A Thermally Stable SO2-Releasing Mechanophore: Facile Activation, Single-Event Spectroscopy, and Molecular Dynamic Simulations.

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 ∼9.0 s-1 at ∼1520 pN, and each reaction of a single TBO domain releases a stored length of ∼0.68 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.

Solvent Polarity Effects on the Mechanochemistry of Spiropyran Ring Opening.

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.

Virus-like Particles Armored by an Endoskeleton.

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.

Mechanochemistry of Pterodactylane.

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.

Reactivity-Guided Depercolation Processes Determine Fracture Behavior in End-Linked Polymer Networks.

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.

Facile mechanochemical cycloreversion of polymer cross-linkers enhances tear resistance.

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.

Synthesis and Ring-Opening Metathesis Polymerization of a Strained trans-Silacycloheptene and Single-Molecule Mechanics of Its Polymer.

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.

Strain-triggered acidification in a double-network hydrogel enabled by multi-functional transduction of molecular mechanochemistry.

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 ∼ 7 to ∼5.

Mechanochemistry of Cubane.

We report the mechanochemical reactivity of the highly strained pentacyclic hydrocarbon cubane. The mechanical reactivity of cubane is explored for three regioisomers with 1,2-, 1,3-, and 1,4-substituted pulling attachments. Whereas all compounds can be activated thermally, mechanical activation is observed via pulsed ultrasonication of cubane-containing polymers only when force is applied via 1,2-attachment. The single observed product of the force-coupled reaction is a thermally inaccessible syn-tricyclooctadiene, in contrast to cyclooctatetraene (observed thermally) or a pair of cyclobutadienes that would result from sequential cyclobutane scission. We further quantify the mechanochemical reactivity of cubane by single molecule force spectroscopy, and force-coupled rate constants for ring opening reach ∼33 s-1 at a force of ∼1.55 nN, lower than forces of 1.8-2.0 nN that are typical of conventional cyclobutanes.

Toughening hydrogels through force-triggered chemical reactions that lengthen polymer strands.

The utility and lifetime of materials made from polymer networks, including hydrogels, depend on their capacity to stretch and resist tearing. In gels and elastomers, those mechanical properties are often limited by the covalent chemical structure of the polymer strands between cross-links, which is typically fixed during the material synthesis. We report polymer networks in which the constituent strands lengthen through force-coupled reactions that are triggered as the strands reach their nominal breaking point. In comparison with networks made from analogous control strands, reactive strand extensions of up to 40% lead to hydrogels that stretch 40 to 50% further and exhibit tear energies that are twice as large. The enhancements are synergistic with those provided by double-network architectures and complement other existing toughening strategies.

Understanding the Mechanochemistry of Ladder-Type Cyclobutane Mechanophores by Single Molecule Force Spectroscopy.

We have recently reported a series of ladder-type cyclobutane mechanophores, polymers of which can transform from nonconjugated structures to conjugated structures and change many properties at once. These multicyclic mechanophores, namely, exo-ladderane/ene, endo-benzoladderene, and exo-bicyclohexene-peri-naphthalene, have different ring structures fused to the first cyclobutane, significantly different free energy changes for ring-opening, and different stereochemistry. To better understand their mechanochemistry, we used single molecule force spectroscopy (SMFS) to characterize their force-extension behavior and measure the threshold forces. The threshold forces correlate with the activation energy of the first bond, but not with the strain of the fused rings distal to the polymer main chain, suggesting that the activation of these ladder-type mechanophores occurs with similar early transition states, which is supported by force-modified potential energy surface calculations. We further determined the stereochemistry of the mechanically generated dienes and observed significant and variable contour length elongation for these mechanophores both experimentally and computationally. The fundamental understanding of ladder-type mechanophores will facilitate future design of multicyclic mechanophores with amplified force-response and their applications as mechanically responsive materials.

Single-Event Spectroscopy and Unravelling Kinetics of Covalent Domains Based on Cyclobutane Mechanophores.

