Incorporation of a self-immolative spacer enables mechanically triggered dual payload release.

Polymers that release functional small molecules in response to mechanical force are promising materials for a variety of applications including drug delivery, catalysis, and sensing. While many different mechanophores have been developed that enable the triggered release of a variety of small molecule payloads, most mechanophores are limited to one specific payload molecule. Here, we leverage the unique fragmentation of a 5-aryloxy-substituted 2-furylcarbinol derivative to design a novel mechanophore capable of the mechanically triggered release of two distinct cargo molecules. Critical to the mechanophore design is the incorporation of a self-immolative spacer to facilitate the release of a second payload. By varying the relative positions of each cargo molecule conjugated to the mechanophore, dual payload release occurs either concurrently or sequentially, demonstrating the ability to fine-tune the release profiles.

Multimechanophore Polymers for Mechanically Triggered Small Molecule Release with Ultrahigh Payload Capacity.

Polymers that release small molecules in response to mechanical force are promising for a variety of applications including drug delivery, catalysis, and sensing. While a number of mechanophores have been developed for the release of covalently bound payloads, existing strategies are either limited in cargo scope or, in the case of more general mechanophore designs, are restricted to the release of one or two cargo molecules per polymer chain. Herein, we introduce a nonscissile mechanophore based on a masked 2-furylcarbinol derivative that enables the preparation of multimechanophore polymers with ultrahigh payload capacity. We demonstrate that polymers prepared via ring-opening metathesis polymerization are capable of releasing hundreds of small-molecule payloads per polymer chain upon ultrasound-induced mechanochemical activation. This nonscissile masked 2-furylcarbinol mechanophore overcomes a major challenge in cargo loading capacity associated with previous 2-furylcarbinol mechanophore designs, enabling applications that benefit from much higher concentrations of delivered cargo.

Anomalous photochromism and mechanochromism of a linear naphthopyran enabled by a polarizing dialkylamine substituent.

In contrast to common angular naphthopyrans that exhibit strong photochromic and mechanochromic behavior, constitutionally isomeric linear naphthopyrans are typically not photochromic, due to the putative instability of the completely dearomatized merocyanine product. The photochemistry of linear naphthopyrans is thus relatively understudied compared to angular naphthopyrans, while the mechanochromism of linear naphthopyrans remains completely unexplored. Here we demonstrate that the incorporation of a polarizing dialkylamine substituent enables photochromic and mechanochromic behavior from polymers containing a novel linear naphthopyran motif. In solution phase experiments, a Lewis acid trap was necessary to observe accumulation of the merocyanine product upon photochemical and ultrasound-induced mechanochemical activation. However, the same linear naphthopyran molecule incorporated as a crosslinker in polydimethylsiloxane elastomers renders the materials photochromic and mechanochromic without the addition of any trapping agent. This study provides insights into the photochromic and mechanochromic reactivity of linear naphthopyrans that have conventionally been considered functionally inert, adding a new class of naphthopyran molecular switches to the repertoire of stimuli-responsive polymers.

Remote control of mechanochemical reactions under physiological conditions using biocompatible focused ultrasound.

External control of chemical reactions in biological settings with spatial and temporal precision is a grand challenge for noninvasive diagnostic and therapeutic applications. While light is a conventional stimulus for remote chemical activation, its penetration is severely attenuated in tissues, which limits biological applicability. On the other hand, ultrasound is a biocompatible remote energy source that is highly penetrant and offers a wide range of functional tunability. Coupling ultrasound to the activation of specific chemical reactions under physiological conditions, however, remains a challenge. Here, we describe a synergistic platform that couples the selective mechanochemical activation of mechanophore-functionalized polymers with biocompatible focused ultrasound (FUS) by leveraging pressure-sensitive gas vesicles (GVs) as acousto-mechanical transducers. The power of this approach is illustrated through the mechanically triggered release of covalently bound fluorogenic and therapeutic cargo molecules from polymers containing a masked 2-furylcarbinol mechanophore. Molecular release occurs selectively in the presence of GVs upon exposure to FUS under physiological conditions. These results showcase the viability of this system for enabling remote control of specific mechanochemical reactions with spatiotemporal precision in biologically relevant settings and demonstrate the translational potential of polymer mechanochemistry.

Naphthopyran molecular switches and their emergent mechanochemical reactivity.

