Supramolecular Chemistry and Self-Assembly in Organic Materials

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Supramolecular Chemistry and Self-Assembly in Organic Materials Design Samuel I. Stupp*,†,‡,§,⊥ and Liam C. Palmer† †

Departments of Chemistry, ‡Materials Science and Engineering, and §Medicine, ⊥Institute for BioNanotechnology in Medicine, Northwestern University, Evanston, Illinois 60208, United States ABSTRACT: Organic materials naturally lend themselves to the crafting of structure and function using the strategies of self-assembly and supramolecular chemistry employed so effectively by biological systems. This perspective illustrates progress over the past two decades on selfassembly in materials chemistry through research on systems where function is directly linked to noncovalent interactions among molecules. The genesis of this approach in chemistry of materials involves the design of relatively simple structures using hydrogen bonding, π−π stacking, metal−ligand interactions, electrostatic forces, strong dipole−dipole association, hydrophobic forces, and steric repulsion. Gradually many new and exciting opportunities have emerged, such as supramolecular nanostructures that assemble into functional bulk materials and supramolecular polymers in which the motif of covalent connections among monomers is imitated by creating one-dimensional assemblies of an arbitrarily large set of molecules in both composition and size. Supramolecular polymers offer the opportunity to create structures that integrate unprecedented order in 1D assemblies with interesting dynamics through bond reversibility. Other fascinating systems are those in which intermolecular interactions and other forces can be used to create the hierarchical and highly functional structures ubiquitous in biology, such as bone and muscle, in which different types of order exist within the same structure at different length scales. Directions that have a bright future include nonequilibrium dynamic materials with the capacity to be adaptive, self-repairing, chemically alterable, and even replicativeall characteristics we see in living organic matter. Additional promising areas include 2D and 3D systems that are not necessarily classical crystals and the rational synthesis of functional organic−inorganic hybrid materials. The most exciting aspect of self-assembly and supramolecular chemistry is their open ended nature, and these are two areas of chemistry for which many new principles will be established in this century. KEYWORDS: hierarchical self-assembly, hybrid materials, organic ferroelectrics, templation

1. INTRODUCTION This perspective is not meant to be an exhaustive review of work in the fields of self-assembly and supramolecular chemistry in organic materials; it is rather a personal reflection on this field, including a description of its scope and some possible future directions. For convenience some of the comments in this perspective are illustrated with examples from the authors’ laboratory over the past two decades. Throughout the second half of the 20th century, the dominant chemistry of organic materials was without a doubt polymerization, particularly after the broad acceptance of the macromolecular hypothesis pioneered by Staudinger and his award of the 1953 Nobel Prize in Chemistry. As we begin the 21st century, judging from an enormous body of literature, the centric areas in organic materials are supramolecular chemistry and self-assembly spanning many length scales from monolayers, nanostructures, vesicles, gels, and membranes to bulk materials. The laboratory of Jean-Marie Lehn introduced the concept of supramolecular chemistry and its connection to functional structures, work recognized with the Nobel Prize three decades after Staudinger.1 In the 1990s, George © XXXX American Chemical Society

Whitesides’ laboratory pioneered the concept of self-assembly of nanoscale structures2−4 and the authors’ laboratory developed the concept of self-assembly for functional bulk materials using designed molecules.5,6 The influence of selfassembly strategies in polymeric materials research is reflected in the strong interest on the organization of well-defined block copolymers into defined superlattices and patterns.7−9 Most notably the exciting new field of supramolecular polymers10 is based on control of noncovalent interactions among monomers and processes of self-assembly to generate ordered 1D structures. In organic nanoscience supramolecular chemistry is key in the design of self-assembling monolayers,11 as well as nanostructures with diverse shapes and dimensionalities.12−14 Supramolecular chemistry has enabled the development of bulk materials such as molecular organic frameworks,15,16 organoSpecial Issue: Celebrating Twenty-Five Years of Chemistry of Materials Received: September 10, 2013 Revised: October 25, 2013

