Molecular Ball Joints: Mechanochemical Perturbation of Bullvalene Hardy-Cope Rearrangements in Polymer Networks.

The solution-state fluxional behavior of bullvalene has fascinated physical organic and supramolecular chemists alike. Little effort, however, has been put into investigating bullvalene applications in bulk, partially due to difficulties in characterizing such dynamic systems. To address this knowledge gap, we herein probe whether bullvalene Hardy-Cope rearrangements can be mechanically perturbed in bulk polymer networks. We use dynamic mechanical analysis to demonstrate that the activation barrier to the glass transition process is significantly elevated for bullvalene-containing materials relative to "static" control networks. Furthermore, bullvalene rearrangements can be mechanically perturbed at low temperatures in the glassy region; such behavior facilitates energy dissipation (i.e., increased hysteresis energy) and polymer chain alignment to stiffen the material (i.e., increased Young's modulus) under load. Computational simulations corroborate our work that showcases bullvalene as a reversible "low-force" covalent mechanophore in the modulation of viscoelastic behavior.

Mechanoredox Catalysis Enables a Sustainable and Versatile Reversible Addition-Fragmentation Chain Transfer Polymerization Process.

The sustainable synthesis of macromolecules with control over sequence and molar mass remains a challenge in polymer chemistry. By coupling mechanochemistry and electron-transfer processes (i.e., mechanoredox catalysis), an energy-conscious controlled radical polymerization methodology is realized. This work explores an efficient mechanoredox reversible addition-fragmentation chain transfer (RAFT) polymerization process using mechanical stimuli by implementing piezoelectric barium titanate and a diaryliodonium initiator with minimal solvent usage. This mechanoredox RAFT process demonstrates exquisite control over poly(meth)acrylate dispersity and chain length while also showcasing an alternative to the solution-state synthesis of semifluorinated polymers that typically utilize exotic solvents and/or reagents. This chemistry will find utility in the sustainable development of materials across the energy, biomedical, and engineering communities.

Stochastic Bullvalene Architecture Modulates Structural Rigidity in π-Rich Macromolecules.

The synthesis and processing of π-rich polymers found in novel electronics and textiles is difficult because chain stiffness leads to low solubility and high thermal transitions. The incorporation of "shape-shifting" molecular cages into π-rich backbone provides an ensemble of structural kinks to modulate chain architecture via a self-contained library of valence isomers. In this work, we report the synthesis and characterization of (bullvalene-co-phenylene)s that feature smaller persistence lengths than a prototypical rigid rod polymer, poly(p-phenylene). By varying the amount of bullvalene incorporation within a poly(p-phenylene) chain (0-50 %), we can tune thermal properties and solution-state conformation. These features are caused by stochastic bullvalene isomers within the polymer backbone that result in kinked architectures. Synthetically, bullvalene incorporation offers a facile method to decrease structural rigidity within π-rich materials without concomitant crystallization. VT NMR experiments confirm that these materials remain dynamic in solution, offering the opportunity for future stimuli-responsive applications.

Upcycling of Polybutadiene Facilitated by Selenium-Mediated Allylic Amination.

Accumulation of end-of-life plastics presents ongoing environmental concerns. One strategy to solve this grand challenge is to invent new techniques that modify post-consumer waste and impart new functionality. While promising approaches for the chemical upcycling of commodity polyolefins and polyaromatics exist, analogous approaches to repurpose unsaturated polymers (e.g., polybutadiene) are scarce. In this work, we propose a method to upcycle polybutadiene, one of the most widely used commercial rubbers, via a mild, metal-free allylic amination reaction. The resulting materials have tunable thermal and surface wetting properties as a function of both sulfonamide identity and grafting density. Importantly, this approach maintains the parent alkene microstructure without evidence of olefin reduction, olefin transposition, and/or chain scission. Based on these findings, we anticipate future applications in the remediation of complex elastomers and vulcanized rubbers.

A Cyclic Ruthenium Benzylidene Initiator Platform Enhances Reactivity for Ring-Expansion Metathesis Polymerization.

