60Co γ-ray irradn. of the nitro compds. in aq. phosphate-buffered propan-2-ol. The reactions were analyzed by reverse-phase HPLC to det. the max. half-life (Mt1/2) of the hydroxylamines generated, and the extent of release of amine from these after 10 half-lives (t∞). The parent (unsubstituted) hydroxylaminobenzyl carbamate had a Mt1/2 of 16 min under these conditions, while that of the corresponding α-Me analog was 9.5 min. Electron-donating substituents on the benzyl ring also accelerated fragmentation, with the data being fitted to the equation log(Mt1/2) = 0.57σ + 1.30, where σ represents σp for 2-substituents and σm for 3-substituents. The acceleration of fragmentation of the hydroxylamines with increasing substituent electron-donation is consistent with the proposed mechanism, and is presumably due to stabilization of the developing pos. charge on the benzylic carbon. The extent of release of amine (t∞) also increased with increasing substituent electron-donation. These data suggest that the std. 4-nitrobenzyl carbamate trigger for nitroreductase enzyme (NTR) prodrugs can likely be improved on, by increasing the rate of fragmentation by the use of α-Me and/or electron-donating benzyl substituents.
- 27Mosey, R. A.; Floreancig, P. E. Versatile approach to α-alkoxy carbamate synthesis and stimulus-responsive alcohol release. Org. Biomol. Chem. 2012, 10, 7980– 7985, DOI: 10.1039/c2ob26571k27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2htb3O&md5=5907239a71b4ba0b2a9aee0c61dad003Versatile approach to α-alkoxy carbamate synthesis and stimulus-responsive alcohol releaseMosey, R. Adam; Floreancig, Paul E.Organic & Biomolecular Chemistry (2012), 10 (39), 7980-7985CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A series of α-alkoxy carbamates that cleave under mild conditions to release alcs. has been synthesized through a multicomponent process. The relationship between structural features in these compds. and the rate of alc. release in the presence of basic hydrogen peroxide has been studied. The prepn. of carbamates that cleave under other conditions has been demonstrated. The prepn. of α-alkoxy carbamates involved a sequence of nitrile hydrozirconation, acylation, and alc. addn. E.g., hydrozirconation of Me3CCN with Cp2Zr(H)Cl, followed by reaction with chloroformate I and addn. of neopentyl alc. gave α-alkoxy carbamate (II). Treatment of the latter with urea.H2O2 led to release of neopentyl alc.
- 28Wang, J.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L. Mechanical gating of a mechanochemical reaction cascade. Nat. Commun. 2016, 7, 13433, DOI: 10.1038/ncomms1343328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVygu7zM&md5=b5927e373fa2420dde7cdacf687a21baMechanical gating of a mechanochemical reaction cascadeWang, Junpeng; Kouznetsova, Tatiana B.; Boulatov, Roman; Craig, Stephen L.Nature Communications (2016), 7 (), 13433pp.CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Covalent polymer mechanochem. offers promising opportunities for the control and engineering of reactivity. To date, covalent mechanochem. has largely been limited to individual reactions, but it also presents potential for intricate reaction systems and feedback loops. Here we report a mol. architecture, in which a cyclobutane mechanophore functions as a gate to regulate the activation of a second mechanophore, dichlorocyclopropane, resulting in a mechanochem. cascade reaction. Single-mol. force spectroscopy, pulsed ultrasonication expts. and DFT-level calcns. support gating and indicate that extra force of >0.5 nN needs to be applied to a polymer of gated gDCC than of free gDCC for the mechanochem. isomerization gDCC to proceed at equal rate. The gating concept provides a mechanism by which to regulate stress-responsive behaviors, such as load-strengthening and mechanochromism, in future materials designs.
