Transient Covalent Polymers through Carbodiimide-Driven Assembly.

Biochemical systems make use of out-of-equilibrium polymers generated under kinetic control. Inspired by these systems, many abiotic supramolecular polymers driven by chemical fuel reactions have been reported. Conversely, polymers based on transient covalent bonds have received little attention, even though they have the potential to complement supramolecular systems by generating transient structures based on stronger bonds and by offering a straightforward tuning of reaction kinetics. In this study, we show that simple aqueous dicarboxylic acids give poly(anhydrides) when treated with the carbodiimide EDC. Transient covalent polymers with molecular weights exceeding 15,000 are generated which then decompose over the course of hours to weeks. Disassembly kinetics can be controlled using simple substituent effects in the monomer design. The impact of solvent polarity, carbodiimide concentration, temperature, pyridine concentration, and monomer concentration on polymer properties and lifetimes has been investigated. The results reveal substantial control over polymer assembly and disassembly kinetics, highlighting the potential for fine-tuned kinetic control in nonequilibrium polymerization systems.

Carbodiimide-Driven Toughening of Interpenetrated Polymer Networks.

Recent work has demonstrated that temporary crosslinks in polymer networks generated by chemical "fuels" afford materials with large, transient changes in their mechanical properties. This can be accomplished in carboxylic-acid-functionalized polymer hydrogels using carbodiimides, which generate anhydride crosslinks with lifetimes on the order of minutes to hours. Here, the impact of the polymer network architecture on the mechanical properties of transiently crosslinked materials was explored. Single networks (SNs) were compared to interpenetrated networks (IPNs). Notably, semi-IPN precursors that give IPNs on treatment with carbodiimide give much higher fracture energies (i.e., resistance to fracture) and superior resistance to compressive strain compared to other network architectures. A precursor semi-IPN material featuring acrylic acid in only the free polymer chains yields, on treatment with carbodiimide, an IPN with a fracture energy of 2400 J/m2, a fourfold increase compared to an analogous semi-IPN precursor that yields a SN. This resistance to fracture enables the formation of macroscopic complex cut patterns, even at high strain, underscoring the pivotal role of polymer architecture in mechanical performance.

Chemically Fueled Reinforcement of Polymer Hydrogels.

Carbodiimide-fueled anhydride bond formation has been used to enhance the mechanical properties of permanently crosslinked polymer networks, giving materials that exhibit transitions from soft gels to covalently reinforced gels, eventually returning to the original soft gels. Temporary changes in mechanical properties result from a transient network of anhydride crosslinks, which eventually dissipate by hydrolysis. Over an order of magnitude increase in the storage modulus is possible through carbodiimide fueling. The time-dependent mechanical properties can be modulated by the concentration of carbodiimide, temperature, and primary chain architecture. Because the materials remain rheological solids, new material functions such as temporally controlled adhesion and rewritable spatial patterns of mechanical properties have been realized.

Engineering Chiral Induction in Centrally Functionalized o-Phenylenes.

Work on foldamers, nonbiological oligomers that mimic the hierarchical structure of biomacromolecules, continues to yield new architectures of ever increasing complexity. o-Phenylenes, a class of helical aromatic foldamers, are well-suited to this area because of their structural simplicity and the straightforward characterization of their folding in solution. However, control of structure requires, by definition, control over folding handedness. Control over o-phenylene twist sense is currently lacking. While chiral induction from groups at o-phenylene termini has been demonstrated, it would be useful to instead direct twisting from internal positions to leave the ends free. Here, we explore chiral induction in a series of o-phenylenes with chiral imides at their centers. Conformational behavior has been studied by nuclear magnetic resonance and circular dichroism spectroscopies and density functional theory calculations. Chiral induction in otherwise unfunctionalized o-phenylenes is generally poor. However, strategic functionalization of the helix surface with trifluoromethyl or methyl groups allows it to better interact with the imide groups, greatly increasing diastereomeric excesses. The sense of chiral induction is consistent with computational models that suggest that it primarily arises from a steric effect.

Conformational Control of ortho-Phenylenes by Terminal Amides.