Naphthopyran molecular switches undergo a ring-opening reaction upon external stimulation to generate intensely colored merocyanine dyes. Their unique modularity and synthetic accessibility afford exceptional control over their properties and stimuli-responsive behavior. Commercial applications of naphthopyrans as photoswitches in photochromic ophthalmic lenses have spurred an extensive body of work exploring naphthopyran-merocyanine structure-property relationships. The recently discovered mechanochromic behavior of naphthopyrans has led to their emergent application in the field of polymer mechanochemistry, enabling advances in the design of force-responsive materials as well as fundamental insights into mechanochemical reactivity. The structure-property relationships established in the photochemical literature serve as a convenient blueprint for the design of naphthopyran molecular force probes with precisely tuned properties. On the other hand, the mechanochemical reactivity of naphthopyran diverges in many cases from the conventional photochemical pathways, resulting in unexpected properties and opportunities for deeper understanding and innovation in polymer mechanochemistry. Here, we highlight the features of the naphthopyran scaffold that render it a powerful platform for the design of mechanochromic materials and review recent advances in naphthopyran mechanochemistry.

Competitive Activation Experiments Reveal Significantly Different Mechanochemical Reactivity of Furan-Maleimide and Anthracene-Maleimide Mechanophores.

During the past two decades, our understanding of mechanochemical reactivity has advanced considerably. Nevertheless, an incomplete knowledge of structure-activity relationships and the principles that govern mechanochemical transformations limits molecular design. The experimental development of mechanophores has thus benefited from simple computational tools like CoGEF, from which quantitative metrics like rupture force can be extracted to estimate reactivity. Furan-maleimide (FM) and anthracene-maleimide (AM) Diels-Alder adducts are widely studied mechanophores that undergo retro-Diels-Alder reactions upon mechanical activation in polymers. Despite possessing significantly different thermal stability, similar rupture forces predicted by CoGEF calculations suggest that these compounds exhibit similar mechanochemical reactivity. Here, we directly probe the relative mechanochemical reactivity of FM and AM adducts through competitive activation experiments. Ultrasound-induced mechanochemical activation of bis-adduct mechanophores comprising covalently tethered FM and AM subunits reveals pronounced selectivity-as high as ∼13:1-for reaction of the FM adduct compared to the AM adduct. Computational models provide insight into the greater reactivity of the FM mechanophore, indicating a more efficient mechanochemical coupling for the FM adduct compared to the AM adduct. The methodology employed here to directly interrogate the relative reactivity of two different mechanophores using a tethered bis-adduct configuration may be useful for other systems where more common sonication-based approaches are limited by poor sensitivity.

Validation of an Accurate and Expedient Initial Rates Method for Characterizing Mechanophore Reactivity.

Understanding structure-mechanochemical reactivity relationships is important for informing the rational design of new stimuli-responsive polymers. To this end, establishing accurate reaction kinetics for mechanophore activation is a key objective. Here, we validate an initial rates method that enables the accurate and rapid determination of rate constants for ultrasound-induced mechanochemical transformations. Experimental reaction profiles are well-aligned with theoretical models, which support that the initial rates method effectively deconvolutes the kinetics of specific mechanophore activation from the competitive process of nonspecific chain scission.

Mechanically gated formation of donor-acceptor Stenhouse adducts enabling mechanochemical multicolour soft lithography.

Stress-sensitive molecules called mechanophores undergo productive chemical transformations in response to mechanical force. A variety of mechanochromic mechanophores, which change colour in response to stress, have been developed, but modulating the properties of the dyes generally requires the independent preparation of discrete derivatives. Here we introduce a mechanophore platform enabling mechanically gated multicolour chromogenic reactivity. The mechanophore is based on an activated furan precursor to donor-acceptor Stenhouse adducts (DASAs) masked as a hetero-Diels-Alder adduct. Mechanochemical activation of the mechanophore unveils the DASA precursor, and subsequent reaction with a secondary amine generates an intensely coloured DASA. Critically, the properties of the DASA are controlled by the amine, and thus a single mechanophore can be differentiated post-activation to produce a wide range of functionally diverse DASAs. We highlight this system by establishing the concept of mechanochemical multicolour soft lithography whereby a complex multicolour composite image is printed into a mechanochemically active elastomer through an iterative process of localized compression followed by reaction with different amines.

Mechanical Force Enables an Anomalous Dual Ring-Opening Reaction of Naphthodipyran.

