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In recent decades, more than 100 different mechanophores with a broad range of activation forces have been developed. For various applications of mechanophores in polymer materials, it is crucial to selectively activate the mechanophores with high efficiency, avoiding nonspecific bond scission of the material. In this study, we embedded cyclobutane-based mechanophore cross-linkers (I and II) with varied activation forces (fa) in the first network of the double network hydrogels and quantitively investigated the activation selectivity and efficiency of these mechanophores. Our findings revealed that cross-linker I, with a lower activation force relative to the bonds in the polymer main chain (fa-I/fa-chain = 0.8 nN/3.4 nN), achieved efficient activation with 100% selectivity. Conversely, an increase of the activation force of mechanophore II (fa-II/fa-chain = 2.5 nN/3.4 nN) led to a significant decrease of its activation efficiency, accompanied by a substantial number of nonspecific bond scission events. Furthermore, with the coexistence of two cross-linkers, significantly different activation forces resulted in the almost complete suppression of the higher-force one (i.e., I and III, fa-I/fa-III = 0.8 nN/3.4 nN), while similar activation forces led to simultaneous activations with moderate efficiencies (i.e., I and IV, fa-I/fa-IV = 0.8 nN/1.6 nN). These findings provide insights into the prevention of nonspecific bond rupture during mechanophore activation and enhance our understanding of the damage mechanism within polymer networks when using mechanophores as detectors. Besides, it establishes a principle for combining different mechanophores to design multiple mechanoresponsive functional materials.
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Polymers that release small molecules in response to mechanical force are promising candidates as next-generation on-demand delivery systems. Despite advancements in the development of mechanophores for releasing diverse payloads through careful molecular design, the availability of scaffolds capable of discharging biomedically significant cargos in substantial quantities remains scarce. In this report, we detail a nonscissile mechanophore built from an 8-thiabicyclo[3.2.1]octane 8,8-dioxide (TBO) motif that releases one equivalent of sulfur dioxide (SO2) from each repeat unit. The TBO mechanophore exhibits high thermal stability but is activated mechanochemically using solution ultrasonication in either organic solvent or aqueous media with up to 63% efficiency, equating to 206 molecules of SO2 released per 143.3 kDa chain. We quantified the mechanochemical reactivity of TBO by single-molecule force spectroscopy and resolved its single-event activation. The force-coupled rate constant for TBO opening reaches â¼9.0 s-1 at â¼1520 pN, and each reaction of a single TBO domain releases a stored length of â¼0.68 nm. We investigated the mechanism of TBO activation using ab initio steered molecular dynamic simulations and rationalized the observed stereoselectivity. These comprehensive studies of the TBO mechanophore provide a mechanically coupled mechanism of multi-SO2 release from one polymer chain, facilitating the translation of polymer mechanochemistry to potential biomedical applications.
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Second row elements in small- and medium-rings modulate strain. Herein we report the synthesis of two novel oligosilyl-containing cycloalkynes that exhibit angle-strain, as observed by X-ray crystallography. However, the angle-strained sila-cyclooctynes are sluggish participants in cycloadditions with benzyl azide. A distortion-interaction model analysis based on density functional theory calculations was performed.
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Hydrogen fluoride (HF) is a versatile reagent for material transformation, with applications in self-immolative polymers, remodeled siloxanes, and degradable polymers. The responsive in situ generation of HF in materials therefore holds promise for new classes of adaptive material systems. Here, we report the mechanochemically coupled generation of HF from alkoxy-gem-difluorocyclopropane (gDFC) mechanophores derived from the addition of difluorocarbene to enol ethers. Production of HF involves an initial mechanochemically assisted rearrangement of gDFC mechanophore to α-fluoro allyl ether whose regiochemistry involves preferential migration of fluoride to the alkoxy-substituted carbon, and ab initio steered molecular dynamics simulations reproduce the observed selectivity and offer insights into the mechanism. When the alkoxy gDFC mechanophore is derived from poly(dihydrofuran), the α-fluoro allyl ether undergoes subsequent hydrolysis to generate 1 equiv of HF and cleave the polymer chain. The hydrolysis is accelerated via acid catalysis, leading to self-amplifying HF generation and concomitant polymer degradation. The mechanically generated HF can be used in combination with fluoride indicators to generate an optical response and to degrade polybutadiene with embedded HF-cleavable silyl ethers (11 mol %). The alkoxy-gDFC mechanophore thus provides a mechanically coupled mechanism of releasing HF for polymer remodeling pathways that complements previous thermally driven mechanisms.
