Nested non-covalent interactions expand the functions of supramolecular polymer networks.

Supramolecular polymer networks contain non-covalent cross-links that enable access to broadly tunable mechanical properties and stimuli-responsive behaviors; the incorporation of multiple unique non-covalent cross-links within such materials further expands their mechanical responses and functionality. To date, however, the design of such materials has been accomplished through discrete combinations of distinct interaction types in series, limiting materials design logic. Here we introduce the concept of leveraging "nested" supramolecular crosslinks, wherein two distinct types of non-covalent interactions exist in parallel, to control bulk material functions. To demonstrate this concept, we use polymer-linked Pd2L4 metal-organic cage (polyMOC) gels that form hollow metal-organic cage junctions through metal-ligand coordination and can exhibit well-defined host-guest binding within their cavity. In these "nested" supramolecular network junctions, the thermodynamics of host-guest interactions within the junctions affect the metal-ligand interactions that form those junctions, ultimately translating to substantial guest-dependent changes in bulk material properties that could not be achieved in traditional supramolecular networks with multiple interactions in series.

Internal Catalysis in Dynamic Hydrogels with Associative Thioester Cross-Links.

Thioesters are an essential functional group in biosynthetic pathways, which has motivated their development as reactive handles in probes and peptide assembly. Thioester exchange is typically accelerated by catalysts or elevated pH. Here, we report the use of bifunctional aromatic thioesters as dynamic covalent cross-links in hydrogels, demonstrating that at physiologic pH in aqueous conditions, transthioesterification facilitates stress relaxation on the time scale of hundreds of seconds. We show that intramolecular hydrogen bonding is responsible for accelerated exchange, evident in both molecular kinetics and macromolecular stress relaxation. Drawing from concepts in the vitrimer literature, this system exemplifies how dynamic cross-links that exchange through an associative mechanism enable tunable stress relaxation without altering stiffness.

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.

Angle-strained sila-cycloalkynes.

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.

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.

Classification of Hemilabile Ligands Using Machine Learning.

Hemilabile ligands have the capacity to partially disengage from a metal center, providing a strategy to balance stability and reactivity in catalysis, but they are not straightforward to identify. We identify ligands in the Cambridge Structural Database that have been crystallized with distinct denticities and are thus identifiable as hemilabile ligands. We implement a semi-supervised learning approach using a label-spreading algorithm to augment a small negative set that is supported by heuristic rules of ligand and metal co-occurrence. We show that a heuristic based on coordinating atom identity alone is not sufficient to identify whether a ligand is hemilabile, and our trained machine-learning classification models are instead needed to predict whether a bi-, tri-, or tetradentate ligand is hemilabile with high accuracy and precision. Feature importance analysis of our models shows that the second, third, and fourth coordination spheres all play important roles in ligand hemilability.

Tailoring Dynamic Hydrogels by Controlling Associative Exchange Rates.

Dithioalkylidenes are a newly-developed class of conjugate acceptors that undergo thiol exchange via an associative mechanism, enabling decoupling of key material properties for sustainability, biomedical, and sensing applications. Here, we show that the exchange rate is highly sensitive to the structure of the acceptor and tunable over four orders of magnitude in aqueous environments. Cyclic acceptors exchange rapidly, from 0.95 to 15.6 M-1s-1, while acyclic acceptors exchange between 3.77x10-3 and 2.17x10-2 M-1s-1. Computational, spectroscopic, and structural data suggest that cyclic acceptors are more reactive than their acyclic counterparts because of resonance stabilization of the tetrahedral exchange intermediate. We parametrize molecular reactivity with respect to computed descriptors of the electrophilic site and leverage this insight to design a compound with intermediate characteristics. Lastly, we incorporate this dynamic bond into hydrogels and demonstrate that the characteristic stress relaxation time (τ) is directly proportional to molecular kex.

Polymer Networks with Cubic, Mixed Pd(II) and Pt(II) M6L12 Metal-Organic Cage Junctions: Synthesis and Stress Relaxation Behavior.

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.

Computational Discovery of Stable Metal-Organic Frameworks for Methane-to-Methanol Catalysis.

The challenge of direct partial oxidation of methane to methanol has motivated the targeted search of metal-organic frameworks (MOFs) as a promising class of materials for this transformation because of their site-isolated metals with tunable ligand environments. Thousands of MOFs have been synthesized, yet relatively few have been screened for their promise in methane conversion. We developed a high-throughput virtual screening workflow that identifies MOFs from a diverse space of experimental MOFs that have not been studied for catalysis, yet are thermally stable, synthesizable, and have promising unsaturated metal sites for C-H activation via a terminal metal-oxo species. We carried out density functional theory calculations of the radical rebound mechanism for methane-to-methanol conversion on models of the secondary building units (SBUs) from 87 selected MOFs. While we showed that oxo formation favorability decreases with increasing 3d filling, consistent with prior work, previously observed scaling relations between oxo formation and hydrogen atom transfer (HAT) are disrupted by the greater diversity in our MOF set. Accordingly, we focused on Mn MOFs, which favor oxo intermediates without disfavoring HAT or leading to high methanol release energies─a key feature for methane hydroxylation activity. We identified three Mn MOFs comprising unsaturated Mn centers bound to weak-field carboxylate ligands in planar or bent geometries with promising methane-to-methanol kinetics and thermodynamics. The energetic spans of these MOFs are indicative of promising turnover frequencies for methane to methanol that warrant further experimental catalytic studies.

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.

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.

Endohedrally Functionalized Metal-Organic Cage-Cross-Linked Polymer Gels as Modular Heterogeneous Catalysts.