Multimodal mechanophores that exhibit complex mechanochromic behavior beyond the typical binary response are capable of distinguishing between multiple stress states through discrete changes in color. Naphthodipyran photoswitches contain two pyran rings fused to a central naphthalene core and represent a potentially promising framework for multimodal reactivity. However, the concurrent ring opening of both pyran moieties has previously proven inaccessible via photochemical activation. Here, we demonstrate that mechanical force supplied to naphthodipyran through covalently linked polymer chains generates the elusive dual ring-opened dimerocyanine product with unique near-infrared absorption properties. Trapping with boron trifluoride renders the merocyanine dyes thermally persistent and reveals apparent sequential ring-opening behavior that departs from the reactivity of previously studied mechanophores under the high strain rates imposed by ultrasound-induced solvodynamic chain extension.

Incorporation of a Tethered Alcohol Enables Efficient Mechanically Triggered Release in Aprotic Environments.

Polymers that release small molecules in response to mechanical force are promising for a wide variety of applications. While offering a general platform for mechanically triggered release, previous mechanophore designs based on masked 2-furylcarbinol derivatives are limited to polar protic solvent environments for efficient release of the chemical payload. Here, we report a masked furfuryl carbonate mechanophore incorporating a tethered primary alcohol that enables efficient release of a hydroxycoumarin cargo in the absence of a protic solvent. Density functional calculations also implicate an intramolecular hydrogen bonding interaction between the tethered alcohol and the carbonyl oxygen of the carbonate that reduces the activation barrier for carbonate fragmentation leading to molecular release. This new mechanophore design expands the generality of the masked 2-furylcarbinol platform for mechanically triggered release, enabling the implementation of this strategy in a wider range of chemical environments.

Examining the Impact of Relative Mechanophore Activity on the Selectivity of Ultrasound-Induced Mechanochemical Chain Scission.

Despite recent advances in polymer mechanochemistry, a more complete understanding of the factors that dictate the ultrasound-induced mechanochemical activation efficiency of mechanophores is necessary. Here, we examine how the identity of a mechanophore, and hence its unique force-coupled reactivity, affects the competition between mechanophore activation and nonspecific polymer backbone scission. Polymers incorporating distinct mechanophores but with putatively similar "chain-centeredness" exhibit widely different mechanochemical activation efficiencies. Furthermore, we employ mechanophores that can be orthogonally cleaved following ultrasonication using heat or light to report on the degree of nonspecific backbone scission that occurs for different mechanophore-containing polymers subjected to ultrasound-induced mechanical force. Our results illustrate that the identity of the mechanophore as well as its position in the polymer chain are inextricably important parameters that together control the selectivity of mechanophore activation during ultrasonication.

Harnessing the Power of Force: Development of Mechanophores for Molecular Release.

Polymers that release small molecules in response to mechanical force are promising materials for a variety of applications ranging from sensing and catalysis to targeted drug delivery. Within the rapidly growing field of polymer mechanochemistry, stress-sensitive molecules known as mechanophores are particularly attractive for enabling the release of covalently bound payloads with excellent selectivity and control. Here, we review recent progress in the development of mechanophore-based molecular release platforms and provide an optimistic, yet critical perspective on the fundamental and technological advancements that are still required for this promising research area to achieve significant impact.

A modular approach to mechanically gated photoswitching with color-tunable molecular force probes.

Molecular force probes conveniently report on mechanical stress and/or strain in polymers through straightforward visual cues. Unlike conventional mechanochromic mechanophores, the mechanically gated photoswitching strategy decouples mechanochemical activation from the ultimate chromogenic response, enabling the mechanical history of a material to be recorded and read on-demand using light. Here we report a completely redesigned, highly modular mechanophore platform for mechanically gated photoswitching that offers a robust, accessible synthesis and late stage diversification through Pd-catalyzed cross-coupling reactions to precisely tune the photophysical properties of the masked diarylethene (DAE) photoswitch. Using solution-phase ultrasonication, the reactivity of a small library of functionally diverse mechanophores is demonstrated to be exceptionally selective, producing a chromogenic response under UV irradiation only after mechanochemical activation, revealing colored DAE isomers with absorption spectra that span the visible region of the electromagnetic spectrum. Notably, mechanically gated photoswitching is successfully translated to solid polymeric materials for the first time, demonstrating the potential of the masked diarylethene mechanophore for a variety of applications in force-responsive polymeric materials.

5-Aryloxy substitution enables efficient mechanically triggered release from a synthetically accessible masked 2-furylcarbinol mechanophore.