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The spiropyran mechanophore (SP) is employed as a reporter of molecular tension in a wide range of polymer matrices, but the influence of surrounding environment on the force-coupled kinetics of its ring opening has not been quantified. Here, we report single-molecule force spectroscopy studies of SP ring opening in five solvents that span normalized Reichardt solvent polarity factors (ETN) of 0.1-0.59. Individual multimechanophore polymers were activated under increasing tension at constant 300 nm s-1 displacement in an atomic force microscope. The extension results in a plateau in the force-extension curve, whose midpoint occurs at a transition force f* that corresponds to the force required to increase the rate constant of SP activation to approximately 30 s-1. More polar solvents lead to mechanochemical reactions that are easier to trigger; f* decreases across the series of solvents, from a high of 415 ± 13 pN in toluene to a low of 234 ± 9 pN in n-butanol. The trend in mechanochemical reactivity is consistent with the developing zwitterionic character on going from SP to the ring-opened merocyanine product. The force dependence of the rate constant (Δx) was calculated for all solvent cases and found to increase with ETN, which is interpreted to reflect a shift in the transition state to a later and more productlike position. The inferred shift in the transition state position is consistent with a double-well (two-step) reaction potential energy surface, in which the second step is rate determining, and the intermediate is more polar than the product.
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Many virus-like particles (VLPs) have good chemical, thermal, and mechanical stabilities compared to those of other biologics. However, their stability needs to be improved for the commercialization and use in translation of VLP-based materials. We developed an endoskeleton-armored strategy for enhancing VLP stability. Specifically, the VLPs of physalis mottle virus (PhMV) and Qß were used to demonstrate this concept. We built an internal polymer "backbone" using a maleimide-PEG15-maleimide cross-linker to covalently interlink viral coat proteins inside the capsid cavity, while the native VLPs are held together by only noncovalent bonding between subunits. Endoskeleton-armored VLPs exhibited significantly improved thermal stability (95 °C for 15 min), increased resistance to denaturants (i.e., surfactants, pHs, chemical denaturants, and organic solvents), and enhanced mechanical performance. Single-molecule force spectroscopy demonstrated a 6-fold increase in rupture distance and a 1.9-fold increase in rupture force of endoskeleton-armored PhMV. Overall, this endoskeleton-armored strategy provides more opportunities for the development and applications of materials.
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Proteínas de la Cápside , Cápside , Proteínas de la Cápside/química , Cápside/química , Maleimidas/análisisRESUMEN
Polymers that amplify a transient external stimulus into changes in their morphology, physical state, or properties continue to be desirable targets for a range of applications. Here, we report a polymer comprising an acid-sensitive, hydrolytically unstable enol ether backbone onto which is embedded gem-dichlorocyclopropane (gDCC) mechanophores through a single postsynthetic modification. The gDCC mechanophore releases HCl in response to large forces of tension along the polymer backbone, and the acid subsequently catalyzes polymer deconstruction at the enol ether sites. Pulsed sonication of a 61 kDa PDHF with 77% gDCC on the backbone in THF with 100 mM H2O for 10 min triggers the subsequent degradation of the polymer to a final molecular weight of less than 3 kDa after 24 h of standing, whereas controls lacking either the gDCC or the enol ether reach final molecular weights of 38 and 27 kDa, respectively. The process of sonication, along with the presence of water and the existence of gDCC on the backbone, significantly accelerates the rate of polymer chain deconstruction. Both acid generation and the resulting triggered polymer deconstruction are translated to bulk, cross-linked polymer networks. Networks formed via thiol-ene cross-linking and subjected to unconstrained quasi-static uniaxial compression dissolve on time scales that are at least 3 times faster than controls where the mechanophore is not covalently coupled to the network. We anticipate that this concept can be extended to other acid-sensitive polymer networks for the stress-responsive deconstruction of gels and solvent-free elastomers.
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Pterodactylane is a [4]-ladderane with substituents on the central rung. Comparing the mechanochemistry of the [4]-ladderane structure when pulled from the central rung versus the end rung revealed a striking difference in the threshold force of mechanoactivation: the threshold force is dramatically lowered from 1.9 nN when pulled on the end rung to 0.7 nN when pulled on the central rung. We investigated the bicyclic products formed from the mechanochemical activation of pterodactylane experimentally and computationally, which are distinct from the mechanochemical products of ladderanes being activated from the end rung. We compared the products of pterodactylane's mechanochemical and thermal activation to reveal differences and similarities in the mechanochemical and thermal pathways of pterodactylane transformation. Interestingly, we also discovered the presence of elementary steps that are accelerated or suppressed by force within the same mechanochemical reaction of pterodactylane, suggesting rich mechanochemical manifolds of multicyclic structures. We rationalized the greatly enhanced mechanochemical reactivity of the central rung of pterodactylane and discovered force-free ground state bond length to be a good low-cost predictor of the threshold force for cyclobutane-based mechanophores. These findings advance our understanding of mechanochemical reactivities and pathways, and they will guide future designs of mechanophores with low threshold forces to facilitate their applications in force-responsive materials.