Ring-expansion metathesis polymerization (REMP) has shown potential as an efficient strategy to access cyclic macromolecules. Current approaches that utilize cyclic olefin feedstocks suffer from poor functional group tolerance, low initiator stability, and slow reaction kinetics. Improvements to current initiators will address these issues in order to develop more versatile and user-friendly technologies. Herein, we report a reinvigorated tethered ruthenium-benzylidene initiator, CB6, that utilizes design features from ubiquitous Grubbs-type initiators that are regularly applied in linear polymerizations. We report the controlled synthesis of functionalized cyclic poly(norbornene)s and demonstrate that judicious ligand modifications not only greatly improve kinetics but also lead to enhanced initiator stability. Overall, CB6 is an adaptable platform for the study and application of cyclic macromolecules via REMP.

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.

Stereochemical Sequence Dictates Unimolecular Diblock Copolymer Assembly.

Deciphering the significance of length, sequence, and stereochemistry in block copolymer self-assembly remains an ongoing challenge. A dearth of methods to access uniform block co-oligomers/polymers with precise stereochemical sequences has precluded such studies. Here, we develop iterative exponential growth methods for the synthesis of a small library of unimolecular stereoisomeric diblock 32-mers. X-ray scattering reveals that stereochemistry modulates the phase behavior of these polymers, which we rationalize based on simulations carried out on a theoretical model system. This work demonstrates that stereochemical sequence can play a crucial role in unimolecular polymer self-assembly.

Iterative Reductive Aromatization/Ring-Closing Metathesis Strategy toward the Synthesis of Strained Aromatic Belts.

The construction of all sp(2)-hybridized molecular belts has been an ongoing challenge in the chemistry community for decades. Despite numerous attempts, these double-stranded macrocycles remain outstanding synthetic challenges. Prior approaches have relied on late-state oxidations and/or acid-catalyzed processes that have been incapable of accessing the envisaged targets. Herein, we describe the development of an iterative reductive aromatization/ring-closing metathesis approach. Successful syntheses of nanohoop targets containing benzo[k]tetraphene and dibenzo[c,m]pentaphene moieties not only provide proof of principle that aromatic belts can be derived by this new strategy but also represent some of the largest aromatic belt fragments reported to date.

Iterative Exponential Growth Synthesis and Assembly of Uniform Diblock Copolymers.

Studies on the phase segregation of unimolecular block copolymers (BCPs) are limited by a lack of reliable, versatile methods for the synthesis of such polymers on the preparative scale. Herein, we describe an advancement of Iterative Exponential Growth (IEG) wherein chiral allyl-based IEG oligomers are subjected to thiol-ene reactions and converted into unimolecular BCPs. With this strategy we have synthesized uniform BCPs with molar masses up to 12.1 kDa on ∼1 g scale. BCPs composed of decane-based side chains and either triethyleneglycol- or thioglycerol-based side chains phase-segregate into hexagonal cylinder morphologies. The assembly is not driven by side-chain crystallization, but is instead the result of amorphous BCP assembly.

Syntheses of the smallest carbon nanohoops and the emergence of unique physical phenomena.