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gels,17,18 and biomolecular materials for medicine based on peptides.19 One facet of self-assembling and supramolecular organic materials that has developed extensively in recent years is the engineering of structures at all scales using Watson− Crick pairing of nucleic acids.20−23 Self-assembly in the context of materials implies that the components are programmed by design to create a functional, ordered structure with little intervention from humans or machines. This process can occur at any scale, ranging from the nano- and micrometer scale to macroscopic dimensions. By far the most popular research in soft matter has been “attempting” to design relatively simple structures using hydrogen bonding, π−π stacking, metal−ligand interactions, electrostatic forces, strong dipole−dipole association, hydrophobic forces, and steric repulsion. The reality is that our ability to predict the structural features from combinations of such interactions, let alone the functional outcomes, in the assembled materials is still in its infancy and in these early times for self-assembly and supramolecular chemistry most of the learning is done in retrospect after discovery of structures and their functions. One of the first examples of self-assembling supramolecular materials was reported by the authors’ laboratory in the form of nanostructure lattices.6 In the system reported in 1997, a triblock molecule labeled as a rodcoil was reported to assemble into mushroomlike noncentrosymmetric objects that were fairly monodisperse (Figure 1a and b). The molecules were described as “rodcoils” because they contained a rigid, easily crystallizable segment that was covalently bonded flexible blocks that were unable to order. We found that nanoscale crystallization of the rod segments brought together the monomers; however, complete crystallization was limited by the repulsive forces among the noncrystallizable coil segments, limiting the size of the aggregates to about 100 molecules. The resulting organic nanoclusters (ca. 5 nm) are zero-dimensional, like quantum dots, but have a noncentrosymmetric, polar shape. The entropy of the coils appears to be integral to the restricted supramolecular growth. Molecular dynamics simulations showed that as the number of crystallized rods in the aggregate increases, the attached coils are more restricted conformationally.24 At larger length scales, the nanostructures formed 2D superlattices stacked in polar fashion giving rise to transparent films with a number of interesting properties characteristic of noncentrosymmetric materials (see Figure 1c). These included contrasting surface chemistry on opposite sides of the films, one reflecting the hydrophilic chemistry of the bottom of mushroom object stems and one expressing the hydrophobic nature of coils in the mushroom cap. Interestingly, cyanosubstituted rodcoil assembles were used in macroscopic films with measurable piezoelectric behavior. The observed electromechanical properties result from interactions between the substrate and polar domains of the film.25 Ordering within these films is further confirmed by small-angle X-ray scattering (SAXS).26 The films were also piezoelectric and capable of generating second harmonics from infrared photons. An even earlier example was a highly designed chiral organic molecule that self-assembled into layered structures that could subsequently be converted into stacks of 2D polymers.5 These materials composed of 2D structures were shown to have the stable second harmonic generation properties of glassy polymers but remained fusible and soluble since they were composed of 2D nanoscale objects. Organic materials designed through supramolecular chemistry can also take the form of 1D assemblies of molecules

Figure 1. (a) Chemical structure of rodcoil molecules. (b) Electron micrographs and electron diffraction patterns (inset) show formation of ordered mushroom assemblies. (c) Schematic of the layering and polar ordering of the mushroom assemblies. Adapted with permission from ref 6. Copyright 1997 AAAS.

whose physical properties may resemble those of covalent polymers.10 This similarity is likely to occur when molecules (monomers) connect to each other through relatively strong noncovalent interactions, but the chain of molecules explores a “random walk” in space and experiences physical entanglements with neighboring chains as it occurs in polymeric materials. However, the fact that the lifetimes of intermonomeric bonds, τ, lie within a range of 1 μs < τ < 1 min provides new properties. Two examples would be the melting of solids into low viscosity liquids that lack macromolecular character and the possibility of re-establishing intermonomeric bonds after chain rupture induced by external forces. These two features lead to novel recycling possibilities and the potential for self-healing behavior in materials.27 Supramolecular polymers also differ from conventional covalent polymers in that the process of 1D self-assembly of the monomers can create assemblies that have internal order and therefore completely new functions and persistence lengths that are not observed in covalent macromolecules.14,19,28−31 Supramolecular polymers with or without internal order offer new regimes of biodegradation and drug delivery due to the absence of a covalent backbone. Other forms of organic supramolecular materials include ordered frameworks15,16,32 and 3D networks33 in which there is crystalline order. These networks can have novel properties B



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Figure 2. Structure, schematic of assembly morphology, and nanoscale structure of 1D nanostructures. (a) Dendron rodcoil ribbons, (b) quadruplex hydrogen bonding twisted ribbons, (c) amphiphilic hexabenzocoronene nanotubes, (d) peptide amphiphile nanofibers, and (e) hairpin assemblies. Images have been adapted with permission from refs 29 (Copyright 2001 American Chemical Society), 53 (Copyright 2003 American Chemical Society), 14 (Copyright 2004 AAAS), and 54 (Copyright 2013 Royal Society of Chemistry).

2. ONE-DIMENSIONAL ASSEMBLIES In the context of organic materials, we learn from nature that 1D assemblies are fundamentally useful and functional. Biology utilizes 1D structures not only in its macromolecules but also as supramolecular structures both in the extracellular and intracellular space. In the extracellular space, the mechanically supportive matrix of cells and the complex protein signaling pathways utilize networks of 1D structures such as fibronectin.37 All the dynamic features of cells that we would like to imitate in organic materials, including migration and replication, are controlled by the 1D assemblies of proteins in the cell’s cytoskeleton, which includes actin filaments, intermediate filaments, and microtubules with diameters in the range of 7−25 nm. Therefore a landmark of synthetic organic materials using the strategies of supramolecular chemistry and self-assembly is understanding how to design molecules that can form 1D structures through noncovalent

as in a recent example from our laboratory that demonstrated the first example of room temperature ferroelectricity in 3D networks of mixed stacks of electron donor and acceptor molecules.33 MOFs with their enormous internal surface area have been of interest as materials to store gases such as hydrogen and also as functional systems for either catalytic or sensing functions.34,35 Generally speaking, it should be possible to integrate order and dynamics in many supramolecular materials given the ease of rupturing and reforming the bonds that define the structure. This integration into materials could enable functions such as optimal signaling by adjustment to the complex landscape of cells, switching of catalytic functions, responsive dynamic behaviors, and management of light and charge transport as interactions among molecules are reversibly formed.10,36 The following sections describe various supramolecular systems with properties that could make them useful as materials. C