The immobilization of homogeneous catalysts onto supports to improve recyclability while maintaining catalytic efficiency is often a trial-and-error process limited by poor control of the local catalyst environment and few strategies to append catalysts to support materials. Here, we introduce a modular heterogenous catalysis platform that addresses these challenges. Our approach leverages the well-defined interiors of self-assembled Pd12L24 metal-organic cages/polyhedra (MOCs): simple mixing of a catalyst-ligand of choice with a polymeric ligand, spacer ligands, and a Pd salt induces self-assembly of Pd12L24-cross-linked polymer gels featuring endohedrally catalyst-functionalized junctions. Semi-empirical calculations show that catalyst incorporation into the MOC junctions of these materials has minimal affect on the MOC geometry, giving rise to well-defined nanoconfined catalyst domains as confirmed experimentally using several techniques. Given the unique network topology of these freestanding gels, they are mechanically robust regardless of their endohedral catalyst composition, allowing them to be physically manipulated and transferred from one reaction to another to achieve multiple rounds of catalysis. Moreover, by decoupling the catalyst environment (interior of MOC junctions) from the physical properties of the support (the polymer matrix), this strategy enables catalysis in environments where homogeneous catalyst analogues are not viable, as demonstrated for the Au(I)-catalyzed cyclization of 4-pentynoic acid in aqueous media.

Nickel-Catalyzed Radical Migratory Coupling Enables C-2 Arylation of Carbohydrates.

Nickel catalysis offers exciting opportunities to address unmet challenges in organic synthesis. Herein we report the first nickel-catalyzed radical migratory cross-coupling reaction for the direct preparation of 2-aryl-2-deoxyglycosides from readily available 1-bromosugars and arylboronic acids. The reaction features a broad substrate scope and tolerates a wide range of functional groups and complex molecular architectures. Preliminary experimental and computational studies suggest a concerted 1,2-acyloxy rearrangement via a cyclic five-membered-ring transition state followed by nickel-catalyzed carbon-carbon bond formation. The novel reactivity provides an efficient route to valuable C-2-arylated carbohydrate mimics and building blocks, allows for new strategic bond disconnections, and expands the reactivity profile of nickel catalysis.

Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis.

Mild methods to cleave the carbon-oxygen (C-O) bond in alkyl ethers could simplify chemical syntheses through the elaboration of these robust, readily available precursors. Here we report that dibromoboranes react with alkyl ethers in the presence of a nickel catalyst and zinc reductant to insert boron into the C-O bond. Subsequent reactivity can effect oxygen-to-nitrogen substitution or one-carbon homologation of cyclic ethers and more broadly streamline preparation of bioactive compounds. Mechanistic studies reveal a cleavage-then-rebound pathway via zinc/nickel tandem catalysis.

[2π + 2π] Photocycloaddition of Enones to Single-Walled Carbon Nanotubes Creates Fluorescent Quantum Defects.

Single-walled carbon nanotubes (SWCNTs) have been widely applied in biomedical fields such as drug delivery, biosensing, bioimaging, and tissue engineering. Understanding their reactivity with biomolecules is important for these applications. We describe here a photoinduced cycloaddition reaction between enones and SWCNTs. By creating covalent and tunable sp3 defects in the sp2 carbon lattice of SWCNTs through [2π + 2π] photocycloaddition, a bright red-shifted photoluminescence was gradually generated. The photocycloaddition functionalization was demonstrated with various organic molecules bearing an enone functional group, including biologically important oxygenated lipid metabolites. The mechanism of this reaction was studied empirically and using computational methods. Density functional theory calculations were employed to elucidate the identity of the reaction product and understand the origin of different substrate reactivities. The results of this study can enable engineering of the optical and electronic properties of semiconducting SWCNTs and provide understanding into their interactions with the lipid biocorona.

Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation.

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free -NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.

Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis.

C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we report a highly C3-selective allylation reaction of 1H-N-(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl 1H-indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory (DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation transition state.

The Thermal Rearrangement of an NHC-Ligated 3-Benzoborepin to an NHC-Boranorcaradiene.

An N-heterocyclic-carbene-ligated 3-benzoborepin with a bridged structure has been synthesized by double radical trans-hydroboration of benzo[3,4]cycloundec-3-ene-1,5-diyne with an N-heterocyclic carbene borane. The thermal reaction of the NHC-ligated borepin at 150 °C gives an isolable NHC-boranorcaradiene. Experiments and density functional theory calculations support a mechanism whereby the borepin initially rearranges to a boranorcaradiene by a thermal 6π-electrocyclic reaction. This is followed by 1,5-boron shift to give a rearranged boranorcaradiene. This shift occurs with stereoinversion at boron through a transition state with open-shell diradical character. This is the first example of the isolation of a boranorcaradiene from a thermal reaction of a borepin.

A Short Synthesis of Delavatine A Unveils New Insights into Site-Selective Cross-Coupling of 3,5-Dibromo-2-pyrone.

The recognition of latent symmetry in delavatine A has enabled a short synthesis of the natural product starting from 3,5-dibromo-2-pyrone. The concise synthetic route features a cascade process involving a 6π electrocyclization to construct the indane core of delavatine A. In addition, we have conducted detailed experimental and computational studies to gain an in-depth understanding of the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. This insight may provide new avenues to achieve the selective cross-coupling of multiply halogenated heteroarenes.

Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions.

Using a mechanically guided ligand design approach, a new ligand (SEGFAST) for the CuH-catalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM-SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, noncovalent ligand-substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for the practical, gram-scale synthesis of these novel hybrid ligand structures.