Current Opinion in Solid State and Materials Science 5 (2001) 355±361

Supramolecular one-dimensional objects Jeffrey D. Hartgerink12 , Eugene R. Zubarev , Samuel I. Stupp* Department of Materials Science and Engineering, Department of Chemistry and Medical School, Northwestern University, 2225 North Campus Dr., Evanston, IL 60208, USA

Abstract

Preparing -like materials through is an area of growing interest, yet full understanding of how non-covalent forces may be used to prepare such materials is lacking and as a result the success of these strategies is often serendipitous. Recent examples of discrete one-dimensional supramolecular ®bers employing the most important types of non-covalent interactions (metal coordination, hydrogen bonding, p±p stacking, hydrophobic effect) illustrate our current ability to prepare these types of materials and point the way for future designs.  2001 Published by Elsevier Science Ltd.

1. Introduction have over traditional covalent such as dynamic assembly and disassembly, and are intimately involved in Advances in our understanding of molecular organiza- such complex processes as motility, chemical transport, tion in living systems have revealed that they are built and structural integrity. These materials are therefore from small building blocks and assembled into complex useful standards by which to judge the potential scope of hierarchies of functional superstructures. Many of them are the ®eld and the relative success of existing synthetic constructed by self-assembly, meaning that the component systems. parts spontaneously aggregate into a well-de®ned object Fig. 1a depicts an actin ®lament (red) coated with based purely on the chemical structure and geometry of the tropomyosin (blue) and myosin (yellow) [5±8]. This subunits and do not require external guidance to yield the complex supramolecular ®ber has two features which may desired product. Lehn was one of the ®rst to realize that characterize advanced supramolecular polymers. First, the these types of self-assembled structures could be mimicked actin polymer is dynamic in that it can be repeatedly by chemists [1] and potentially have properties and appli- assembled and disassembled in a controlled fashion based cations unique to this new class of materials [2,3]. One on the environment in which it is located (subunit, ion and important subclass of these supramolecular materials are ATP concentration). Second, the polymeric ®lament dis- those that are one-dimensional, yielding a ®ber or string- plays a chemically diverse surface allowing it to interact like object. These systems have also been termed sup- with its environment in a speci®c and sophisticated way ramolecular polymers [4]. Nature utilizes many different (actin±myosin interactions are responsible for muscle one-dimensional supramolecular polymers, for example contraction and cell division amongst other things). The actin ®laments and microtubules. These ®bers illustrate ability to prepare this type of advanced polymer that can some of the chief advantages that supramolecular polymers react and adapt to the environment in which it is placed is clearly desirable. This goal will only be achieved with an understanding of the types of weak interactions normally *Corresponding author. Present address: Department of Materials involved in their synthesis. A stable well-de®ned nano- Science and Engineering, Northwestern University, 2225 North Campus structure can only form if it has a signi®cant thermo- Dr., Evanston, IL 60208, USA. Tel.: 11-847-491-3002; fax: 11-847- dynamic advantage in comparison with the starting materi- 491-3010. al and all the possible intermediates. In other words, the E-mail addresses: [email protected] (J.D. Hartgerink), ®nal supramolecular product should represent the global [email protected] (E.R. Zubarev), [email protected] (S.I. Stupp). thermodynamic minimum for a given set of self-assem- 1Tel.: 11-847-491-5952; fax: 11-847-491-3010. bling subunits. Therefore, the interactions between the 2Tel.: 11-847-467-7889; fax: 11-847-491-3010. structural building blocks should be highly directional and

1359-0286/01/$ ± see front matter  2001 Published by Elsevier Science Ltd. PII: S1359-0286(01)00019-5 356 J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science 5 (2001) 355±361