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interactions. This is contrary to the common 3D “crystal” formed universally by assemblies of identical molecules at low temperatures and is thus a key objective in organic materials chemistry. The science here has to include learning not only to design for spontaneous self-assembly of 1D structures but also to control the details of their architecture. They can be cylindrical assemblies, flat or twisted ribbons, tubes, and many other shapes that can be stabilized in one and not two or three dimensions. We describe some examples of 1D assemblies that have been developed and studied in the context of materials over the past decade. Inspired by our earlier work on rodcoil molecules that selfassemble into noncentrosymmetric nanostructures,6,38 we designed a molecule with a dendritic block at the end of the rod segment that we refer to as a dendron rodcoil (DRC) (Figure 2a).29 These molecules could assemble into 1D ribbons that are ∼10 nm wide and ∼2 nm thick, as shown by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Self-supporting gels could be formed at concentrations as low as 0.2 wt % of DRC 1 in CH2Cl2. Synthetically modifying each of the dendron, rod, and coil segments revealed the importance of each portion on the selfassembly behavior.30 For example, the DRC terminated with a G1 dendron forms ribbon assemblies with head-to-head hydrogen bonds, whereas higher-generation dendrons inhibit self-assembly and only isolated aggregates were observed. Similarly, the length of the rod section also affects the selfassembly: a single biphenyl ester gives a viscous, isotropic solution, two biphenyl esters affords a weak gel, and three or four biphenyl ester units, results in purple, birefringent gels. The gels usually indicate the presence of 1D assemblies that create 3D networks. To introduce the functionality into the system, the rigid oligo(biphenyl ester) rod can be replaced with other aromatic groups, such as oligothiophene or oligo(phenylenevinylene).39 An iodine-doped film cast from selfassembled oligothiophene DRC molecules shows conductivity that is 1000-fold higher than the same molecules cast from the unassembled state. Around this same time, other groups were working on complementary approaches to 1D nanostructures with potential electronic function. For example, Meijer’s group found that molecules functionalized at each end with ureidopyrimidinones assemble through self-complementary hydrogen bonds into supramolecular polymers that display effective molecular weights of 500 000 Da, giving them mechanical properties similar to covalent polymers at room temperatures and low viscosities when heated (Figure 2b).40 These structures can also incorporate conjugated aromatic oligo(phenylene vinylene) groups to form stacks with mobilities for holes and electrons on the order of 10−3 cm2 V−1 s−1.41 Other 1D structures have been developed based on disk-shaped aromatics like hexabenzocoronene, which very strong π−π stacking interactions and do not require additional interactions for assembly.42 For example, Hill et al. reported hexabenzocoronene with ethylene glycol tails on one side and alkyl tails on the other that self-assemble into hollow tubes (Figure 2c).14 A solution of these graphitic tubes can be drawn into macroscopic fibers with anisotropic conductivity along the fiber’s long axis.43 More than a decade ago, our group discovered a class of peptide amphiphiles (PAs) that self-assemble into 1D nanostructures in water (Figure 2d).19 The self-assembling PA molecule was based on a palmitoyl tail covalently linked to

the N-terminus of electrostatically charged peptide sequences with a propensity to form a β-sheet secondary structure. Hydrophobic collapse of the alkyl tails and hydrogen bonding interactions drive assembly into high-aspect-ratio nanofibers that are ∼6−10 nm in diameter and up to micrometers long. The morphology of the PA assemblies has been characterized by transmission and scanning electron microscopy techniques (TEM and SEM), atomic force microscopy (AFM), circular dichroism (CD), and infrared (IR) spectroscopy. These supramolecular materials have revealed in vivo efficacy in models of spinal cord injury,44,45 cartilage regeneration,46 bone regeneration,47−49 myocardial infarction,50 peripheral vascular disease,51 and peripheral nerve regeneration.52 Hartgerink et al. studied the effects of N-methylating the amide nitrogens at each amino acid position of a PA molecule.55 Even a small N-methyl group on the amide considerably affected the self-assembly into a cylindrical structure the secondary structure, particularly at the residue closest to the core. On the basis of the structural importance of this innermost amino acid, we prepared a PA with the oligopeptide sequence GVVVAAAEEE in which the nitrogen of the N-terminal amide was blocked with a 2-nitrobenzyl photocleavable group.56 Transmission electron microscopy (TEM) revealed high-aspect-ratio architectures composed of a quadruple helix with a nearly uniform width and helical pitch of 33 ± 2 and 92 ± 4 nm, respectively. After irradiation at 350 nm, the helical structures disappeared completely and only cylindrical fibrils with a diameter of 11 nm were observed. We hypothesized that increased steric bulk induces torsional strain that is released as the photocleavable group is released. This system suggests future strategies to create functional, photoresponsive materials that may be useful in sensing or actuation. We found we could control the presentation of surface epitopes using a similar strategy. Placing the photocleavable group on the innermost amide of GAAEERGDS showed only a solution of nanospheres. Upon irradiation, nanofiber gel formed and increased the response of cells to the bioactive RGDS signal.57 Extending this concept to future biomaterials applications will benefit from photocleavable groups with two-photon cross sections in the near-infrared region of the spectrum.58 In addition to using photoactive groups to change epitope presentation, the same group can be used to release soluble factors.59 This controlled release would greatly expand potential functions of importance in advanced medicine. Nanofiber bundling was found to reduce the presentation of hydrophobic bioactive epitopes on their surfaces.60 IKVAK is a relatively hydrophobic epitope that is known to be important in signaling to neurons. Interdigitation of the hydrophobic peptides leads to fiber bundling and has the effect of masking the IKVAV epitopes from receptors leads to a lower effective concentration of IKVAV epitopes available for binding. The bundling could be suppressed by increasing electrostatic repulsions among the nanofibers, resulting in greater neurite outgrowth of cells exposed to PA nanofibers with higher net charge. Gosh et al. recently reported a series of peptide amphiphiles self-assemble into 1D nanofibers in response to small changes in pH.61 While most of the peptide amphiphiles studied by our group form cylindrical nanostructures, we discovered that changing the peptide sequence can eliminate all their curvature resulting in completely flat ribbons and belts. In addition to hydrogen bonding and van der Waals interactions, π−π stacking is important in the self-assembly of many peptides and proteins, D