The design and construction of non-natural products have fascinated and perplexed organic chemists for years. Their assembly, akin to what has been accomplished for the total synthesis of natural products, has stretched the limits of what can be prepared in the laboratory. Unlike many natural products, however, carbon-rich structures often lack heteroatoms, further complicating their construction. Consider some of the classical molecules in this genre: cubane and dodecahedrane. While highly symmetric, their assembly is far from trivial. These fascinating hydrocarbon targets have fueled the development of carbon-carbon bond-forming reactions, as new methods are needed to access these types of compounds. Among these carbon-rich structures, polycyclic aromatics such as helicenes, fullerenes, and some fullerenes share common ground due to the distortion of one or more aromatic rings out of planarity. Recently added to this group are the [n]cycloparaphenylenes ([n]CPPs), "carbon nanohoops". Here, a linear string of benzene rings connected at the para positions is wrapped back upon itself to form a cyclic structure. Clearly a simple linear p-oligophenylene cannot be cyclized in this manner without extremely harsh reaction conditions. In order to access these structures using solution-phase organic chemistry, clever synthetic strategies that can compensate for this severe distortion are required. Although cycloparaphenylenes can be considered the smallest possible fragment of an armchair carbon nanotube (CNT), they were envisioned as synthetic targets long before CNTs were discovered in 1991. CPP synthesis was first attempted in 1934, almost 70 years before Iijima's first report on CNTs. The long-forgotten targets reemerged in 1993 with a report from Vögtle, though he ultimately was unsuccessful in achieving their synthesis. More than a decade later, in 2008, CPPs succumbed to total synthesis by Jasti and Bertozzi, allowing access to three different-sized carbon nanohoops in milligram quantities. Since then, the Jasti group has embraced the smallest CPPs as inspiring synthetic targets, challenging us to develop new methodology to construct increasingly strained macrocycles. Having recently synthesized [5]-, [6]- and [7]CPP, the three smallest nanohoops synthesized to date, we have been able to realize a variety of new physical phenomena unique to these structures. Perhaps most significantly, unlike linear p-phenylenes and inorganic quantum dots, the HOMO-LUMO gaps of the CPPs narrow with decreasing CPP size. The smallest CPPs discussed in this Account illustrate this feature exceptionally well, as their HOMO-LUMO gaps become narrower than those of even the longest p-polyphenylenes. The smaller CPPs are fascinating from a structural standpoint as well because of the high amount of distortion in each benzene ring. From the synthesis of [7]CPP (84 kcal/mol of strain energy) to that of [5]CPP (119 kcal/mol of strain energy), our laboratory has been able to test the boundaries of synthetic and physical organic chemistry. In this Account, we detail how these challenging macrocycles were synthesized and the unique properties these structures possess.

Self-trapping of excitons, violation of Condon approximation, and efficient fluorescence in conjugated cycloparaphenylenes.

Cycloparaphenylenes, the simplest structural unit of armchair carbon nanotubes, have unique optoelectronic properties counterintuitive in the class of conjugated organic materials. Our time-dependent density functional theory study and excited state dynamics simulations of cycloparaphenylene chromophores provide a simple and conceptually appealing physical picture explaining experimentally observed trends in optical properties in this family of molecules. Fully delocalized degenerate second and third excitonic states define linear absorption spectra. Self-trapping of the lowest excitonic state due to electron-phonon coupling leads to the formation of spatially localized excitation in large cycloparaphenylenes within 100 fs. This invalidates the commonly used Condon approximation and breaks optical selection rules, making these materials superior fluorophores. This process does not occur in the small molecules, which remain inefficient emitters. A complex interplay of symmetry, π-conjugation, conformational distortion and bending strain controls all photophysics of cycloparaphenylenes.

Shake, shear, and grind! - the evolution of mechanoredox polymerization methodology.

In the last half decade, mechanoredox catalysis has enabled an entirely new genre of polymerization methodology. In this paradigm, mechanical force, such as ultrasonic cavitation bubble collapse or ball mill grinding, polarizes piezoelectric nanoparticles; the resultant piezopotential drives the redox processes necessary for free- and controlled-radical polymerizations. Since being introduced, evolution of these methods facilitates exploration of mechanistic underpinnings behind key electron-transfer events. Mechanical force has not only been identified as a "greener" alternative to more traditional reaction stimuli (e.g., heat, light) for the synthesis of commodity polymers, but also a potential technology to enable the production of novel thermoplastic and thermoset materials that are either challenging, or even impossible, to access using conventional solution-state approaches. In this Feature Article, significant contributions to such methods are highlighted within. Advances and ongoing challenges in both ultrasound and ball milling driven reactions for radical polymerization and crosslinking are identified and discussed.

Ancillary Ligand Lability Improves Control in Cyclic Ruthenium Benzylidene Initiated Ring-Expansion Metathesis Polymerizations.