- 29Hu, X.; McFadden, M. E.; Barber, R. W.; Robb, M. J. Mechanochemical Regulation of a Photochemical Reaction. J. Am. Chem. Soc. 2018, 140, 14073– 14077, DOI: 10.1021/jacs.8b0962829https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFeqsLbO&md5=2af17aef65e04a91bc27e984a0a9f5fdMechanochemical Regulation of a Photochemical ReactionHu, Xiaoran; McFadden, Molly E.; Barber, Ross W.; Robb, Maxwell J.Journal of the American Chemical Society (2018), 140 (43), 14073-14077CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We introduce the concept of mechanochem. gated photoswitching. Mech. regulation of a photochem. reaction is exemplified using a newly designed mechanophore based on a cyclopentadiene-maleimide Diels-Alder adduct. Ultrasound-induced mech. activation of the photochem. inert mechanophore in polymers generates a diarylethene photoswitch via a retro-[4 + 2] cycloaddn. reaction that photoisomerizes between colorless and colored states upon exposure to UV and visible light. Control expts. demonstrate the thermal stability of the cyclopentadiene-maleimide adduct and confirm the mech. origin of the "unlocked" photochromic reactivity. This technol. holds promise for applications such as lithog. and stress-sensing, enabling the mech. history of polymeric materials to be recorded and read on-demand.
- 30Fan, 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, DOI: 10.1039/C7CC06410A30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aksb3I&md5=6de1e6447f10d080a568a34f0f01db2aThermo-responsive self-immolative nanoassemblies: direct and indirect triggeringFan, Bo; Trant, John F.; Hemery, Gauvin; Sandre, Olivier; Gillies, Elizabeth R.Chemical Communications (Cambridge, United Kingdom) (2017), 53 (89), 12068-12071CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A thermo-responsive end-cap based on a retro-Diels-Alder and subsequent furan elimination reaction was developed. It was used to cap poly(Et glyoxylate), allowing end-to-end depolymn. upon thermal triggering. Using block copolymers, thermo-responsive micelles and vesicles were prepd. and shown to disassemble upon heating. Thermal degrdn. could also be triggered indirectly by magnetic field hyperthermia after incorporation of iron oxide nanoparticles into the assemblies.
- 31Schmid, K. M.; Jensen, L.; Phillips, S. T. A Self-Immolative Spacer That Enables Tunable Controlled Release of Phenols under Neutral Conditions. J. Org. Chem. 2012, 77, 4363– 4374, DOI: 10.1021/jo300400q31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xltl2hu70%253D&md5=b0bb0447e0dccf2d26bb12b2c08ed596A Self-Immolative Spacer That Enables Tunable Controlled Release of Phenols under Neutral ConditionsSchmid, Kyle M.; Jensen, Lasse; Phillips, Scott T.Journal of Organic Chemistry (2012), 77 (9), 4363-4374CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A current challenge in the area of responsive materials is the design of reagents and polymers that provide controlled release of phenols in environments that are less polar than water. In these contexts, a mol. strategy that enables release of nearly any phenol with predictable and tunable rates and without complication from background hydrolysis would substantially increase the precision with which materials can be designed to respond to a particular signal. This Article addresses this problem at the fundamental level by describing the design, synthesis, and phys.-org. characterization of two small mol. self-immolative spacers that are capable of releasing phenols in org. and mixed org.-aq. solns. The rate of release from these small mol. model systems is predictable and tunable, such that nearly any type of phenol, regardless of pKa value, can be released in neutral solns. without complications from nonspecific background release due to hydrolysis. Furthermore, the release properties of the spacers can be predicted from bond length and conformation data (obtained from crystal structures). On the basis of these results, it should now be possible to incorporate these design elements into materials to enable precise response properties in environments that are not 100% aq.
- 32Nichol, M. F.; Clark, K. D.; Dolinski, N. D.; Read de Alaniz, J. Multi-stimuli responsive trigger for temporally controlled depolymerization of self-immolative polymers. Polym. Chem. 2019, 10, 4914– 4919, DOI: 10.1039/C9PY00301K32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFKisr3E&md5=26c59341e6cb081ab852a96cc7efc58bMulti-stimuli responsive trigger for temporally controlled depolymerization of self-immolative polymersNichol, Meghan F.; Clark, Kyle D.; Dolinski, Neil D.; Read de Alaniz, JavierPolymer Chemistry (2019), 10 (36), 4914-4919CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)For many decades, stimuli-responsive materials have been studied and utilized in various fields, ranging from chem. sensors to controlled drug release. Among these responsive materials are self-immolative polymers (SIPs) that allow for end-to-end depolymn. and the ability to release a desired cargo on demand or amplify analyte detection. However, in typical SIP systems, the triggering event leads to a relatively uncontrolled degrdn. process. Herein we present a multi-stimuli trigger that utilizes the combination of heat and acid to impart control over the trigger event and thus the degrdn. process. By controlling this reaction, we achieve temporal control over the trigger cleavage and subsequent depolymn. and release of cargo from the SIP.