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pathways to create the assemblies affect their final structure and therefore their properties. There is evidence in recent work that kinetically controlled changes in the nature of solvents, and other processing issues such as heating and cooling rates or even stirring, can have profound effects on the nature of the final structures.73−75 For example, we found that conjugated molecules that interact through π−π stacking form stacks with long-range orientational order, gel-like networks, or crystals depending on the rate at which a self-assembly solvent is introduced in solution.75 In another recent example, we have also explored the design of novel p-type molecules that can self-assemble into 1D nanostructures in the active layer of organic bulk heterojunction solar cells. The nanostructures were produced from hairpin shaped molecules based on the trans-1,2-diamidocyclohexane motif, which is known to promote gelation of many organic solvents.76 We synthesized a hairpin-shaped molecule that incorporated a semiconducting moiety (sexithiophene) in the arms to produce extended 1D structures.77 Briefly mixing the preassembled fibers with fullerene based n-type material that we used in bulk heterojunction photovoltaics.78 In these devices, we observed 23% higher power conversion efficiency (PCE) compared to a linear control molecule that lacks the hydrogen-bonding motif. More recently, we explored a molecular with the same hairpin shape and a diketopyrrolopyrrole semiconducting group, which was 54% higher than the corresponding control due to better morphology and better charge transport characteristics (Figure 2e).54 Würthner has also shown a strong pathway dependence in hairpin-shaped molecules bearing merocyanine dyes.79,80

such as KLVFF sequence from the protein amyloid β (Aβ).62 Ulijn reported hydrogels based on the self-assembly of Fmocdiphenylalanine into highly stable 1D nanotubes.63 The groups of Xu and Ulijn have shown that other Fmoc-dipeptides also assemble into 1D fibers that form gels with variable mechanical properties and can be used to culture cells.64,65 In our work, we explored the effect of aromatic interactions in the context of a self-assembling PA molecule with the peptide sequence FFFEEE.66 In water this molecule forms twisted ribbons that show a high degree of internal crystalline order by XRD and FTIR spectroscopy, similar to that observed in fibrillar protein aggregates like Aβ. This morphology likely introduces frustration in the packing of the β-sheets. Over a period of several days, the assembly slowly transforms into helical ribbons, presumably allowing more uniform twisting of the βsheets as well as greater π−π stacking and crystallization of the palmitoyl tails. By synthesizing a tetrapeptide amphiphile with alternating hydrophobic (valine) and hydrophilic amino acid (glutamic acid) amino acids. That peptide forms belt-like structures that have heights of 4.3 nm, widths on the order of 150 nm, and lengths of up to 100 μm.67 We hypothesize that in aqueous solution, the valine side chains have a strong tendency to associate with each other in order to minimize exposure to water, resulting in an attractive dimerization of two peptide segments. This dimerization allows close packing among neighboring peptides, leading to the nanobelt morphology and a loss of curvature frequently observed in self-assemblies of peptides. When we disrupted the alternating hydrophobic and hydrophilic amino acid sequence by replacing the VEVE peptide segment by VVEE, the resulting nanostructures regain their interfacial curvature, forming cylindrical nanofibers. Variations in monomer concentration generate a broom-like morphology with domains of both belt and twisted ribbon character, suggesting a mechanism through which giant nanobelts form. We also synthesized alternating sequences with different peptide lengths or tails. As the number of dimeric repeats is increased from two to six, the lateral width of the assemblies monotonically decreased from 100 to 10 nm.68 CD spectroscopy revealed that the degree of β-sheet twisting within the supramolecular assemblies is directly proportional to the number of dimeric repeats in the PA molecule. Interestingly, as twisting increased, a threshold is reached where cylinders rather than flat assemblies become the dominant morphology. Changing the length of a simple headgroup offers a clear strategy to control the degree of curvature of self-assembled 1D nanostructures. Alternatively, when we replaced the fatty acid tail with a short aromatic segment (terthiophene), π−π interactions compete with the hydrogen bonding, thereby frustrating the assembly process and resulting in a variety of nanostructures including nanotubes, spiral sheets, and giant, flat sheets.69 While it is difficult to predict these morphologies based on current theories, the identity of the side chain of the amino acid closest to the hydrophobic moiety clearly plays a complicated role in determining the overall morphology. Longer peptide sequences that promote β-sheet formation have been found to drive self-assembly of the oligothiophenes into nanofibers.70−72 As self-assembly codes for 1D supramolecular structures become better understood, small molecule-based organic materials could emerge for functions in a wide variety of areas. An interesting direction in this area is to explore how

