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.

Improved Syntheses of Halogenated Benzene-1,2,3,4-Tetracarboxylic Diimides.

The preparation of halogenated benzene-1,2,3,4-tetracarboxylic diimide derivatives is challenging because of the possibility of competitive incorrect cyclizations and SNAr reactivity. Here, we demonstrate that bypassing traditional cyclic anhydrides and instead directly reacting dihalobenzene-1,2,3,4-tetracarboxylic acids with primary amines in acetic acid solvent successfully provides a range of desirable ortho-diimide products in good yields. Furthermore, we demonstrate that sterically challenging N-derivatizations can be readily achieved under microwave reactor conditions. The halogenated diimides described here are attractive building blocks for organic materials chemistry.

Cata-Annulated Azaacene Bisimides.

Ultra-electron-deficient azaacenes were synthesized via Buchwald-Hartwig coupling of ortho-diaminoarenes with chlorinated mellophanic diimide followed by oxidation of the intermediate N,N'-dihydro compounds with MnO2 or PbO2 . The resulting cata-annulated bisimide azaacenes have ultrahigh electron affinities with first reduction potentials as low as -0.35 V recorded for a tetraazapentacene. Attempts to prepare a tetrakis(dicarboximide)tetraazaheptacene resulted in the formation of a symmetric butterfly dimer.

A Highly Stabilized Phosphonium Ylide that Forms Supramolecular Dimers in Solution and the Solid State.

This work describes the unexpected formation of an unusual phosphonium ylide when attempting the synthesis of bisphosphonium pyromellitic diimides. Spectroscopic and crystallographic characterization reveals that a combination of π-π and CH⋅⋅⋅O interactions leads to supramolecular homodimerization of the ylide both in solution and in the solid-state. Only strong acids are able to protonate the ylide, which is otherwise inert to Wittig and alkylation reactivity. Taken together, these observations indicate that this compound is one of the most highly stabilized phosphonium ylides discovered to date.

Redox-Active Heteroacene Chromophores Derived from a Nonlinear Aromatic Diimide.

This work describes a three-step chromatography-free protocol for the synthesis of a novel organic materials building block, dichlorinated mellophanic diimide (MDI), that is shown to undergo nucleophilic substitution with a variety of ortho disubstituted benzenes to yield a series of chromophores. Furthermore, 1,2,4,5-tetrasubstituted benzenes can be used to synthesize tetraimide heteropentacene derivatives endcapped by MDI motifs. The fine-tuning effects of heteroatom identity were investigated by UV-vis and fluorescence spectroscopy, cyclic and differential pulse voltammetries, and density functional theory calculations. Oxidation of diamino MDI derivatives yields di- and tetraimide functionalized azaacenes with significantly lowered LUMO levels (down to -4.49 eV), narrowed band gaps (down to 1.81 eV), and high molar absorptivities (up to 84,000 M-1 cm-1).

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.