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The fracture of polymer networks is tied to the molecular behavior of strands within the network, yet the specific molecular-level processes that determine the mechanical limits of a network remain elusive. Here, the question of reactivity-guided fracture is explored in otherwise indistinguishable end-linked networks by tuning the relative composition of strands with two different mechanochemical reactivities. Increasing the substitution of less mechanochemically reactive ("strong") strands into a network comprising more reactive ("weak") strands has a negligible impact on the fracture energy until the strong strand content reaches approximately 45%, at which point the fracture energy sharply increases with strong strand content. This aligns with the measured strong strand percolation threshold of 48 ± 3%, revealing that depercolation, or the loss of a percolated network structure, is a necessary criterion for crack propagation in a polymer network. Coarse-grained fracture simulations agree closely with the tearing energy trend observed experimentally, confirming that weak strand scissions dominate the failure until the strong strands approach percolation. The simulations further show that twice as many strands break in a mixture than in a pure network.
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Metal-organic cages/polyhedra (MOCs) are versatile building blocks for advanced polymer networks with properties that synergistically blend those of traditional polymers and crystalline frameworks. Nevertheless, constructing polyMOCs from very stable Pt(II)-based MOCs or mixtures of metal ions such as Pd(II) and Pt(II) has not, to our knowledge, been demonstrated, nor has exploration of how the dynamics of metal-ligand exchange at the MOC level may impact bulk polyMOC energy dissipation. Here, we introduce a new class of polymer metal-organic cage (polyMOC) gels featuring polyethylene glycol (PEG) strands of varied length cross-linked through bis-pyridyl-carbazole-based M6L12 cubes, where M is Pd(II), Pt(II), or mixtures thereof. We show that, while polyMOCs with varied Pd(II) content have similar network structures, their average stress-relaxation rates are tunable over 3 orders of magnitude due to differences in Pd(II)- and Pt(II)-ligand exchange rates at the M6L12 junction level. Moreover, mixed-metal polyMOCs display relaxation times indicative of intrajunction cooperative interactions, which stands in contrast to previous materials based on point metal junctions. Altogether, this work (1) introduces a novel MOC architecture for polyMOC design, (2) shows that polyMOCs can be prepared from mixtures of Pd(II)/Pt(II), and (3) demonstrates that polyMOCs display unique relaxation behavior due to their multivalent junctions, offering a strategy for controlling polyMOC properties independently of their polymer components.
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Allosteric control of reaction thermodynamics is well understood, but the mechanisms by which changes in local geometries of receptor sites lower activation reaction barriers in electronically uncoupled, remote reaction moieties remain relatively unexplored. Here we report a molecular scaffold in which the rate of thermal E-to-Z isomerization of an alkene increases by a factor of as much as 104 in response to fast binding of a metal ion to a remote receptor site. A mechanochemical model of the olefin coupled to a compressive harmonic spring reproduces the observed acceleration quantitatively, adding the studied isomerization to the very few reactions demonstrated to be sensitive to extrinsic compressive force. The work validates experimentally the generalization of mechanochemical kinetics to compressive loads and demonstrates that the formalism of force-coupled reactivity offers a productive framework for the quantitative analysis of the molecular basis of allosteric control of reaction kinetics. Important differences in the effects of compressive vs. tensile force on the kinetic stabilities of molecules are discussed.
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Most elastomers undergo strain-induced crystallization (SIC) under tension; as individual chains are held rigidly in a fixed position by an applied strain, their alignment along the strain field results in a shift from strain-hardening (SH) to SIC. A similar degree of stretching is associated with the tension necessary to accelerate mechanically coupled, covalent chemical responses of mechanophores in overstretched chains, raising the possibility of an interplay between the macroscopic response of SIC and the molecular response of mechanophore activation. Here, thiol-yne-derived stereoelastomers doped covalently with a dipropiolate-derivatized spiropyran (SP) mechanophore (0.25-0.38 mol%) are reported. The material properties of SP-containing films are consistent with undoped controls, indicating that the SP is a reporter of the mechanical state of the polymer. Uniaxial tensile tests reveal correlations between mechanochromism and SIC, which are strain-rate-dependent. When mechanochromic films are stretched slowly to the point of mechanophore activation, the covalently tethered mechanophore remains trapped in a force-activated state, even after the applied stress is removed. Mechanophore reversion kinetics correlate with the applied strain rate, resulting in highly tunable decoloration rates. Because these polymers are not covalently crosslinked, they are recyclable by melt-pressing into new films, increasing their potential range of strain-sensing, morphology-sensing, and shape-memory applications.