3. TEMPLATED LENGTH CONTROL In systems that form supramolecular objects on the nano- and micrometer scale, it is desirable to precisely control nanostructure size in all dimensions. Organic materials chemistry is still far from this goal, which is necessary to completely design functional structures at any scale and with hierarchical character when necessary. In supramolecular polymers, this can be controlled to a limited extent by the monomer concentration or the use of end-caps.81,82 The general problem of length control of self-assembled systems with nanoscale dimensions requires a more versatile approach. Biology often achieves synthesis of materials with structural features and functions across scales using templates; this strategy is very common in biomineralization. Templating is also a biological strategy in the formation of viruses, particularly filamentous viruses in which nucleic acids prevent the unlimited self-assembly of the capsid proteins through specific molecular interactions.83 The monodisperse filamentous objects obtained by this templating strategy could in principle be translated to artificial structures for more effective delivery systems in medicine, new types of liquid crystals, precise scaffolds for catalysts, and monodisperse components for devices or materials, among others. To date the only way to access such monodisperse organic structures would be to use filamentous viruses themselves.84 Inspired by this natural self-assembly system, the authors’ laboratory designed a dumbbell-shaped template molecule that contains a rigid oligo(p-phenyleneethynylene) core where the hydrophobic rigid rod is encapsulated within the nanofiber and defines a precise length and bulky polyethylene glycol (PEG) terminal groups block fiber growth.85 An aqueous mixture of the PA and template (200:1 molar ratio) revealed small aggregates by AFM and E



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with water-solubilizing PEG chains and cationic spermine segments (to interact with the nucleic acid template) at the other. In solution these peptides self-assemble into capsomerlike heptameric nanostructures. With a DNA template, we found that monodisperse and uniformly shaped filamentous complexes only formed with a high molecular weight of terminal PEG segments. We proposed that sufficiently long PEG chains turn on steric forces after dense electrostatic attachment of the nanostructures to the template. These steric forces in turn prevent the highly dynamic buckling of DNA thus enabling templating into monodisperse virus-like structures with high fidelity. In the absence of these steric forces the structures formed are heterogeneous in shape and dimension. The templated self-assembly of the 1D filaments using monodisperse DNA suggests strategies for further development of similar structures with other chemistries. The great challenge is to identify sources of monodisperse templates that are not based on nucleic acids.

TEM, rather than the nanofibers observed for PA alone. CD spectroscopy confirmed the presence of β-sheets in solution of the PA with and without the template, showing that the intermolecular basis of PA self-assembly remains unchanged. Monodisperse nucleic acids provide a great opportunity for precise templating of nonclosed structures at larger length scales. Meijer et al. used a single-stranded oligothymine template for several self-assembling molecules and found that the assembly requires careful balancing of π−π stacking interactions and hydrogen bonding.86 This approach could also allow the DNA template to define the sequence of complementary self-assembling units. They also demonstrated that pH can be used to control the internal structure (helicity) of these assemblies by changing the protonation state of the recognition group.87 Very recently, we reported the first example of precise templating with long double-stranded DNA molecules in a process that is biomimetic of the TMV virus. This work describes the encapsulation of a linear or circular double-stranded DNA template with preassembled mushroom-shaped nanostructures having a positively charged domain into 1D nanostructures of precisely controlled length (see Figure 3).88 The capsomer-like nanostructure forms by self-assembly of coiled-coil peptides conjugated at one terminus

4. TWO- AND THREE-DIMENSIONAL ASSEMBLIES OF MOLECULES The possibility of creating distinct 2D structures either as part of crystals or as discrete supramolecular nanostructures through noncovalent interactions is of interest in designing materials. Within crystals, this level of control could be used to direct macroscopic shapes, electron transfer processes (and thus optical properties), or unique features of charge transport. Well-defined 2D nanostructures, either covalent or supramolecular are interesting in the context of liquid crystals, electronic devices, and surface properties in general. The authors’ laboratory reported in 1993 the design of molecules that self-assembled into 2D structures that could subsequently be polymerized to create 2D polymers.5,89 These materials were interesting because they could exhibit the stability of 3D covalent networks but remain soluble and fusible into liquid crystals. The covalent forms of 2D nanostructures are now popular in materials chemistry because of rising interest in graphene and its derivatives, and this area continues to flourish.42 The ultimate goal is, of course, to control the structure in 3D assemblies of molecules. This could include the ability to control structure in organic crystals or those formed by their coordination with metals. The most exciting directions here have to do with our ability to control 3D assemblies of two or more different molecules because it is in these systems that there is the most potential for function. For example, a single crystal grown off an electrode surface with orientational control and containing electron donor and acceptor molecules could offer ideal active media for photovoltaics. This would be especially interesting if these binary crystals would have structures that facilitate charge transport between electrodes and do not promote electron−hole recombination following optical absorption. Searching for such structures will benefit enormously from further developments in atomistic computational chemistry. 5. FERROELECTRIC ORGANICS Ferroelectric materials show spontaneous electric polarization that can be reversed by an external electric field and are of potential interest as sensors, photonic crystals and energyefficient memories. In contrast to their inorganic counterparts, organic ferroelectrics can be inexpensive to synthesize, easily