Control over the folding of oligomers, be it broad induction of a preferred helical handedness or subtle changes in the orientations of individual functional groups, is important for applications ranging from molecular recognition to long-range conformational communication. Here, we report a series of ortho-phenylene hexamers functionalized with achiral and chiral amides at their termini. NMR spectroscopy, taking advantage of 19F labeling, allows multiple conformers to be detected for each compound. In combination with CD spectroscopy and DFT calculations, specific geometries corresponding to each conformer have been identified and quantified. General conclusions about the effect of sterics and the amide linker on conformational behavior have been drawn, revealing some similarities to and key differences from previously reported imines. A model for twist sense control has been developed that is supported by computational models.

PET-RAFT Polymerization of Star Polymers with Folded ortho-Phenylene Cores.

ortho-Phenylenes are one of the simplest classes of aromatic foldamers, adopting helical geometries because of aromatic stacking interactions. The folding and misfolding of ortho-phenylenes are slow on the NMR timescale at or below room temperature, allowing detection of folding states using 1 H NMR spectroscopy. Herein, an ortho-phenylene hexamer is coupled with a RAFT chain transfer agent (CTA) on each repeat unit. A variety of acrylic monomers are polymerized onto the CTA-functionalized ortho-phenylene using PET-RAFT to yield functionalized star polymers with ortho-phenylene cores. The steric bulk of the acrylate monomer units as well as the chain length of each arm of the star polymer is varied. 1 H NMR spectroscopy shows that the folding of the ortho-phenylenes do not vary, providing a robust helical core for star polymer systems.

Guest-Driven Control of Folding in a Crown-Ether-Functionalized ortho-Phenylene.

A crown-ether-functionalized o-phenylene tetramer has been synthesized and coassembled with monotopic and ditopic, achiral and chiral secondary ammonium ion guests. NMR spectroscopy shows that the o-phenylene forms both 1:1 and 1:2 complexes with monotopic guests while remaining well-folded. Binding of an elongated ditopic guest, however, forces the o-phenylene to misfold by pulling the terminal rings apart. A chiral ditopic guest biases the o-phenylene twist sense.

Substituent Effects on Transient, Carbodiimide-Induced Geometry Changes in Diphenic Acids.

Nucleotide-induced conformational changes in motor proteins are key to many important cell functions. Inspired by this biological behavior, we report a simple chemically fueled system that exhibits carbodiimide-induced geometry changes. Bridging via transient anhydride formation leads to a significant reduction of the twist about the biaryl bond of substituted diphenic acids, giving a simple molecular clamp. The kinetics are well-described by a simple mechanism, allowing structure-property effects to be determined. The kinetic parameters can be used to derive important characteristics of the system such as the efficiencies (anhydride yields), maximum anhydride concentrations, and overall lifetimes. Transient diphenic anhydrides tolerate steric hindrance ortho to the biaryl bond but are significantly affected by electronic effects, with electron-deficient substituents giving lower yields, peak conversions, and lifetimes. The results provide useful guidelines for the design of functional systems incorporating diphenic acid units.

Fluorine Labeling of ortho-Phenylenes to Facilitate Conformational Analysis.

1H NMR spectroscopy is a powerful tool for the conformational analysis of ortho-phenylene foldamers in solution. However, as o-phenylenes are integrated into ever more complex systems, we are reaching the limits of what can be analyzed by 1H- and 13C-based NMR techniques. Here, we explore fluorine labeling of o-phenylene oligomers for analysis by 19F NMR spectroscopy. Two series of fluorinated oligomers have been synthesized. Optimization of monomers for Suzuki coupling enables an efficient stepwise oligomer synthesis. The oligomers all adopt well-folded geometries in solution, as determined by 1H NMR spectroscopy and X-ray crystallography. 19F NMR experiments complement these methods well. The resolved singlets of one-dimensional 19F{1H} spectra are very useful for determining relative conformer populations. The additional information from two-dimensional 19F NMR spectra is also clearly valuable when making 1H assignments. The comparison of 19F isotropic shielding predictions to experimental chemical shifts is not, however, currently sufficient by itself to establish o-phenylene geometries.

The Transient Covalent Bond in Abiotic Nonequilibrium Systems.