- 33Alouane, A.; Labruère, R.; Le Saux, T.; Schmidt, F.; Jullien, L. Self-Immolative Spacers: Kinetic Aspects, Structure-Property Relationships, and Applications. Angew. Chem., Int. Ed. 2015, 54, 7492– 7509, DOI: 10.1002/anie.20150008833https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXps1eguro%253D&md5=fe98dd1aff7066a9a58073ee3c57f688Self-immolative spacers: kinetic aspects, structure-property relationships, and applicationsAlouane, Ahmed; Labruere, Raphael; Le Saux, Thomas; Schmidt, Frederic; Jullien, LudovicAngewandte Chemie, International Edition (2015), 54 (26), 7492-7509CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chem. bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller mols. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chem., anal. chem., and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic expts. and fully exploit the rich perspectives of self-immolative spacers.
- 34Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. Ultrasound-Induced Site-Specific Cleavage of Azo-Functionalized Poly(ethylene glycol). Macromolecules 2005, 38, 8975– 8978, DOI: 10.1021/ma051394n34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVeht73P&md5=4251e187f5a324bd20b2de4aff6f4dc2Ultrasound-induced site-specific cleavage of azo-functionalized poly(ethylene glycol)Berkowski, Kimberly L.; Potisek, Stephanie L.; Hickenboth, Charles R.; Moore, Jeffrey S.Macromolecules (2005), 38 (22), 8975-8978CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Ultrasound-induced site-specific cleavage of a polymer was accomplished by incorporating a single weak, azo linkage into the backbone of poly(ethylene glycol). The ultrasonic fragmentation of azo-functionalized polymers differs from the previously reported degrdn. of homopolymers or block copolymers in two important ways. First, the rate of ultrasonic cleavage is appreciably faster in the azo-centered polymers due to the weak bond in the polymer backbone. In addn., the azo-functionalized polymer cleaves with a high degree of bond specificity, resulting in one type of chain end and fragments of low polydispersity. Ultrasound-induced site-specific cleavage of polymers could be extended as an alternative to thermal or photoinduced reactions.
- 35Nguyen, N. H.; Rosen, B. M.; Lligadas, G.; Percec, V. Surface-Dependent Kinetics of Cu(0)-Wire-Catalyzed Single-Electron Transfer Living Radical Polymerization of Methyl Acrylate in DMSO at 25 °C. Macromolecules 2009, 42, 2379– 2386, DOI: 10.1021/ma802856235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjt1Gqtbc%253D&md5=921611687412818360b4dd32ef292a95Surface-Dependent Kinetics of Cu(0)-Wire-Catalyzed Single-Electron Transfer Living Radical Polymerization of Methyl Acrylate in DMSO at 25 °CNguyen, Nga H.; Rosen, Brad M.; Lligadas, Gerard; Percec, VirgilMacromolecules (Washington, DC, United States) (2009), 42 (7), 2379-2386CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The effect of Cu(0) wire dimensions on the Cu(0) wire/Me6-TREN-catalyzed heterogeneous single-electron transfer living radical polymn. (SET-LRP) of Me acrylate (MA) initiated with Me 2-bromopropionate (MBP) in DMSO at 25 °C was analyzed by kinetic expts. These kinetic results were compared with those of Cu(0) powder/Me6-TREN-catalyzed SET-LRP. Both wire and powder produce perfect SET-LRP with a first-order rate of polymn. in growing species up to 100% conversion. Nevertheless, Cu(0) wire expts. demonstrated SET-LRP with greater perfection, allowing for the accurate detn. of the external rate order (vis-a-vis surface area) for heterogeneous Cu(0) catalyst and accurate prediction of kpapp from wire dimension. Cu(0) wire also exhibited a significantly greater control of mol. wt. distribution than Cu(0) powder. The combined advantages of easier catalyst prepn., handling, predictability, tunability, simple recovery/recycling, and enhanced control of mol. wt. distribution make Cu(0)-wire-catalyzed SET-LRP the ideal methodol. for the synthesis of tailored polyacrylates.