Figure 3. (a) Chemical structure self-assembled DNA-binding molecules. TEM microscopy of the peptide Sp-CC-PEG5000 mixed with plasmid DNA of (b) 2686, (c) 4361, or (d) 10 153 bp in Tris buffer (pH 7.4, 25 mM). (e) Analytical ultracentrifugation shows the dependence of aggregate size on the length of the DNA template. Adapted with permission from ref 88. Copyright 2013 American Chemical Society. F



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processed, and integrated with many substrates. We discovered that hydrogen-bonding interactions among “simple” and small electron donor and electron acceptor molecules lead to ferroelectric single crystals at room temperature (Figure 4).33

Figure 4. (a) Chemical structure of donor and acceptor molecules and (b) their X-ray cocrystal structure. Polarization versus electric field hysteresis curves (c) at 72 K and (d) at room temperature. Reprinted with permission from ref 33. Copyright 2012 Nature Publishing Group.

Figure 5. (a) SEM demonstrating the hierarchical structure of the PA−HA sac membrane, including the initial contact layer of fibers parallel to the membrane (region 2) and the dense arrangement of fibers perpendicular to the membrane (region 3). (b) Schematic representation of membrane formed by polymer diffusion into the small molecule compartment. (c) Birefringence of a single string suggesting alignment along the string axis. (d) Calcein-labeled aligned cells cultured in string. (e) SEM images of a single cell in a string (inset is the zoom-out view; the arrow indicates the alignment direction). (f) Peptide amphiphile filaments crystallize into hexagonal nanofibers. Adapted with permission from refs 88 (Copyright 2013 American Chemical Society), 94 (Copyright 2003 Nature Publishing Group), and 100 (Copyright 2012 Wiley).

The background to this discovery was the vision and experimental demonstration that organic electron donor and acceptor molecules arranged in mixed stacks can form ferroelectric crystals.90 In these systems, electron transfer in a crystalline mixed stack of alternating donors and acceptors can create a dipole moment. If symmetry is broken during this process so that dimers form, then a large array of head-to-tail dipoles is established in the crystal. Switching of polarization under an applied electric field opposing the dipoles can occur by simple exchange of electron transfer partners from front to back or vice versa within each stack. The donor and acceptor molecules that formed the room temperature ferroelectric were functionalized with hydrogen bonding recognition sites to accelerate the cocrystallization of electron donors and acceptors into tightly packed networks of mixed stacks locked by hydrogen bonds, π−π stacking, and charge transfer interactions (Figure 5). In contrast to earlier mixed-stack systems that only switched below 81 K,91−93 we demonstrated ferroelectricity above room temperature in three different cocrystals.

can be used to understand the phenomena that will get us there. Examples of such discoveries in the authors’ laboratory, which were post facto analyzed mechanistically to understand the science behind them, are described below. Self-Assembly of Hierarchical Membranes at Liquid− Liquid Interfaces. In a recent discovery, we found that hierarchically ordered membranes at the interface between droplets of aqueous solutions of a high molecular weight polyelectrolyte (hyaluronic acid, HA) and an oppositely charged peptide amphiphile (Figure 5a and b).96 These two aqueous solutions would be expected to mix rapidly by simple diffusion, but surprisingly at appropriate values of charge density, as established by zeta potential measurements, a solid membrane forms at the liquid−liquid interface on millisecond time scales. SEM revealed that the membrane has a hierarchical structure containing three regions: an amorphous polymer layer, a narrow region of PA fibers parallel to the interface, and a layer of fibers perpendicular to the interface whose length depends on the time the two solutions are in contact. The initial electrostatic complexation between the oppositely charged molecules rapidly forms a layer at the interface that acts as a diffusion barrier and prevents chaotic mixing of the two solutions. At longer time scales, the initially formed membrane serves as a mesh that uncoils the polyelectrolytes as they are “drawn” through it by osmotic pressure and templates formation of perpendicular fibers with assemblies of PA molecules over minutes, hours, and days. We hypothesized that the formation and growth of the perpendicular fibers is driven by a synergy of the dynamic osmotic pressure difference

6. MATERIALS WITH HIERARCHICAL STRUCTURE In living organisms, we observe materials with hierarchical structures in which different order parameters exist at different scales that are part of a structural continuum from which function emerges. Great examples include the structure of muscles in which fibers form well-defined bundles that in turn are aligned over long macroscopic distances.94 In cartilage, complex fibers with both peptides and polysaccharides change their collective orientation in defined ways along the thickness direction of this tissue.95 Many propertiescoefficient of friction, stiffness, and toughnessare simultaneously controlled as a result of the mesoscale structure. Developing artificial organic materials with these attributes will be transformative for scientific and technical reasons. We are in the very early stages of developing such systems, and we are certainly not yet in a position to predict them structurally and functionally. However, as research in organic materials shifts into the supramolecular direction there will be discoveries that G