Biochemical systems accomplish many critical functions with by operating out-of-equilibrium using the energy of chemical fuels. The formation of a transient covalent bond is a simple but very effective tool in designing analogous reaction networks. This Minireview focuses on the fuel chemistries that have been used to generate transient bonds in recent demonstrations of abiotic nonequilibrium systems (i.e., systems that do not make use of biological components). Fuel reactions are divided into two fundamental classifications depending on whether the fuel contributes structural elements to the activated state, a distinction that dictates how they can be used. Reported systems are further categorized by overall fuel reaction (e.g., hydrolysis of alkylating agents, carbodiimide hydration) and illustrate how similar chemistry can be used to effect a wide range of nonequilibrium behavior, ranging from self-assembly to the operation of molecular machines.

Structure-Property Effects in the Generation of Transient Aqueous Benzoic Acid Anhydrides by Carbodiimide Fuels.

The design of dissipative systems, which operate out-of-equilibrium by consuming chemical fuels, is challenging. As yet, there are a few examples of privileged fuel chemistries that can be broadly applied in abiotic systems in the same way that ATP hydrolysis is exploited throughout biochemistry. The key issue is that designing nonequilibrium systems is inherently about balancing the relative rates of coupled reactions. The use of carbodiimides as fuels to generate transient aqueous carboxylic anhydrides has recently been used in examples of new nonequilibrium materials and supramolecular assemblies. Here, we explore the kinetics of formation and decomposition of a series of benzoic anhydrides generated from the corresponding acids and EDC under typical conditions (EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride). The reactions can be described by a simple mechanism that merges known behavior for the two processes independently. Structure-property effects in these systems are dominated by differences in the anhydride decomposition rate. The kinetic parameters allow trends in concentration-dependent properties to be simulated, such as reaction lifetimes, peak anhydride concentrations, and yields. For key properties, there are diminishing returns with the addition of increasing amounts of fuel. These results should provide useful guidelines for the design of functional systems making use of this chemistry.

Dissipative Assembly of Macrocycles Comprising Multiple Transient Bonds.

Dissipative assembly has great potential for the creation of new adaptive chemical systems. However, while molecular assembly at equilibrium is routinely used to prepare complex architectures from polyfunctional monomers, species formed out of equilibrium have, to this point, been structurally very simple. In most examples the fuel simply effects the formation of a single short-lived covalent bond. Herein, we show that chemical fuels can assemble bifunctional components into macrocycles containing multiple transient bonds. Specifically, dicarboxylic acids give aqueous dianhydride macrocycles on treatment with a carbodiimide. The macrocycles are assembled efficiently as a consequence of both fuel-dependent and fuel-independent mechanisms; they undergo slower decomposition, building up as the fuel recycles the components, and are a favored product of the dynamic exchange of the anhydride bonds. These results create new possibilities for generating structurally sophisticated out-of-equilibrium species.

Twisted Macrocycles with Folded ortho-Phenylene Subunits.

Many foldamers, oligomers that adopt well-defined secondary structures, are now known, including many exhibiting functional behavior. However, examples of foldamer subunits within larger architectures remain rare, despite the importance of higher-order structure in biomacromolecules. Here, we investigate the dynamic covalent assembly of short o-phenylenes, a simple class of aromatic foldamers, into twisted macrocycles. o-Phenylene tetramers have been combined with rod-shaped p-phenylene-, tolane-, and diphenylbutadiyene-based linkers using imine formation. Macrocyclization proceeds efficiently, inducing folding of the o-phenylenes. The resulting [3 + 3] macrocycles (three o-phenylenes and three linkers) are shape-persistent, triangular structures with twisted cores and internal diameters up to approximately 2 nm. The homochiral D3-symmetric and heterochiral C2-symmetric conformers can be distinguished by NMR spectroscopy. Analysis of the conformational distribution for the p-phenylene-linked macrocycle suggests that the o-phenylene units are largely decoupled, with the less-symmetrical configuration therefore entropically favored. Conformational dynamics were assessed by variable-temperature NMR spectroscopy. Confinement within the macrocyclic architecture slows the inversion of the o-phenylene moieties.

Dissipative Assembly of Aqueous Carboxylic Acid Anhydrides Fueled by Carbodiimides.