The synthesis of well-defined cyclic polymers is crucial to exploring applications spanning engineering, energy, and biomedicine. These materials lack chain-ends and are therefore imbued with unique bulk properties. Despite recent advancements, the general methodology for controlled cyclic polymer synthesis via ring-expansion metathesis polymerization (REMP) remains challenging. Low initiator activity leads to high molar mass polymers at short reaction times that subsequently "evolve" to smaller polymeric products. In this work, we demonstrate that in situ addition of pyridine to the tethered ruthenium-benzylidene REMP initiator CB6 increases ancillary ligand lability to synthesize controlled and low dispersity cyclic poly(norbornene) on a short time scale without relying on molar mass evolution events.

Synthesis, characterization, and computational studies of cycloparaphenylene dimers.

Two novel arene-bridged cycloparaphenylene dimers (1 and 2) were prepared using a functionalized precursor, bromo-substituted macrocycle 7. The preferred conformations of these dimeric structures were evaluated computationally in the solid state, as well as in the gas and solution phases. In the solid state, the trans configuration of 1 is preferred by 34 kcal/mol due to the denser crystal packing structure that is achieved. In contrast, in the gas phase and in solution, the cis conformation is favored by 7 kcal/mol (dimer 1) and 10 kcal/mol (dimer 2), with a cis to trans activation barrier of 20 kcal/mol. The stabilization seen in the cis conformations is attributed to the increased van der Waals interactions between the two cycloparaphenylene rings. These calculations indicate that the cis conformation is accessible in solution, which is promising for future efforts toward the synthesis of short carbon nanotubes (CNTs) via cycloparaphenylene monomers. In addition, the optoelectronic properties of these dimeric cycloparaphenylenes were characterized both experimentally and computationally for the first time.

Diaryliodonium salts facilitate metal-free mechanoredox free radical polymerizations.

Mechanically-induced redox processes offer a promising alternative to more conventional thermal and photochemical synthetic methods. For macromolecule synthesis, current methods utilize sensitive transition metal additives and suffer from background reactivity. Alternative methodology will offer exquisite control over these stimuli-induced mechanoredox reactions to couple force with redox-driven chemical transformations. Herein, we present the iodonium-initiated free-radical polymerization of (meth)acrylate monomers under ultrasonic irradiation and ball-milling conditions. We explore the kinetic and structural consequences of these complementary mechanical inputs to access high molecular weight polymers. This methodology will undoubtedly find broad utility across stimuli-controlled polymerization reactions and adaptive material design.

Bottlebrush polymers with flexible enantiomeric side chains display differential biological properties.

Chirality and molecular conformation are central components of life: biological systems rely on stereospecific interactions between discrete (macro)molecular conformers, and the impacts of stereochemistry and rigidity on the properties of small molecules and biomacromolecules have been intensively studied. Nevertheless, how these features affect the properties of synthetic macromolecules has received comparably little attention. Here we leverage iterative exponential growth and ring-opening metathesis polymerization to produce water-soluble, chiral bottlebrush polymers (CBPs) from two enantiomeric pairs of macromonomers of differing rigidity. Remarkably, CBPs with conformationally flexible, mirror image side chains show several-fold differences in cytotoxicity, cell uptake, blood pharmacokinetics and liver clearance; CBPs with comparably rigid, mirror image side chains show no differences. These observations are rationalized with a simple model that correlates greater conformational freedom with enhanced chiral recognition. Altogether, this work provides routes to the synthesis of chiral nanostructured polymers and suggests key roles for stereochemistry and conformational rigidity in the design of future biomaterials.

Selective synthesis of strained [7]cycloparaphenylene: an orange-emitting fluorophore.

[n]Cycloparaphenylenes, which are short fragments of carbon nanotubes, have unique size-dependent optical properties. In this communication, we describe the first synthesis of [7]cycloparaphenylene ([7]CPP), the smallest cycloparaphenylene prepared to date. In order to access this structure, we have developed a synthetic route that capitalizes on successive orthogonal Suzuki-Miyaura coupling reactions. [7]CPP has 83 kcal/mol of strain energy and an orange emission at 592 nm.