- 36Beyer, M. K. The mechanical strength of a covalent bond calculated by density functional theory. J. Chem. Phys. 2000, 112, 7307– 7312, DOI: 10.1063/1.48133036https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXis1ansr0%253D&md5=1586bc3690c4f8fafcb64cb264a7b88bThe mechanical strength of a covalent bond calculated by density functional theoryBeyer, Martin K.Journal of Chemical Physics (2000), 112 (17), 7307-7312CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The rupture forces of covalent bonds in a polymer as a function of bond lifetime are calcd. with an Arrhenius kinetics model based on high-level d. functional theory calcns. Relaxed potential energy surface scans of small model mols. yield potential functions that account for the deformations and hybridizations caused by the application of force. Morse potentials chosen to exhibit the same well depth and max. force are used as an analytic representation of an individual bond in an infinitely long one-dimensional polymer. Application of force deforms the potential, and the activation energy for the bond rupture event together with the frequency of an optical phonon in the one-dimensional polymer are the two Arrhenius parameters. Rupture forces of the bonds C-C, C-N, C-O, Si-C, Si-N, Si-O, and Si-Si are reported as a function of the lifetime of the bond.
- 37Klein, I. M.; Husic, C. C.; Kovács, D. P.; Choquette, N. J.; Robb, M. J. Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry. J. Am. Chem. Soc. 2020, 142, 16364– 16381, DOI: 10.1021/jacs.0c0686837https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslKgur3N&md5=c9c569611172a826776b8419c2843058Validation of the CoGEF method as a predictive tool for polymer mechanochemistryKlein, Isabel M.; Husic, Corey C.; Kovacs, David P.; Choquette, Nicolas J.; Robb, Maxwell J.Journal of the American Chemical Society (2020), 142 (38), 16364-16381CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The development of force-responsive mols. called mechanophores is a central component of the field of polymer mechanochem. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to mol. release and self-healing materials. Nevertheless, an insufficient understanding of structure-activity relationships limits exptl. development, and thus computation is necessary to guide the structural design of mechanophores. The constrained geometries simulate external force (CoGEF) method is a highly accessible and straightforward computational technique that simulates the effect of mech. force on a mol. and enables the prediction of mechanochem. reactivity. Here, we use the CoGEF method to systematically evaluate every covalent mechanophore reported to date and compare the predicted mechanochem. reactivity to exptl. results. Mols. that are mechanochem. inactive are also studied as neg. controls. In general, mechanochem. reactions predicted with the CoGEF method at the common B3LYP/6-31G* level of d. functional theory are in excellent agreement with reactivity detd. exptl. Moreover, bond rupture forces obtained from CoGEF calcns. are compared to exptl. measured forces and demonstrated to be reliable indicators of mechanochem. activity. This investigation validates the CoGEF method as a powerful tool for predicting mechanochem. reactivity, enabling its widespread adoption to support the developing field of polymer mechanochem. Secondarily, this study provides a contemporary catalog of over 100 mechanophores developed to date.
- 38Konda, S. S. M.; Brantley, J. N.; Varghese, B. T.; Wiggins, K. M.; Bielawski, C. W.; Makarov, D. E. Molecular Catch Bonds and the Anti-Hammond Effect in Polymer Mechanochemistry. J. Am. Chem. Soc. 2013, 135, 12722– 12729, DOI: 10.1021/ja405110838https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SlsbzN&md5=3521e7dfc2772f1f3388186ddff3b9a7Molecular Catch Bonds and the Anti-Hammond Effect in Polymer MechanochemistryKonda, Sai Sriharsha M.; Brantley, Johnathan N.; Varghese, Bibin T.; Wiggins, Kelly M.; Bielawski, Christopher W.; Makarov, Dmitrii E.Journal of the American Chemical Society (2013), 135 (34), 12722-12729CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)While the field of polymer mechanochem. has traditionally focused on the use of mech. forces to accelerate chem. processes, theor. considerations predict an underexplored alternative: the suppression of reactivity through mech. perturbation. Here, we use electronic structure calcns. to analyze the mech. reactivity of six mechanophores, or chem. functionalities that respond to mech. stress in a controlled manner. Our computational results indicate that appropriately directed tensile forces could attenuate (as opposed to facilitate) mechanochem. phenomena. Accompanying exptl. studies supported the theor. predictions and demonstrated that relatively simple computational models may be used to design new classes of mech. responsive materials. In addn., our computational studies and theor. considerations revealed the prevalence of the anti-Hammond (as opposed to Hammond) effect (i.e., the increased structural dissimilarity between the reactant and transition state upon lowering of the reaction barrier) in the mech. activation of polyat. mols.