Biochemical systems make extensive use of chemically fueled processes (e.g., using ATP), but analogous abiotic systems remain rare. A key challenge is the identification of transformations that can be adapted to a range of applications and make use of readily available chemical fuels. In this context, the generation of transient covalent bonds is a fundamental tool for nonequilibrium systems chemistry. Here, we show that carbodiimides constitute a simple class of chemical fuels for dissipative assembly, taking advantage of their known reactivity to produce (hydrolytically unstable) anhydrides from carboxylic acids in water. Both aliphatic and aromatic anhydrides are formed on convenient time scales using the common, commercially available peptide coupling agent 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC). An important feature of this reaction is that no part of the carbodiimide is incorporated into the transient species; that is, the fuel is decoupled from the structure-and thus function-of the assembled state. We show that intramolecular anhydride formation of oligo(ethylene glycol) diacids gives macrocycles analogous to crown ethers, representing minimal examples of out-of-equilibrium supramolecular hosts. The kinetics and yields of macrocycle formation respond to cation guests, with the presence of matched cations decreasing their overall production.

Folding of ortho-Phenylenes.

In nature, the folding of oligomers and polymers is used to generate complex three-dimensional structures, yielding macromolecules with diverse functions in catalysis, recognition, transport, and charge- and energy-transfer. Over the past 20-30 years, chemists have sought to replicate this strategy by developing new foldamers: oligomers that fold into well-defined secondary structures in solution. A wide array of abiotic foldamers have been developed, ranging from non-natural peptides to aromatics. The ortho-phenylenes represent a recent addition to the family of aromatic foldamers. Despite their structural simplicity (chains of benzenes connected at the ortho positions), it was not until 2010 that systematic studies of o-phenylenes showed that they reliably fold into helices in solution (and in the solid state). This conformational behavior is of fundamental interest: o-Arylene and o-heteroarylene structures are found embedded within many other systems, part of an emerging interest in sterically congested polyphenylenes. Further, o-phenylenes are increasingly straightforward to synthesize because of continuing developments in arene-arene coupling, the Asao-Yamamoto benzannulation, and benzyne polymerization. In this Account, we discuss the folding of o-phenylenes with emphasis on features that make them unique among aromatic foldamers. Interconversion between their different backbone conformers is slow on the NMR time scale around room temperature. The (1)H NMR spectra of oligomers can therefore be deconvoluted to give sets of chemical shifts for different folding states. The chemical shifts are both highly sensitive to conformation and readily predicted using ab initio methods, affording critical information about the conformational distribution. The picture that emerges is that o-phenylenes fold into helices with offset stacking between every third repeat unit. In general, misfolding occurs primarily at the oligomer termini (i.e., "frayed ends"). Because of their structural simplicity, the folding can be described by straightforward models. The overall population can be divided into two enantiomeric pools, with racemization and misfolding as two distinct processes. Examination of substituent effects on folding reveals that the determinant of the relative stability of different conformers is (offset) aromatic stacking interactions parallel to the helical axis. That is, the folding of o-phenylenes is analogous to that of α-helices, with aromatic stacking in place of hydrogen bonding. The folding propensity can be tuned using well-known substituent effects on aromatic stacking, with moderate electron-withdrawing substituents giving nearly perfect folding. The combination of a simple folding mechanism and readily characterized conformational populations makes o-phenylenes attractive structural motifs for incorporation into more-complex architectures, an important part of the next phase of foldamer research.

Solvent effects on the folding of o-phenylene oligomers.

ortho-Phenylene oligomers fold into compact helical conformations in solution, and have therefore recently emerged as a class of foldamers. Previous work has shown that their folding is controlled by arene-arene stacking interactions parallel to the helical axis. Such interactions might reasonably be expected to be sensitive to solvent, but little is known of solvent effects in this system. Here, we report on the behavior of a representative set of o-phenylene oligomers in solvents ranging from non-polar (benzene) to polar and protic (methanol and water). The oligomers have been synthesized using post-oligomerization functionalization by click chemistry. Their folding is good in all solvents studied, but becomes measurably worse as the dielectric constant of the solvent increases. Thus, in contrast to the behavior of many other classes of aromatic foldamers, the folding propensity of o-phenylenes does not appear to be strongly affected by the solvophobic effect. Instead, the greater polarity of "frayed end" states governs their behavior.

Two- and Three-Tiered Stacked Architectures by Covalent Assembly.

Simple discotic cores functionalized with reactive arms have been assembled into two- and three-tiered covalent stacks through imine formation. The targets are obtained in good yields, but competing formation of misassembled byproducts highlights some of the challenges inherent to the thermodynamically controlled assembly of rigid, compact, three-dimensional architectures. The structures comprise a central stack of arenes surrounded by a triple helix of interconnected arms. The racemization rate is strongly dependent on the number of tiers, suggesting cooperative conformational coupling in these multi-tiered structures.