Mechanochemical reactions that lead to an increase in polymer contour length have the potential to serve as covalent synthetic mimics of the mechanical unfolding of noncovalent "stored length" domains in structural proteins. Here we report the force-dependent kinetics of stored length release in a family of covalent domain polymers based on cis-1,2-substituted cyclobutane mechanophores. The stored length is determined by the size (n) of a fused ring in an [n.2.0] bicyclic architecture, and it can be made sufficiently large (>3 nm per event) that individual unravelling events are resolved in both constant-velocity and constant-force single-molecule force spectroscopy (SMFS) experiments. Replacing a methylene in the pulling attachment with a phenyl group drops the force necessary to achieve rate constants of 1 s-1 from ca. 1970 pN (dialkyl handles) to 630 pN (diaryl handles), and the substituent effect is attributed to a combination of electronic stabilization and mechanical leverage effects. In contrast, the kinetics are negligibly perturbed by changes in the amount of stored length. The independent control of unravelling force and extension holds promise as a probe of molecular behavior in polymer networks and for optimizing the behaviors of materials made from covalent domain polymers.

Substituent Effects in Mechanochemical Allowed and Forbidden Cyclobutene Ring-Opening Reactions.

Woodward and Hoffman once jested that a very powerful Maxwell demon could seize a molecule of cyclobutene at its methylene groups and tear it open in a disrotatory fashion to obtain butadiene (Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Angew. Chem., Int. Ed. 1969, 8, 781-853). Nearly 40 years later, that demon was discovered, and the field of covalent polymer mechanochemistry was born. In the decade since our demon was befriended, many fundamental investigations have been undertaken to build up our understanding of force-modified pathways for electrocyclic ring-opening reactions. Here, we seek to extend that fundamental understanding by exploring substituent effects in allowed and forbidden ring-opening reactions of cyclobutene (CBE) and benzocyclobutene (BCB) using a combination of single-molecule force spectroscopy (SMFS) and computation. We show that, while the forbidden ring-opening of cis-BCB occurs at a lower force than the allowed ring-opening of trans-BCB on the time scale of the SMFS experiment, the opposite is true for cis- and trans-CBE. Such a reactivity flip is explained through computational analysis and discussion of the so-called allowed/forbidden gap.

Mechanism Dictates Mechanics: A Molecular Substituent Effect in the Macroscopic Fracture of a Covalent Polymer Network.

The fracture of rubbery polymer networks involves a series of molecular events, beginning with conformational changes along the polymer backbone and culminating with a chain scission reaction. Here, we report covalent polymer gels in which the macroscopic fracture "reaction" is controlled by mechanophores embedded within mechanically active network strands. We synthesized poly(ethylene glycol) (PEG) gels through the end-linking of azide-terminated tetra-arm PEG (Mn = 5 kDa) with bis-alkyne linkers. Networks were formed under identical conditions, except that the bis-alkyne was varied to include either a cis-diaryl (1) or cis-dialkyl (2) linked cyclobutane mechanophore that acts as a mechanochemical "weak link" through a force-coupled cycloreversion. A control network featuring a bis-alkyne without cyclobutane (3) was also synthesized. The networks show the same linear elasticity (G' = 23-24 kPa, 0.1-100 Hz) and equilibrium mass swelling ratios (Q = 10-11 in tetrahydrofuran), but they exhibit tearing energies that span a factor of 8 (3.4 J, 10.6, and 27.1 J·m-2 for networks with 1, 2, and 3, respectively). The difference in fracture energy is well-aligned with the force-coupled scission kinetics of the mechanophores observed in single-molecule force spectroscopy experiments, implicating local resonance stabilization of a diradical transition state in the cycloreversion of 1 as a key determinant of the relative ease with which its network is torn. The connection between macroscopic fracture and a small-molecule reaction mechanism suggests opportunities for molecular understanding and optimization of polymer network behavior.

Single-Molecule Activation and Quantification of Mechanically Triggered Palladium-Carbene Bond Dissociation.