- 39Robb, M. J.; Kim, T. A.; Halmes, A. J.; White, S. R.; Sottos, N. R.; Moore, J. S. Regioisomer-Specific Mechanochromism of Naphthopyran in Polymeric Materials. J. Am. Chem. Soc. 2016, 138, 12328– 12331, DOI: 10.1021/jacs.6b0761039https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyht7fN&md5=05af4225a1f310ab4f7dafe1791bd508Regioisomer-Specific Mechanochromism of Naphthopyran in Polymeric MaterialsRobb, Maxwell J.; Kim, Tae Ann; Halmes, Abigail J.; White, Scott R.; Sottos, Nancy R.; Moore, Jeffrey S.Journal of the American Chemical Society (2016), 138 (38), 12328-12331CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Transformation of naphthopyran into a colored merocyanine species in polymeric materials is achieved using mech. force. We demonstrate that the mechanochem. reactivity of naphthopyran is critically dependent on the regiochem., with only one particular substitution pattern leading to successful mechanochem. activation. Two alternative regioisomers with different polymer attachment points are demonstrated to be mechanochem. inactive. This trend in reactivity is accurately predicted by DFT calcns., reinforcing predictive capabilities in mechanochem. systems. We rationalize the reactivity differences between naphthopyran regioisomers in terms of the alignment of the target C-O pyran bond with the direction of the applied mech. force and its effect on mechanochem. transduction along the reaction coordinate.
- 40Stevenson, R.; De Bo, G. Controlling Reactivity by Geometry in Retro-Diels-Alder Reactions under Tension. J. Am. Chem. Soc. 2017, 139, 16768– 16771, DOI: 10.1021/jacs.7b0889540https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCiur3J&md5=14b87c5c0efbac3c19dbc3e9058baa42Controlling Reactivity by Geometry in Retro-Diels-Alder Reactions under TensionStevenson, Richard; De Bo, GuillaumeJournal of the American Chemical Society (2017), 139 (46), 16768-16771CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mech. force, with its ability to distort, bend, and stretch chem. bonds, is unique in the way it activates chem. reactions. In polymer mechanochem., the force is transduced in a directional fashion, and the efficiency of activation depends on how well the force is transduced from the polymer to the scissile bond in the mechanophore (i.e., mechanochem. coupling). We have studied the effects of regio- and stereochem. on the rate of force-accelerated retro-Diels-Alder reactions of furan/maleimide adducts. Four adducts, presenting an endo or exo configuration and proximal or distal geometry, were activated in soln. by ultrasound-generated elongational forces. A combination of structural (1H NMR) and computational (CoGEF) analyses allowed us to interrogate the mechanochem. activation of these adducts. We found that, unlike its thermal counterpart where the reactivity is dictated by the stereochem., the mech. reactivity is mainly dependent on the regiochem. Remarkably, the thermally active distal-exo adduct becomes inert under tension due to poor mechanochem. coupling.