Enhanced helical folding of ortho-phenylenes through the control of aromatic stacking interactions.

The ortho-phenylenes are a simple class of foldamers, with the formation of helices driven by offset aromatic stacking interactions parallel to the helical axis. For the majority of reported o-phenylene oligomers, the perfectly folded conformer comprises perhaps 50-75% of the total population. Given the hundreds or thousands of possible conformers for even short oligomers, this distribution represents a substantial bias toward the folded state. However, "next-generation" o-phenylenes with better folding properties are needed if these structures are to be exploited as functional units within more complex architectures. Here, we report several new series of o-phenylene oligomers, varying both the nature and orientation of the substituents on every repeat unit. The conformational behavior was probed using a combination of NMR spectroscopy, DFT calculations, and X-ray crystallography. We find that increasing the electron-withdrawing character of the substituents gives oligomers with substantially improved folding properties. With moderately electron-withdrawing groups (acetoxy), we observe >90% of the perfectly folded conformer, and stronger electron withdrawing groups (triflate, cyano) give oligomers for which misfolded states are undetectable by NMR. The folding of these oligomers is only weakly solvent-dependent. General guidelines for the assessment of o-phenylene folding by NMR and UV-vis spectroscopy are also discussed.

Solution-phase dimerization of an oblong shape-persistent macrocycle.

A new shape-persistent macrocycle comprising two 2,3-triphenylene moieties bridged by m-phenylene ethynylenes has been synthesized. UV-vis and fluorescence spectroscopies indicate limited interaction between the two triphenylene units. The compound, which has a pronounced oblong shape (the core measures approximately 2.2 × 1.0 nm), aggregates in CDCl3 and toluene-d8 to give stacked dimers, as indicated by the (1)H NMR signals corresponding to protons on or near the core, which shift upfield with increasing concentration. These changes in NMR shielding were modeled using DFT calculations on candidate dimer geometries. The best match to the experimental data was obtained for a dimer consisting of arene-arene stacking by 3.6 Å (on average) with a displacement along the molecular long axis of 3.5-4.0 Å. This displacement is larger than can be explained by the electronic effects of aromatic stacking interactions. Instead, the minimization of steric interactions between the side chains appears to control the dimer geometry, with the alkoxy groups of one molecule sliding into registry with the gaps along the periphery of the other. Such lateral displacement (as opposed to rotation) is a direct consequence of the extended oval shape of the compound.

The role of arene-arene interactions in the folding of ortho-phenylenes.

The ortho-phenylenes are a simple class of helical oligomers and representative of the broader class of sterically congested polyphenylenes. Recent work has shown that o-phenylenes fold into well-defined helical conformations (in solution and, typically, in the solid state); however, the specific causes of this folding behavior have not been determined. Here, we report the effect of substituents on the conformational distributions of a series of o-phenylene hexamers. These experiments are complemented by dispersion-corrected DFT calculations on model oligomers (B97-D/TZV(2d,2p)). The results are consistent with a deterministic role for offset arene-arene stacking interactions on the folding behavior. On the basis of the experimental and computational results, we propose a model for o-phenylene folding with two simple rules. (1) Conformers are forbidden if they include a particular sequence of biaryl torsional states that causes excessive steric strain. These "ABA" states correspond to consecutive dihedral angles of -55°/+130°/-55° (or +55°/-130°/+55). (2) The stability of the remaining conformers is determined by offset arene-arene stacking interactions that are easily estimated as an additive function of the number of well-folded torsional states (±55°) along the backbone. For the parent, unsubstituted poly(o-phenylene), each interaction contributes roughly 0.5 kcal/mol to the helix stability (in chloroform), although their strength is sensitive to substituent effects. The behavior of the o-phenylenes as a class is discussed in the context of this model. They are analogous to α-helices, with axial aromatic stacking interactions in place of hydrogen bonding. The model predicts that the overall folding propensity should be quite sensitive to relatively small changes in the strength of the arene-arene stacking. In a broader sense, these results demonstrate that polyphenylenes may exhibit folding behavior that is amenable to simple models, and validate the use of diffusion-corrected DFT methods in predicting their three-dimensional structures.