Publisher Correction: Cleavable comonomers enable degradable, recyclable thermoset plastics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cleavable comonomers enable degradable, recyclable thermoset plastics.

Thermosets-polymeric materials that adopt a permanent shape upon curing-have a key role in the modern plastics and rubber industries, comprising about 20 per cent of polymeric materials manufactured today, with a worldwide annual production of about 65 million tons1,2. The high density of crosslinks that gives thermosets their useful properties (for example, chemical and thermal resistance and tensile strength) comes at the expense of degradability and recyclability. Here, using the industrial thermoset polydicyclopentadiene as a model system, we show that when a small number of cleavable bonds are selectively installed within the strands of thermosets using a comonomer additive in otherwise traditional curing workflows, the resulting materials can display the same mechanical properties as the native material, but they can undergo triggered, mild degradation to yield soluble, recyclable products of controlled size and functionality. By contrast, installation of cleavable crosslinks, even at much higher loadings, does not produce degradable materials. These findings reveal that optimization of the cleavable bond location can be used as a design principle to achieve controlled thermoset degradation. Moreover, we introduce a class of recyclable thermosets poised for rapid deployment.

Self-Amplified HF Release and Polymer Deconstruction Cascades Triggered by Mechanical Force.

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.

Remolding and Deconstruction of Industrial Thermosets via Carboxylic Acid-Catalyzed Bifunctional Silyl Ether Exchange.

Convenient strategies for the deconstruction and reprocessing of thermosets could improve the circularity of these materials, but most approaches developed to date do not involve established, high-performance engineering materials. Here, we show that bifunctional silyl ether, i.e., R'O-SiR2-OR'', (BSE)-based comonomers generate covalent adaptable network analogues of the industrial thermoset polydicyclopentadiene (pDCPD) through a novel BSE exchange process facilitated by the low-cost food-safe catalyst octanoic acid. Experimental studies and density functional theory calculations suggest an exchange mechanism involving silyl ester intermediates with formation rates that strongly depend on the Si-R2 substituents. As a result, pDCPD thermosets manufactured with BSE comonomers display temperature- and time-dependent stress relaxation as a function of their substituents. Moreover, bulk remolding of pDCPD thermosets is enabled for the first time. Altogether, this work presents a new approach toward the installation of exchangeable bonds into commercial thermosets and establishes acid-catalyzed BSE exchange as a versatile addition to the toolbox of dynamic covalent chemistry.

Clip Chemistry: Diverse (Bio)(macro)molecular and Material Function through Breaking Covalent Bonds.

In the two decades since the introduction of the "click chemistry" concept, the toolbox of "click reactions" has continually expanded, enabling chemists, materials scientists, and biologists to rapidly and selectively build complexity for their applications of interest. Similarly, selective and efficient covalent bond breaking reactions have provided and will continue to provide transformative advances. Here, we review key examples and applications of efficient, selective covalent bond cleavage reactions, which we refer to herein as "clip reactions." The strategic application of clip reactions offers opportunities to tailor the compositions and structures of complex (bio)(macro)molecular systems with exquisite control. Working in concert, click chemistry and clip chemistry offer scientists and engineers powerful methods to address next-generation challenges across the chemical sciences.

Cleavable Comonomers for Chemically Recyclable Polystyrene: A General Approach to Vinyl Polymer Circularity.

Many common polymers, especially vinyl polymers, are inherently difficult to chemically recycle and are environmentally persistent. The introduction of low levels of cleavable comonomer additives into existing vinyl polymerization processes could facilitate the production of chemically deconstructable and recyclable variants with otherwise equivalent properties. Here, we report thionolactones that serve as cleavable comonomer additives for the chemical deconstruction and recycling of vinyl polymers prepared through free radical polymerization, using polystyrene (PS) as a model example. Deconstructable PS of different molar masses (∼20-300 kDa) bearing varied amounts of statistically incorporated thioester backbone linkages (2.5-55 mol %) can be selectively depolymerized to yield well-defined thiol-terminated fragments (<10 kDa) that are suitable for oxidative repolymerization to generate recycled PS of nearly identical molar mass to the parent material, in good yields (80-95%). A theoretical model is provided to generalize this molar mass memory effect. Notably, the thermomechanical properties of deconstructable PS bearing 2.5 mol % of cleavable linkages and its recycled product are similar to those of virgin PS. The additives were also shown to be effective for deconstruction of a cross-linked styrenic copolymer and deconstruction and repolymerization of a polyacrylate, suggesting that cleavable comonomers may offer a general approach toward circularity of many vinyl (co)polymers.

Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.

Navigating the Biological-Material Interface with the Guide of Chemical Biology.

Research at the biological-material interface often has translation in mind, with applications in medical implants, drug delivery, and regenerative medicine. While the clinical impact of this research is undeniable, a clearer picture of the in vivo behavior of materials is needed to address longstanding limitations in performance and function. Advances in chemical biology and biotechnology have propelled our understanding of how small molecules and biologics behave in living systems. Adapting these techniques to the study of synthetic materials, enabled by modern polymer chemistry, will bring molecular resolution to biological-material interactions and guide the development of next-generation biomaterials for therapeutic and diagnostic applications.

Direct Intracellular Delivery of Cell-Impermeable Probes of Protein Glycosylation by Using Nanostraws.

Bioorthogonal chemistry is an effective tool for elucidating metabolic pathways and measuring cellular activity, yet its use is currently limited by the difficulty of getting probes past the cell membrane and into the cytoplasm, especially if more complex probes are desired. Here we present a simple and minimally perturbative technique to deliver functional probes of glycosylation into cells by using a nanostructured "nanostraw" delivery system. Nanostraws provide direct intracellular access to cells through fluid conduits that remain small enough to minimize cell perturbation. First, we demonstrate that our platform can deliver an unmodified azidosugar, N-azidoacetylmannosamine, into cells with similar effectiveness to a chemical modification strategy (peracetylation). We then show that the nanostraw platform enables direct delivery of an azidosugar modified with a charged uridine diphosphate group (UDP) that prevents intracellular penetration, thereby bypassing multiple enzymatic processing steps. By effectively removing the requirement for cell permeability from the probe, the nanostraws expand the toolbox of bioorthogonal probes that can be used to study biological processes on a single, easy-to-use platform.

Imaging bacterial peptidoglycan with near-infrared fluorogenic azide probes.

Fluorescent probes designed for activation by bioorthogonal chemistry have enabled the visualization of biomolecules in living systems. Such activatable probes with near-infrared (NIR) emission would be ideal for in vivo imaging but have proven difficult to engineer. We present the development of NIR fluorogenic azide probes based on the Si-rhodamine scaffold that undergo a fluorescence enhancement of up to 48-fold upon reaction with terminal or strained alkynes. We used the probes for mammalian cell surface imaging and, in conjunction with a new class of cyclooctyne D-amino acids, for visualization of bacterial peptidoglycan without the need to wash away unreacted probe.

CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum.

Fluorescent bioorthogonal smart probes across the visible spectrum will enable sensitive visualization of metabolically labeled molecules in biological systems. Here we present a unified design, based on the principle of photoinduced electron transfer, to access a panel of highly fluorogenic azide probes that are activated by conversion to the corresponding triazoles via click chemistry. Termed the CalFluors, these probes possess emission maxima that range from green to far red wavelengths, and enable sensitive biomolecule detection under no-wash conditions. We used the CalFluor probes to image various alkyne-labeled biomolecules (glycans, DNA, RNA, and proteins) in cells, developing zebrafish, and mouse brain tissue slices.

Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry.

Vertebrate glycans constitute a large, important, and dynamic set of post-translational modifications that are notoriously difficult to manipulate and image. Although the chemical reporter strategy has been used in conjunction with bioorthogonal chemistry to image the external glycosylation state of live zebrafish and detect tumor-associated glycans in mice, the ability to image glycans systemically within a live organism has remained elusive. Here, we report a method that combines the metabolic incorporation of a cyclooctyne-functionalized sialic acid derivative with a ligation reaction of a fluorogenic tetrazine, allowing for the imaging of sialylated glycoconjugates within live zebrafish embryos.