- 41Boutelle, R. C.; Northrop, B. H. Substituent Effects on the Reversibility of Furan-Maleimide Cycloadditions. J. Org. Chem. 2011, 76, 7994– 8002, DOI: 10.1021/jo201606z41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOmsbvP&md5=cc7c272bf128aeeb80d220810aef7956Substituent Effects on the Reversibility of Furan-Maleimide CycloadditionsBoutelle, Robert C.; Northrop, Brian H.Journal of Organic Chemistry (2011), 76 (19), 7994-8002CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The effects of furan and maleimide substitution on the dynamic reversibility of their Diels-Alder reactivity have been investigated computationally and by 1H NMR spectroscopy. Furan and furan derivs. bearing methoxy, Me, or formyl groups at their 2- or 3-positions were investigated with maleimide and maleimide derivs. bearing N-Me, N-allyl, and N-Ph substituents. Computational predictions indicate that electronic and regiochem. effects of furan substitution significantly influence their Diels-Alder reactivity with maleimide, with reaction free energies of exo adduct formation ranging from ΔG = -9.4 to 0.9 kcal/mol and transition state barriers to exo adduct formation ranging from ΔG‡ = 18.9 to 25.6 kcal/mol. Much less variation was obsd. for the reactivity of N-substituted maleimide derivs. and furan, with reaction and transition state free energies each falling within a range of 1.1 kcal/mol. Dynamic exchange expts. monitored by 1H NMR spectroscopy support computational predictions. The results indicate the reactivity and reversibility of furan-maleimide cycloaddns. can be tuned significantly through the addn. of appropriate substituents and have implications in the use of furan and maleimide derivs. in the construction of thermally responsive org. materials.
- 42Foster, R. W.; Benhamou, L.; Porter, M. J.; Bučar, D.-K.; Hailes, H. C.; Tame, C. J.; Sheppard, T. D. Irreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-Cantharimides. Chem. - Eur. J. 2015, 21, 6107– 6114, DOI: 10.1002/chem.20140628642https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvF2ls7g%253D&md5=555455dd7c3d4c40d74c87a3f5d8fe7eIrreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-CantharimidesFoster, Robert W.; Benhamou, Laure; Porter, Michael J.; Bucar, Dejan-Kresimir; Hailes, Helen C.; Tame, Christopher J.; Sheppard, Tom D.Chemistry - A European Journal (2015), 21 (16), 6107-6114CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The [4+2] cycloaddn. of 3-alkoxyfurans with N-substituted maleimides provides the first general route for prepg. endo-cantharimides [e.g., 3-methoxy-2-(2-phenylethyl)furan + N-methylmaleimide → I (89% yield, 80:20 endo/exo)]. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substituted furans including alkyl, arom., and heteroarom. groups. The cycloaddn. products were converted into a range of cantharimide products with promising lead-like properties for medicinal chem. programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivs. under mild conditions. DFT calcns. have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels-Alder reaction.
- 43Kryger, M. J.; Munaretto, A. M.; Moore, J. S. Structure-Mechanochemical Activity Relationships for Cyclobutane Mechanophores. J. Am. Chem. Soc. 2011, 133, 18992– 18998, DOI: 10.1021/ja208672843https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyjsr7F&md5=252f8108c6f1317a91e0c2865b64d23aStructure-Mechanochemical Activity Relationships for Cyclobutane MechanophoresKryger, Matthew J.; Munaretto, Alexander M.; Moore, Jeffrey S.Journal of the American Chemical Society (2011), 133 (46), 18992-18998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Ultrasound activation of mechanophores embedded in polymer backbones was extensively studied of late as a method for realizing chem. reactions using force. To date, however, there were few attempts at systematically investigating the effects of mechanophore structure upon rates of activation by an acoustic field. Herein, we develop a method for comparing the relative reactivities of various cyclobutane mechanophores. Through the synthesis and ultrasonic irradn. of a mol. wt. series of poly(Me acrylate) polymers in which each macromol. has a single chain-centered mechanophore, we find measurable and statistically significant shifts in mol. wt. thresholds for mechanochem. activation that depend on the structure of the mechanophore. We also show that calcns. based on the constrained geometries simulate external force method reliably predict the trends in mechanophore reactivity. These straightforward calcns. and the exptl. methods described herein may be useful in guiding the design and the development of new mechanophores for targeted applications.