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The mechanical properties of covalent polymer networks often arise from the permanent end-linking or cross-linking of polymer strands, and molecular linkers that break more easily would likely produce materials that require less energy to tear. We report that cyclobutane-based mechanophore cross-linkers that break through force-triggered cycloreversion lead to networks that are up to nine times as tough as conventional analogs. The response is attributed to a combination of long, strong primary polymer strands and cross-linker scission forces that are approximately fivefold smaller than control cross-linkers at the same timescales. The enhanced toughness comes without the hysteresis associated with noncovalent cross-linking, and it is observed in two different acrylate elastomers, in fatigue as well as constant displacement rate tension, and in a gel as well as elastomers.
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The cis- and trans-isomers of a silacycloheptene were selectively synthesized by the alkylation of a silyl dianion, a novel approach to strained cycloalkenes. The trans-silacycloheptene (trans-SiCH) was significantly more strained than the cis isomer, as predicted by quantum chemical calculations and confirmed by crystallographic signatures of a twisted alkene. Each isomer exhibited distinct reactivity toward ring-opening metathesis polymerization (ROMP), where only trans-SiCH afforded high-molar-mass polymer under enthalpy-driven ROMP. Hypothesizing that the introduction of silicon might result in increased molecular compliance at large extensions, we compared poly(trans-SiCH) to organic polymers by single-molecule force spectroscopy (SMFS). Force-extension curves from SMFS showed that poly(trans-SiCH) is more easily overstretched than two carbon-based analogues, polycyclooctene and polybutadiene, with stretching constants that agree well with the results of computational simulations.
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Over the past 20 years, the field of polymer mechanochemistry has amassed a toolbox of mechanophores that translate mechanical energy into a variety of functional responses ranging from color change to small-molecule release. These productive chemical changes typically occur at the length scale of a few covalent bonds (Å) but require large energy inputs and strains on the micro-to-macro scale in order to achieve even low levels of mechanophore activation. The minimal activation hinders the translation of the available chemical responses into materials and device applications. The mechanophore activation challenge inspires core questions at yet another length scale of chemical control, namely: What are the molecular-scale features of a polymeric material that determine the extent of mechanophore activation? Further, how do we marry advances in the chemistry of polymer networks with the chemistry of mechanophores to create stress-responsive materials that are well suited for an intended application? In this Perspective, we speculate as to the potential match between covalent polymer mechanochemistry and recent advances in polymer network chemistry, specifically, topologically controlled networks and the hierarchical material responses enabled by multi-network architectures and mechanically interlocked polymers. Both fundamental and applied opportunities unique to the union of these two fields are discussed.
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Matrimonio , Polímeros , Polímeros/química , Química OrgánicaRESUMEN
Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.
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Diabetes Mellitus Tipo 2 , Humanos , Exenatida , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polietilenglicoles/química , Péptidos/química , Antígenos , Preparaciones de Acción RetardadaRESUMEN
This paper provides a summary of the Faraday Discussions meeting on "Mechanochemistry: fundamentals, applications, and future" in the context of broad themes whose exploration might contribute to a unified framework of mechanochemical phenomena.
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Recent work has demonstrated that force-triggered mechanochemical reactions within a polymeric material are capable of inducing measurable changes in macroscopic material properties, but examples of bulk property changes without irreversible changes in shape or structure are rare. Here, we report a double-network hydrogel that undergoes order-of-magnitude increases in acidity when strained, while recovering its initial shape after large deformation. The enabling mechanophore design is a 2-methoxy-gem-dichlorocyclopropane mechanoacid that is gated within a fused methyl methoxycyclobutene carboxylate mechanophore structure. This gated mechanoacid is incorporated via radical co-polymerization into linear and network polymers. Sonication experiments confirm the mechanical release of HCl, and single-molecule force spectroscopy reveals enhanced single-molecular toughness in the covalent strand. These mechanochemical functions are incorporated into a double-network hydrogel, leading to mechanically robust and thermally stable materials that undergo strain-triggered acid release. Both quasi-static stretching and high strain rate uniaxial compression result in substantial acidification of the hydrogel, from pH â¼ 7 to â¼5.