Fig. 1. (a) An actin ®lament decorated with myosin heads. (b) Terech's monomolecular thread prepared using metal ligation. (c) Meijer's helical ®ber formed through hydrogen bonding. (d) Nolte's double helix formed through p±p stacking. cooperative, and should readily occur on a time scale of come together to form larger and more complicated objects the self-assembling process. Most studies of molecular in a rapid and facile way. recognition are based on a speci®c type of non-covalent interactions, i.e. hydrogen bonding [9±11], metal±ligand coordination [12±14], or aromatic p±p stacking [15±17], since their geometry is often predictable. This review 3. Hydrogen bonding focuses on recent application of these forces to prepare discrete one-dimensional materials. Utilization of hydrogen bonding is the most common method of driving molecules into supramolecular struc- tures in both natural and synthetic systems. Recently Meijer and coworkers described a beautiful example which 2. Metal coordination forms a one-dimensional supramolecular polymer [*20] depicted in Fig. 1c. His system is based on the hydrogen Fig. 1b [18,*19] is an example of a self-assembling bonding of a functionalized ureidotriazine moiety which one-dimensional polymer in which the primary force can form a homodimer connected by four hydrogen bonds. guiding the assembly is metal coordination. Terech uses a To the periphery of this pair are attached solubilizing simple ligand (ethylhexanoic acid) to bind Cu21 ions. This chains which can be modi®ed to allow solubility in both forms a sandwich-like structure composed of two copper organic solvents and water. The subunits dimerize in ions coordinated by four alkylacid ligands. These hydrogen bonding permissive solvents and these pairs are sandwiches are able to stack upon one another in such a then able to stack upon one another in non-polar solvents way that the copper ion from one pair can favorably such as dodecane to form columnar aggregates. Meijer interact with an oxygen of an adjacent copper±ligand takes this system to a higher level of sophistication by sandwich. Although a given bimetallic tetracarboxylate linking two of the ureidotriazine units to one another via a complex is relatively rigid, inter-complex interactions are ¯exible spacer and using a chiral solubilizing chain. more ¯exible and allow for curvature of the `monomolecu- Together this forces the columnar aggregates to adopt a lar thread'. Terech's organometallic wires illustrate one of helical conformation in solvents that promote hydrogen the great attractions of self-assembling systems in that bonding and pair stacking. The helical columns thus simple subunits of proper chemistry and geometry may formed have a diameter of 1.5 nm and have a con- J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science 5 (2001) 355±361 357 centration dependent length ranging from 10 nm at 0.2% tants. In other words, formation of these worm-like mi- by weight and up to 19 nm at 1.0% by weight. celles does not require any additional stabilization which is normally achieved by packing interactions between cylin- ders. The most outstanding achievement of this work is the 4. p±p Stacking highly controlled covalent ®xation of these structures through internal cross-linking of the butadiene core. The Although aromatic p±p stacking interactions are much authors performed cryo-transmission electron microscopy weaker than metal±ligand coordination or - experiments which clearly demonstrated that the cylindri- ing, their utilization for construction of one-dimensional cal morphology remains intact upon the conversion of ensembles can be very successful as well. Nolte and these supramolecular objects into covalent macromolecules co-workers [*21] have recently reported on the self-assem- (Fig. 2a). The molecular weight of the resultant polymer bly of chiral disk-shaped molecules that spontaneously can be as high as one billion daltons which is nearly three organize into helical superstructures exclusively via p±p orders of magnitude higher than that of typical synthetic stacking interactions. These molecules have a central polymers. This particular system proves yet another time phtalocyanine ring with four crown ether substituents that supramolecular chemistry can