Design strategies for bioorthogonal smart probes.

Bioorthogonal chemistry has enabled the selective labeling and detection of biomolecules in living systems. Bioorthogonal smart probes, which become fluorescent or deliver imaging or therapeutic agents upon reaction, allow for the visualization of biomolecules or targeted delivery even in the presence of excess unreacted probe. This review discusses the strategies used in the development of bioorthogonal smart probes and highlights the potential of these probes to further our understanding of biology.

Thiol-triggered deconstruction of bifunctional silyl ether terpolymers via an SNAr-triggered cascade.

While Si-containing polymers can often be deconstructed using chemical triggers such as fluoride, acids, and bases, they are resistant to cleavage by mild reagents such as biological nucleophiles, thus limiting their end-of-life options and potential environmental degradability. Here, using ring-opening metathesis polymerization, we synthesize terpolymers of (1) a "functional" monomer (e.g., a polyethylene glycol macromonomer or dicyclopentadiene); (2) a monomer containing an electrophilic pentafluorophenyl (PFP) substituent; and (3) a cleavable monomer based on a bifunctional silyl ether . Exposing these polymers to thiols under basic conditions triggers a cascade of nucleophilic aromatic substitution (SNAr) at the PFP groups, which liberates fluoride ions, followed by cleavage of the backbone Si-O bonds, inducing polymer backbone deconstruction. This method is shown to be effective for deconstruction of polyethylene glycol (PEG) based graft terpolymers in organic or aqueous conditions as well as polydicyclopentadiene (pDCPD) thermosets, significantly expanding upon the versatility of bifunctional silyl ether based functional polymers.

Hydrogen Peroxide-Triggered Disassembly of Boronic Ester-Cross-Linked Brush-Arm Star Polymers.

The concentrations of reactive oxygen species (ROS), e.g., H2O2, are often elevated in diseased tissue microenvironments. Therefore, the selective detection of ROS could enable new diagnostic methods or tools for chemical biology. Here, we report the synthesis of boronic ester-bis-norbornene core-cross-linked brush-arm star polymers (BASPs) with polyethylene glycol (PEG) or PEG-branch-spirocyclohexyl nitroxide (chex) shells. Size exclusion chromatography (SEC) and dynamic light scattering (DLS) showed that these BASPs have narrowly dispersed molar masses and average hydrodynamic diameters of 23 ± 2 nm, respectively. Moreover, due to their core-shell structures, these BASPs disassemble into bottlebrush fragments with improved selectivity for H2O2 over ROS such as peroxynitrite (ONOO-) and hypochlorite (-OCl). Finally, H2O2 induced disassembly of chex-containing BASPs induces a change in transverse magnetic relaxivity that can be detected via magnetic resonance imaging (MRI). Chex-BASPs may represent a valuable new diagnostic tool for H2O2 sensing.

A Model Ensemble Approach Enables Data-Driven Property Prediction for Chemically Deconstructable Thermosets in the Low-Data Regime.

Thermosets present sustainability challenges that could potentially be addressed through the design of deconstructable variants with tunable properties; however, the combinatorial space of possible thermoset molecular building blocks (e.g., monomers, cross-linkers, and additives) and manufacturing conditions is vast, and predictive knowledge for how combinations of these molecular components translate to bulk thermoset properties is lacking. Data science could overcome these problems, but computational methods are difficult to apply to multicomponent, amorphous, statistical copolymer materials for which little data exist. Here, leveraging a data set with 101 examples, we introduce a closed-loop experimental, machine learning (ML), and virtual screening strategy to enable predictions of the glass transition temperature (Tg) of polydicyclopentadiene (pDCPD) thermosets containing cleavable bifunctional silyl ether (BSE) comonomers and/or cross-linkers with varied compositions and loadings. Molecular features and formulation variables are used as model inputs, and uncertainty is quantified through model ensembling, which together with heavy regularization helps to avoid overfitting and ultimately achieves predictions within <15 °C for thermosets with compositionally diverse BSEs. This work offers a path to predicting the properties of thermosets based on their molecular building blocks, which may accelerate the discovery of promising plastics, rubbers, and composites with improved functionality and controlled deconstructability.