Controlled Polymerization of Norbornene Cycloparaphenylenes Expands Carbon Nanomaterials Design Space.

Carbon-based materials-such as graphene nanoribbons, fullerenes, and carbon nanotubes-elicit significant excitement due to their wide-ranging properties and many possible applications. However, the lack of methods for precise synthesis, functionalization, and assembly of complex carbon materials has hindered efforts to define structure-property relationships and develop new carbon materials with unique properties. To overcome this challenge, we employed a combination of bottom-up organic synthesis and controlled polymer synthesis. We designed norbornene-functionalized cycloparaphenylenes (CPPs), a family of macrocycles that map onto armchair carbon nanotubes of varying diameters. Through ring-opening metathesis polymerization, we accessed homopolymers as well as block and statistical copolymers constructed from "carbon nanohoops" with a high degree of structural control. These soluble, sp2-carbon-dense polymers exhibit tunable fluorescence emission and supramolecular responses based on composition and sequence. This work represents an important advance toward bridging the gap between small molecules and functional carbon-based materials.

Brush-First and ROMP-Out with Functional (Macro)monomers: Method Development, Structural Investigations, and Applications of an Expanded Brush-Arm Star Polymer Platform.

The efficient synthesis of complex functional polymeric nanomaterials is often challenging. Ru-initiated ring-opening metathesis polymerization (ROMP) of multivalent macromonomers followed by cross-linking to form brush-arm star (BASP) polymers enables access to well-defined nano-structures with diverse functionality. This "brush-first" method leaves active Ru in the BASP microgel core, which could potentially be used in a subsequent "ROMP-out" (RO) step to introduce further modifications to the BASP structure via the addition of (macro)monomers. Here, we study this RO approach in depth. The efficiency of RO is assessed for a variety of BASP compositions using a combination of inductively coupled plasma mass spectrometry and gel permeation chromatography. To demonstrate the modularity of the RO process, arylboronic acid-functionalized BASPs were prepared; uptake of these RO-BASPs into hypersialylated cancer cells was enhanced relative to non-functionalized BASPs as determined by flow cytometry and fluorescence microscopy. In addition, the self-assembly of miktoarm BASPs prepared via brush-first and RO with different macromonomers is demonstrated. The combination of brush-first ROMP with RO provides a simple, modular strategy for access to a wide array of functional nanomaterials.

Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging.

Nitroxides occupy a privileged position among plausible metal-free magnetic resonance imaging (MRI) contrast agents (CAs) due to their inherently low-toxicity profiles; nevertheless, their translational development has been hindered by a lack of appropriate contrast sensitivity. Nanostructured materials with high nitroxide densities, where each individual nitroxide within a macromolecular construct contributes to the image contrast, could address this limitation, but the synthesis of such materials remains challenging. Here, we report a modular and scalable synthetic approach to nitroxide-based brush-arm star polymer (BASP) organic radical CAs (ORCAs) with high nitroxide loadings. The optimized ∼30 nm diameter "BASP-ORCA3" displays outstanding T2 sensitivity with a very high molecular transverse relaxivity ( r2 > 1000 mM-1 s-1). BASP-ORCA3 further exhibits excellent stability in vivo, no acute toxicity, and highly desirable pharmacokinetic and biodistribution profiles for longitudinal detection of tumors by MRI. When injected intravenously into mice bearing subcutaneous plasmacytomas, BASP-ORCA3 affords distinct in vivo visualization of tumors on translationally relevant time scales. Leveraging its high sensitivity, BASP-ORCA3 enables efficient mapping of tumor necrosis, which is an important biomarker to predict therapeutic outcomes. Moreover, BASP-ORCA3 allows for detection of millimetric tumor implants in a disseminated murine model of advanced-stage human ovarian cancer that possess genetic, histological, and vascular characteristics that are similar to those seen in patients. This work establishes BASP-ORCA3 as a promising metal-free spin contrast agent for MRI.