Polymers that release small molecules in response to mechanical force are attractive materials for a wide variety of applications. Here, we report a new mechanophore platform based on a masked 2-furylcarbinol derivative that incorporates a 5-aryloxy group, which serves as both an electron-rich substituent to accelerate molecular release and the position of polymer attachment proximal to the furan-maleimide junction. The mechanophore is readily synthesized and efficiently releases both phenol and arylamine payloads following mechanical activation.

Mechanically Triggered Release of Functionally Diverse Molecular Payloads from Masked 2-Furylcarbinol Derivatives.

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.

Generation of an Elusive Permanent Merocyanine via a Unique Mechanochemical Reaction Pathway.

We report the discovery of a 2H-naphtho[1,2-b]pyran mechanophore that produces a permanent merocyanine dye upon mechanochemical activation, in contrast to the reversible product generated photochemically. Experiments suggest that the irreversibility of the mechanically generated merocyanine is due to a unique reaction in which the scission of an ester C-O bond reveals a ß-hydroxy ketone that locks the merocyanine through an intramolecular H-bonding interaction. In addition to demonstrating the reactivity using solution-phase ultrasonication, permanent merocyanine generation is also achieved in solid polymeric materials. The permanent coloration achieved with the naphthopyran mechanophore affords unique opportunities for sensing and force-recording applications as well as fundamental studies limited by the reversibility of typical colorimetric force probes.

Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry.

The development of force-responsive molecules called mechanophores is a central component of the field of polymer mechanochemistry. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to molecular release and self-healing materials. Nevertheless, an insufficient understanding of structure-activity relationships limits experimental 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 mechanical force on a molecule and enables the prediction of mechanochemical reactivity. Here, we use the CoGEF method to systematically evaluate every covalent mechanophore reported to date and compare the predicted mechanochemical reactivity to experimental results. Molecules that are mechanochemically inactive are also studied as negative controls. In general, mechanochemical reactions predicted with the CoGEF method at the common B3LYP/6-31G* level of density functional theory are in excellent agreement with reactivity determined experimentally. Moreover, bond rupture forces obtained from CoGEF calculations are compared to experimentally measured forces and demonstrated to be reliable indicators of mechanochemical activity. This investigation validates the CoGEF method as a powerful tool for predicting mechanochemical reactivity, enabling its widespread adoption to support the developing field of polymer mechanochemistry. Secondarily, this study provides a contemporary catalog of over 100 mechanophores developed to date.

Designing naphthopyran mechanophores with tunable mechanochromic behavior.

Mechanochromic molecular force probes conveniently report on stress and strain in polymeric materials through straightforward visual cues. We capitalize on the versatility of the naphthopyran framework to design a series of mechanochromic mechanophores that exhibit highly tunable color and fading kinetics after mechanochemical activation. Structurally diverse naphthopyran crosslinkers are synthesized and covalently incorporated into silicone elastomers, where the mechanochemical ring-opening reactions are achieved under tension to generate the merocyanine dyes. Strategic structural modifications to the naphthopyran mechanophore scaffold produce dramatic differences in the color and thermal electrocyclization behavior of the corresponding merocyanine dyes. The color of the merocyanines varies from orange-yellow to purple upon the introduction of an electron donating pyrrolidine substituent, while the rate of thermal electrocyclization is controlled through electronic and steric factors, enabling access to derivatives that display both fast-fading and persistent coloration after mechanical activation and subsequent stress relaxation. In addition to identifying key structure-property relationships for tuning the behavior of the naphthopyran mechanophore, the modularity of the naphthopyran platform is demonstrated by leveraging blends of structurally distinct mechanophores to create materials with desirable multicolor mechanochromic and complex stimuli-responsive behavior, expanding the scope and accessibility of force-responsive materials for applications such as multimodal sensing.

Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate.

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

Force-Dependent Multicolor Mechanochromism from a Single Mechanophore.

We report a bis-naphthopyran mechanophore that exhibits force-dependent changes in visible absorption. A series of polymers incorporating a chain-centered bis-naphthopyran mechanophore was synthesized and mechanically activated using ultrasonication. By varying the length of the polymer chains, the force delivered to the mechanophore is modulated systematically. We demonstrate that the relative distribution of two distinctly colored merocyanine products is altered predictably with different magnitudes of applied force, resulting in gradient multicolor mechanochromism. The mechanochemical reactivity of bis-naphthopyran is supported by density functional theory calculations and described by a theoretical model that provides insight into the force-color relationship.