Fluorogenic azidofluoresceins for biological imaging.

Fluorogenic probes activated by bioorthogonal chemical reactions can enable biomolecule imaging in situations where it is not possible to wash away unbound probe. One challenge for the development of such probes is the a priori identification of structures that will undergo a dramatic fluorescence enhancement by virtue of the chemical transformation. With the aid of density functional theory calculations reported previously by Nagano and co-workers, we identified azidofluorescein derivatives that were predicted to undergo an increase in fluorescence quantum yield upon Cu-catalyzed or Cu-free cycloaddition with linear or cyclic alkynes, respectively. Four derivatives were experimentally verified in model reactions, and one, a 4-azidonaphthylfluorescein analogue, was further shown to label alkyne-functionalized proteins in vitro and glycoproteins on cells with excellent selectivity. The azidofluorescein derivative also enabled cell imaging under no-wash conditions with good signal above background. This work establishes a platform for the rational design of fluorogenic azide probes with spectral properties tailored for biological imaging.

Chemically Induced Cell Wall Stapling in Bacteria.

Transpeptidation reinforces the structure of cell-wall peptidoglycan, an extracellular heteropolymer that protects bacteria from osmotic lysis. The clinical success of transpeptidase-inhibiting ß-lactam antibiotics illustrates the essentiality of these cross-linkages for cell-wall integrity, but the presence of multiple, seemingly redundant transpeptidases in many species makes it challenging to determine cross-link function. Here, we present a technique to link peptide strands by chemical rather than enzymatic reaction. We employ biocompatible click chemistry to induce triazole formation between azido- and alkynyl-d-alanine residues that are metabolically installed in the peptidoglycan of Gram-positive or Gram-negative bacteria. Synthetic triazole cross-links can be visualized using azidocoumarin-d-alanine, an amino acid derivative that undergoes fluorescent enhancement upon reaction with terminal alkynes. Cell-wall stapling protects Escherichia coli from treatment with the broad-spectrum ß-lactams ampicillin and carbenicillin. Chemical control of cell-wall structure in live bacteria can provide functional insights that are orthogonal to those obtained by genetics.

Tailored silyl ether monomers enable backbone-degradable polynorbornene-based linear, bottlebrush and star copolymers through ROMP.

Ring-opening metathesis polymerization of norbornene-based (macro)monomers is a powerful approach for the synthesis of macromolecules with diverse compositions and complex architectures. Nevertheless, a fundamental limitation of polymers prepared by this strategy is their lack of facile degradability, limiting their utility in a range of applications. Here we describe a class of readily available bifunctional silyl ether-based cyclic olefins that copolymerize efficiently with norbornene-based (macro)monomers to provide copolymers with backbone degradability under mildly acidic aqueous conditions and degradation rates that can be tuned over several orders of magnitude, depending on the silyl ether substituents. These monomers can be used to manipulate the in vivo biodistribution and clearance rate of polyethylene glycol-based bottlebrush polymers, as well as to synthesize linear, bottlebrush and brush-arm star copolymers with degradable segments. We expect that this work will enable preparation of degradable polymers by ROMP for biomedical applications, responsive self-assembly and improved sustainability.

Imaging Mycobacterial Trehalose Glycolipids.

Cell surface trehalose mycolates are important modulators of mycobacterial pathogenesis and host immune response. We discuss the use of fluorescent and fluorogenic trehalose probes for the detection of the mycobacterial trehalose glycolipids. These probes enable real-time imaging of trehalose mycolate biosynthesis and mycomembrane dynamics in the laboratory as well as in clinical settings for the detection of mycobacteria in patient samples.