be used very effectively attached to its periphery. The crown ether moieties, in turn, for the preparation of structures and materials inaccessible bear chiral aliphatic tails. When the aggregation occurs in via traditional synthesis. organic solvents the disk-like molecules form one-dimen- sional stacks with a twisted morphology, so that the plane of each disk is rotated by 6.58 along the stack axis with 6. Multiple non-covalent interactions respect to adjacent neighbors. The self-assembling process then brings the system to the next hierarchical level when All the systems described above involve one primary two or more right-handed one-dimensional objects wrap type of non-covalent interaction. This general feature around each other to produce left-handed superhelical makes the quest for even more sophisticated systems quite structures (Fig. 1d). Perhaps, the most interesting ®nding obvious. That is the synthesis of self-assemblers that made by authors is related to blocking of `helicity transfer' would be driven to aggregate through different types of from the peripheral chiral tails to the central aromatic core. interactions simultaneously. Recently such a system was This was achieved by adding potassium ions prior to reported by Fenniri et al. [*26]. The authors synthesized a aggregation of disk-like molecules. Strong complexation molecule which has complementary hydrogen bonding between the crown ether moieties and K1 ions prevents sites analogous to those existing in natural nucleobases staggering orientation of molecules which instead pack (guanine and cytosine) and attached a chiral amino acid on exactly one on top of the other in an `eclipsed' (face-to- its periphery. They also introduced a hydrophobic methyl face) fashion. As a result, the ®bers adopt a cylindrical group on the outside of the nucleobase-like moiety in order morphology and the helicity disappears almost completely to reduce the competition of water molecules for the in spite of the presence of chiral side chains. This example hydrogen bonding and facilitate the formation of six- demonstrates that supramolecular chirality of one-dimen- membered macrocycle referred to as a rosette. It was found sional objects can be tuned in a controlled way by simply that the self-assembling process in water proceeds through changing the strength and directionality of non-covalent two consecutive steps: ®rst the molecules organize into interactions. rosettes and then these macrocycles stack into one-dimen- sional objects or nanotubes (Fig. 2b). The formation of rosettes is primarily driven by hydrogen bonding, whereas 5. Hydrophobic effect their stacking is caused by electrostatic interactions [27,28] and hydrophobic effect [29,30]. This is the ®rst example of Entropically driven formation of micelles in aqueous both H-bonded macrocycles and nanotubular objects solutions [22±24] is one of the simplest and well-known spontaneously forming in water and is a particularly examples of self-organization of amphiphilic molecules. beautiful example of molecular programming. Therefore it offers an easy way for construction of Our laboratory has also become interested in one-dimen- supramolecular and covalent polymers with exceptionally sional supramolecular polymers. Two examples have re- high molecular weights. This was recently demonstrated cently been prepared, one to investigate its ability to by Bates and co-workers [*25], who reported on worm-like interface with biological systems and the other to modify micelles formed by diblock of ethylene oxide traditional synthetic polymers. The ®rst example deals with and butadiene in water. These ¯exible cylindrical objects a system designed to promote the healing of damaged and have a well-de®ned cross-section and lengths on the order diseased tissue [31]. Toward this end the one-dimensional of microns. The structures can exist in a fully isolated state ®bers are prepared via the self-assembly of biocompatible in a dilute concentration regime due to their much greater peptide-amphiphiles (Fig. 2c). These amphiphiles have the amphiphilicity relative to conventional non-ionic surfac- geometry such that they will prefer to self-assemble into 358 J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science 5 (2001) 355±361