Metal-complexed N-heterocyclic carbene (NHC) mechanophores are latent reactants and catalysts for a range of mechanically driven chemical responses, but mechanochemical scission of the metal-NHC bond has not been experimentally characterized. Here we report the single-molecule force spectroscopy of ligand dissociation from a pincer NHC-pyridine-NHC Pd(II) complex. The force-coupled rate constant for ligand dissociation reaches 50 s-1 at forces of approximately 930 pN. Experimental and computational observations support a dissociative, rather than associative, mechanism of ligand displacement, with rate-limiting scission of the Pd-NHC bond followed by rapid dissociation of the pyridine moiety from Pd.

Distal conformational locks on ferrocene mechanophores guide reaction pathways for increased mechanochemical reactivity.

Mechanophores can be used to produce strain-dependent covalent chemical responses in polymeric materials, including stress strengthening, stress sensing and network remodelling. In general, it is desirable for mechanophores to be inert in the absence of force but highly reactive under applied tension. Metallocenes possess potentially useful combinations of force-free stability and force-coupled reactivity, but the mechanistic basis of this reactivity remains largely unexplored. Here, we have used single-molecule force spectroscopy to show that the mechanical reactivities of a series of ferrocenophanes are not correlated with ring strain in the reactants, but with the extent of rotational alignment of their two cyclopentadienyl ligands. Distal attachments can be used to restrict the mechanism of ferrocene dissociation to proceed through ligand 'peeling', as opposed to the more conventional 'shearing' mechanism of the parent ferrocene, leading the dissociation rate constant to increase by several orders of magnitude at forces of ~1 nN. It also leads to improved macroscopic, multi-responsive behaviour, including mechanochromism and force-induced cross-linking in ferrocenophane-containing polymers.

Enhanced polymer mechanical degradation through mechanochemically unveiled lactonization.

The mechanical degradation of polymers is typically limited to a single chain scission per triggering chain stretching event, and the loss of stress transfer that results from the scission limits the extent of degradation that can be achieved. Here, we report that the mechanically triggered ring-opening of a [4.2.0]bicyclooctene (BCOE) mechanophore sets up a delayed, force-free cascade lactonization that results in chain scission. Delayed chain scission allows many eventual scission events to be initiated within a single polymer chain. Ultrasonication of a 120 kDa BCOE copolymer mechanically remodels the polymer backbone, and subsequent lactonization slowly (~days) degrades the molecular weight to 4.4 kDa, > 10× smaller than control polymers in which lactonization is blocked. The force-coupled kinetics of ring-opening are probed by single molecule force spectroscopy, and mechanical degradation in the bulk is demonstrated. Delayed scission offers a strategy to enhanced mechanical degradation and programmed obsolescence in structural polymeric materials.

Mechanically Gated Degradable Polymers.

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

A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials.

Mechanically coupled proton transduction offers potential for stress-responsive polymeric materials whose properties can be switched via acid-triggered coloration, polymerization/cross-linking, or degradation. 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, we report a new mechanoacid based on 2-methoxy-substituted gem-dichlorocyclopropane (MeO-gDCC). Pulsed ultrasonication leads to the mechanochemical 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-molecule 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 mechanical activation leads to a strain-triggered color change prior to fracture of the elastomer. The postactivation kinetics of coloration are used to demonstrate a new concept in mechanochromism, namely, a spectroscopic indicator of not only whether and where a mechanical event has occurred but when it occurred.

Combined Constant-Force and Constant-Velocity Single-Molecule Force Spectroscopy of the Conrotatory Ring Opening Reaction of Benzocyclobutene.

Single-molecule force spectroscopy (SMFS) of multi-mechanophore polymers has been used to provide kinetic and mechanistic insights into mechanochemical reactions. Whereas biological systems have benefitted from force clamp spectroscopy, synthetic polymers have been studied primarily with constant-velocity methods. Here, force clamp SMFS is applied to the mechanically accelerated conrotatory ring opening of benzocyclobutene, and a comparison with constant-velocity SMFS extends the range of available rate-versus-force data and corroborates the use of constant-velocity SMFS to extract force dependencies.