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crystal at concentrations that are surprisingly low. By manually dragging this liquid crystal of bundled supramolecular filaments onto salty media in order to screen charges, it is possible to extend the alignment over centimeters, creating macroscopic monodomain viscoelastic strings. Divalent ions interact with the nanofibers and the very slow relaxation times of the long filaments of bundled nanofibers enables formation of the macroscopic monodomains. We found by small-angle X-ray scattering (SAXS) and SEM that strings generated from the heated solutions contained extraordinarily long arrays of aligned nanofiber bundles, whereas simply dragging an unheated PA did not lead to significant alignment. Spontaneous long-range alignment of molecules is known to occur in liquid crystals,103 but its fixation in the solid state normally requires chemical reactions that are not likely to be compatible with living cells. Electrospinning of polymers has been used to create aligned matrices, but requires high mechanical and electrical energy.104 The example described here is therefore the first to show that very weak external forces can instruct formation of a hierarchical structure from small self-assembling molecules. In these systems, cells can be mixed with the solutions and they become encapsulated and remain viable during the process in the resulting monodomain gels.102 After dispersing mesenchymal stem cells (MSCs) in heated and cooled PA solutions, we pipetted these solutions onto salty media to form noodle-shaped strings with encapsulated stem cells. Optical, fluorescence, and electron microscopy demonstrated that both cell bodies and filopodia were aligned with PA nanofiber bundles in the extracellular space. A “cellular wire” based on the noodle-like string could also serve as a bridge to direct cells spatially for function or migration from one site to another. Furthermore, these materials could provide environments with anisotropic diffusion or mechanical properties. Organization of Highly Charged Filaments. It is known from biological105,106 and synthetic107 systems that like-charged nanofibers can form crystalline bundles with spacings on the order of their diameter. This excluded volume effect is useful in the design of devices, liquid crystals, high-strength materials, bioactive hydrogels, and other functional structures. In biological systems, the bundling, orientation, and mechanical networking of 1D cytoskeleton components such as filamentous actin and microtubules mediate cellular events such as mitosis, protein transport, and signal transduction. We discovered that like-charge peptide amphiphile (PA) cylindrical nanofibers can self-assemble into large crystalline arrays at surprisingly large distances from each other (up to 32 nm) in water (see Figure 5f).108 This crystallization is spontaneous beyond a given PA concentration but interestingly can be triggered reversibly by ionizing X-rays at lower concentrations. We observed that the SAXS profiles of 0.5 wt % solutions dramatically changed upon continuous X-ray exposure. Successive irradiation on the same spot yielded a series of Bragg peaks whose relative positions are characteristic of a highly ordered 2D hexagonal lattice. Analytical HPLC and mass spectrometry of samples after a large X-ray dose confirmed that chemical damage is not involved in the observed reversible phenomenon. Since PA nanofibers can encapsulate CNTs,109 bind porphyrins,110 and nucleate semiconductor nanoparticles,111 these crystallized nanofibers could offer a route to template hybrid structures with precise control over interparticle spacing. On the basis of SAXS profiles, the size of the bundles of supramolecular nanofibers in this hierarchical

between the solutions and static self-assembly. The membrane structure, mechanical properties, and water permeability, quantified by membrane inflation and osmotic swelling, depend on the incubation time and HA concentration.97 Recently our group reported the formation of a self-assembled membrane using HA and a peptide sequence with an affinity for heparin (a sulfated polysaccharide known to promote angiogenesis).98 In vitro studies on these membranes showed enhanced growth factor retention and increased angiogenesis. When the membrane is formed from a mixture of PAs with and without the anticancer sequence (KLAKLAK)2, the resulting membranes can provide localized surface cytotoxicity or reservoirs of sustained release of cytotoxicity through enzymatic degradation.99 This strategy to hierarchically assembled membranes could also provide a nonlithographic route to template structures of interest in energy, such as cathodes and anodes for capacitors. Since the self-assembly between the PA and polyelectrolyte solutions appears to be intrinsically driven by excess osmotic pressure of counterions and limited by rates of diffusion, we also formed the membranes in an applied external electric field to promote the directional diffusion of charged molecules. The membranes stimulated by the electric field were more mature and had structures similar to membranes matured for longer times without stimulation.100 The external electric field suppresses or promotes the diffusion of some charged components, thus changing the balance in kinetics of selfassembly relative to the system driven only by osmotic pressure. We obtained even more sophisticated control over the structure by generating various electric field profiles. For example, when the electric field was oriented parallel to the PA−HA interface, we found large regions of the membrane consisting of PA nanofibers exclusively oriented parallel to the interface without any sign of perpendicular fibers. Integrating external electrical fields and self-assembly could allow the patterning of distinct structures and gradients and therefore greater complexity in structure and properties. Sac-like microcapsules (MCs) can be produced with sizes smaller than 100 μm using the electrospray-based production of polymer microdroplets.101 The nebulized microdroplets of the aqueous alginate were directly ejected into an aqueous solution of cationic C16VVVAAAKKK PA to induce rapid membrane formation through self-assembly. The shells of these MCs are highly structured and their surfaces are fully covered with nanoscale filaments. Their fibrous surfaces and shell walls could be customized for functions by changing the chemical structure of PAs, and the microcapsule cores can harbor polymers, liposomes, or other nanostructures. Aligned Supramolecular Bundled Filaments of Small Molecules. A recent discovery in the authors’ laboratory identified a thermal pathway that leads small molecules to assemble into a monodomain gel of macroscopically aligned bundled filaments that can be made by dispensing a solution from a pipet.102 This construct was prepared from PAs with a variety of different sequences that form nanofibers of very high aspect ratio, such as C16−VVVAAAEEE(CO2H). Electron micrographs of dilute solutions of these small molecules (0.5−1 wt %) heated to 80 °C for 30 min revealed a 2D structure with internal fibrous texture, presumably through dehydration of the headgroups. Upon cooling, that 2D structures spontaneously into large domains of bundled nanofibers and forms a strongly birefringent liquid (Figure 5c−e). The dilute solution thus converts to a lyotropic liquid H