- 44May, P. A.; Munaretto, N. F.; Hamoy, M. B.; Robb, M. J.; Moore, J. S. Is Molecular Weight or Degree of Polymerization a Better Descriptor of Ultrasound-Induced Mechanochemical Transduction?. ACS Macro Lett. 2016, 5, 177– 180, DOI: 10.1021/acsmacrolett.5b0085544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKmsrY%253D&md5=609f5da3274065405bfc464702d997a4Is Molecular Weight or Degree of Polymerization a Better Descriptor of Ultrasound-Induced Mechanochemical Transduction?May, Preston A.; Munaretto, Nicholas F.; Hamoy, Michael B.; Robb, Maxwell J.; Moore, Jeffrey S.ACS Macro Letters (2016), 5 (2), 177-180CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)A detailed understanding of the fundamental processes that govern mech. transduction in covalent polymer mechanochem. is essential to advance innovation in this field. In contrast to progress in the development of new mechanophores, the influence of polymer structure and compn. on mechanochem. activity has received relatively little attention. In order to address this gap in knowledge, a continuous flow system with synchronous UV-vis absorption capabilities was designed to quantify the ultrasound-induced mech. activation of a spiropyran mechanophore in real-time. Measurements of reaction kinetics with polymer tethers of varying repeating unit structure demonstrate that d.p. is the key descriptor of mechanochem. activity, independent of mol. wt. and pendant group constitution. These results have important implications for the rationalization of mechanochem. properties and the design of new mechanochem. active polymer systems.
- 45Schaefer, M.; Icli, B.; Weder, C.; Lattuada, M.; Kilbinger, A. F. M.; Simon, Y. C. The Role of Mass and Length in the Sonochemistry of Polymers. Macromolecules 2016, 49, 1630– 1636, DOI: 10.1021/acs.macromol.5b0236245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWksrg%253D&md5=1543fe09e55603f3e3815156dc053c91The Role of Mass and Length in the Sonochemistry of PolymersSchaefer, Mark; Icli, Burcak; Weder, Christoph; Lattuada, Marco; Kilbinger, Andreas F. M.; Simon, Yoan C.Macromolecules (Washington, DC, United States) (2016), 49 (5), 1630-1636CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The ultrasound-induced cleavage of macromols. has become a routine expt. in the emerging field of polymer mechanochem. To date, it has not been conclusively proven whether the mol. wt. of a polymer or its contour length is the detg. factor for chain scission upon ultrasonication. Here we report comparative expts. that confirm unequivocally that the contour length is the decisive parameter. We utilized postpolymn. modifications of specifically designed precursor polymers to create polymers with identical chain length but different mol. mass. To demonstrate the universality of the findings, two different polymer backbones were utilized-poly(styrene) and poly(norbornene imide alkyne)-whose mol. wts. were altered by bromination and removal of pendant triisopropylsilyl protecting groups, resp. Solns. of the resp. polymer pairs were subjected to pulsed ultrasound at 20 kHz and 10.4 W/cm2 in order to investigate the chain scission trends. The effects of cleavage and sonochem. treatments were monitored by size exclusion chromatog. In both series, exptl. data and calcns. show that the mol. wt. redn. upon sonication is the same for polymers with the same contour length.
- 46Lenhardt, J. M.; Black Ramirez, A. L.; Lee, B.; Kouznetsova, T. B.; Craig, S. L. Mechanistic Insights into the Sonochemical Activation of Multimechanophore Cyclopropanated Polybutadiene Polymers. Macromolecules 2015, 48, 6396– 6403, DOI: 10.1021/acs.macromol.5b0167746https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVyntbrO&md5=25afd446a21a52da702b3b9e56343f63Mechanistic Insights into the Sonochemical Activation of Multimechanophore Cyclopropanated Polybutadiene PolymersLenhardt, Jeremy M.; Black Ramirez, Ashley L.; Lee, Bobin; Kouznetsova, Tatiana B.; Craig, Stephen L.Macromolecules (Washington, DC, United States) (2015), 48 (18), 6396-6403CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Structure-activity relationships in the mechanochem. of gem-dichlorocyclopropane (gDCC)-based polymer solns. triggered by pulsed ultrasound are reported. Insights into the flow-induced mechanochem. transformations of gDCC mechanophores into the corresponding 2,3-dichloroalkenes are obtained by monitoring the mechanochem. as a function of initial polymer mol. wt. and sonication conditions. The competition between gDCC activation and polymer chain scission is invariant to sonication power, temp., polymer concn., and solvent but is sensitive to initial polymer mol. wt. The results have practical implications for the use of polymer sonochem. as a tool for quantifying the relative mech. strength of scissile polymers and conceptual implications for thinking about the nature of the force distributions experienced during sonochem. expts.
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