Fig. 2. (a) Bates' giant worm-like micelles showing both the reduced (top) and covalently captured (bottom) forms. (b) Fenniri's nanotube which displays two stages of self-assembly: formation of disks through hydrogen bonding and stacking of these disks to form a tube through the hydrophobic effect. (c) Stupp's peptide-amphiphile nano®bers which can be reversibly self-assembled and covalently captured. (d) Stupp's dendron rodcoil nanoribbon which utilizes p±p stacking and hydrogen bonding during self-assembly. cylindrical micelles as judged by the rules for amphiphile self-assembly described by Israelichvilli's theory [32]. The use of a short peptide allows for rapid and facile synthesis using standard solid phase methodology and incorporation of nearly any natural or unnatural amino acid allows for a broad range of chemistries to be displayed on the one- dimensional object's surface. Initial studies have focused on molecule 1 shown below.

The amino acid selection for the peptide-amphiphile 1 provides for several important characteristics of the materi- al. First, the highly charged nature of the peptide allows the material to be readily dissolved in water at neutral pH. However, upon acidi®cation of the solution, the net charge of the molecule changes from 23 to neutral as several of the acidic groups are protonated. When this occurs, the coulombic repulsion between molecules is eliminated and the hydrophobic alkyl tails are able to aggregate to form a cylindrical micelle (Fig. 3). These charges create a pH Fig. 3. Negative stain transmission electron microscopy image of mole- induced switch for self-assembly allowing the system to cule 1 after pH induced self-assembly. Average ®ber diameter is between assemble and disassemble based on the pH environment. 5 and 8 nm while the length can be in excess of a micron. J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science 5 (2001) 355±361 359

Second, the tetra-cysteine sequence just before the hydro- initial observation suggested formation of a network which phobic tail allows the self-assembled material to be can immobilize organic solvent in a highly effective way. covalently captured through the formation of intermolecu- Speci®cally, the ratio of solvent to DRC molecules can be lar disul®de bonds. Covalent capture is an effective tool for as high as 7000:1. Transmission electron microscopy of stabilization of preorganized self-assembled structures as the samples prepared from the DRC gels diluted in excess illustrated in the work of Bates [25] above and other dichloromethane revealed the presence of one-dimensional examples in the literature [33±37]. This effectively allows structures with uniform width of 10 nm and length on the the system to be locked into a covalent material with the order of microns (Fig. 4). same morphology as that of the self-assembled object. This The width of these strands is consistent with bimolecular makes the crosslinked product stable at high pH where packing of DRC molecules which are |6.5 nm long in before crosslinking it would have disassembled. Given the their fully extended conformation. The morphology of molecular weight of the peptide-amphiphile and the length these structures was determined by atomic force micro- of the self-assembled ®bers as imaged by transmission scopy experiments which showed that the strands have a electron microscopy, the molecular weight of the polymer uniform thickness of 2 nm. Therefore DRC forms well- after crosslinking is |23107 Da. Because the tetra-cys- de®ned bimolecular ribbons which lay ¯at on the substrate teine region is centered in the peptide-amphiphile the used for imaging. formation of disul®de bonds only occurs within a single There are several important features of these sup- ®ber and does not link multiple ®bers to one another. Like ramolecular structures which distinguish them from typical the pH induced self-assembly, the covalent capture is also organogel ®bers [39]. First, the width and the thickness of reversible simply by oxidizing and reducing the material. DRC ribbons is on the size scale of individual molecules, These two reversible steps allow one to move from whereas most organogelators form strands with diameters dissolved molecule to supramolecular ®ber to high molecu- hundreds or even thousands of times greater than the size lar weight polymer and back again at will, simply by of the ®ber-forming molecules. The cross-section of DRC altering the environment in which the material is placed. ribbons is nearly monodisperse throughout their entire The second system prepared in our laboratory represents length, which is in contrast to typical organogel ®bers a unique example of highly directional self-assembly which display a continuous variation in their diameter. involving cooperative interplay of both hydrogen bonds Second, the DRC nanoribbons exist in a fully isolated state and p-stacking of rigid aromatic units (Fig. 2d). We (at low concentration) as opposed to uncontrolled sponta- synthesized triblock molecule 2 referred to as dendron neous formation of bundles of ®bers observed in most rodcoil (DRC) which is composed of the hydroxyl-termi- other systems regardless of concentration. We believe that nated dendron (generation 1), biphenyl-ester mid-section, the presence of two wedge-shaped dendritic segments and oligoisoprene tail [*38] located in the center of the nanoribbon prevents their

. Each block plays its speci®c role in the self-assembling process. Phenolic and carbonyl groups of the dendron are strongly driven to form hydrogen bonds in non-polar solvents resulting in formation of head-to-head dimers. The biphenyl ester units can then stack the preformed dimers in at least one dimension via aromatic p-stacking interactions. The oligoisoprene segment, on the other hand, is readily solvated by non-polar organic solvents and can remain rotationally free after the aggregation of molecules through the rod-dendron portion takes place. This reduces the loss of conformational entropy upon the aggregation and makes the self-assembling process thermodynamically more favorable. When the DRC is dissolved in aprotic solvents, a spontaneous gelation rapidly occurs and the organic media transforms into birefringent gel at exceed- Fig. 4. Transmission electron microscopy image of DRC structures ingly small concentrations of DRC (|0.2 wt.%). 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