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structure can have domains on the order of micrometers, thus containing thousands of filaments.

7. SELF-ASSEMBLED HYBRID ORGANIC−INORGANIC MATERIALS The area of organic−inorganic hybrid materials in which selfassembly and supramolecular chemistry play key roles holds enormous potential to design new materials. The use of supramolecular chemistry to design the organic phases brings the possibility of high degrees of order relative to polymeric phases in conventional composite materials. An example would be phases that need to sustain high charge mobility, or have special properties such as those linked to noncentrosymmetric structures such as piezoelectricity, ferroelectricity, and secondorder nonlinear optical activity, among others. Supramolecular phases could also introduce rationally an ordered porous structure as it exists in molecular organic frameworks. The use of a self-assembly strategy, on the other hand, could generate the hybrid from solution forming a specific hybrid architecture templated by the molecules themselves due to their strong interaction with the inorganic phase. We illustrate this direction below with an example from our laboratory in which a periodic lamellar hybrid was created from solution containing a supramolecular phase. Semiconductor−Organic Hybrids. The synthesis of highly ordered nanostructured organic−inorganic hybrids in which both components contribute to overall functionality offers potential for high performance optoelectronic devices. Our group has demonstrated the growth of an ordered hybrid lamellar material consisting of alternating n-type ZnO and ptype conjugated organic molecules with a lamellar periodicity on the order of 2−3 nm.112 The growth of this film occurs by electrodeposition on the transparent conducting indium tin oxide (ITO). Our general approach takes advantage of interactions among conjugated molecules to create a “supramolecular phase” that templates the positioning of inorganic lamellae, thus growing a periodic hybrid structure. In this case, the supramolecular phase becomes a dense, π−π stacked p-type conduction pathway. Top-down and cross-sectional SEM images show that the macroscale morphology grows from the substrate surface as a flake-like structure (Figure 6). Bright-field TEM images show the high degree of order between the inorganic Zn-rich phase and organic surfactant, such as 1pyrenebutyric acid. Using a high-energy synchrotron X-ray source, we were also able to show that the inorganic phase initially deposits as zinc hydroxide and can be transformed to semiconducting zinc oxide with conservation of the lamellar architecture upon annealing.112 Furthermore, we found that only surfactants with conjugated moieties and π−π stacking within the lamellar were able to stabilize the structure during this transformation and maintain the lamellar periodicity. In order to demonstrate the electronic properties of these materials, we fabricated photodetectors from these lamellar films (Figure 7). In this type of device, electrons are injected from the organic into the inorganic, with the remaining hole on the organic serving as a long lifetime trap state. Such trap states enable photoconductive gain while minimizing transport noise associated with the interfaces between crystallites. Incorporating organic dyes into the network can offer additional benefits such as tuning the optical photoaction spectra and the lifetime of trap states with molecular structure. The photoconductor devices were prepared using a methylated quinquethiophene dicarbox-

Figure 6. (a) Top-down and (b) cross-sectional SEM images of lamellar hybrid nanostructure morphology from deposited platelets using 1-pyrenebutyric acid. (c) TEM image showing lamellar sheets within platelets deposited. (d) Schematic diagram of lamellar ordering composed of inorganic Zn-rich regions and bilayers of pyrenebutyric acid. Adapted with permission from ref 112. Copyright 2009 Nature Publishing Group.

Figure 7. Current−voltage curves of a photoconducting device measured in dark and under white light (∼100 mW cm−2). (top inset) Photograph of a fabricated device. (bottom inset) Timedependent conductivity measured at 1 V showing photoresponse on excitation with 500-nm light (410 μW cm−2). Adapted with permission from ref 112. Copyright 2009 Nature Publishing Group.

ylic acid whose conjugated segment has absorption energy onset below the ZnO bandgap (Figure 7). Electrodeposition using this surfactant resulted in fiber-like morphology that had a well-defined lamellar ordering and a very high loading density of chromophores. At 500 nm the photocurrent response varied over 3 orders of magnitude of incident intensity, corresponding to a dynamic range >60 dB and comparable to current CMOS image sensors. These room temperature, low bias (

Supramolecular Chemistry and Self-Assembly in Organic Materials

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