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

Supramolecular one-dimensional objects1 2 *Jeffrey D. Hartgerink , 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 polymer-like materials through supramolecular chemistry is an area of growing interest, yet full understanding of hownon-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 fibers 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 materialsand point the way for future designs. 2001 Published by Elsevier Science Ltd.

1. Introduction have over traditional covalent polymers such as dynamicassembly 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 thereforefrom small building blocks and assembled into complex useful standards by which to judge the potential scope ofhierarchies of functional superstructures. Many of them are the field and the relative success of existing syntheticconstructed by self-assembly, meaning that the component systems.parts spontaneously aggregate into a well-defined object Fig. 1a depicts an actin filament (red) coated withbased purely on the chemical structure and geometry of the tropomyosin (blue) and myosin (yellow) [5–8]. Thissubunits and do not require external guidance to yield the complex supramolecular fiber has two features which maydesired product. Lehn was one of the first to realize that characterize advanced supramolecular polymers. First, thethese types of self-assembled structures could be mimicked actin polymer is dynamic in that it can be repeatedlyby chemists [1] and potentially have properties and appli- assembled and disassembled in a controlled fashion basedcations unique to this new class of materials [2,3]. One on the environment in which it is located (subunit, ion andimportant subclass of these supramolecular materials are ATP concentration). Second, the polymeric filament dis-those that are one-dimensional, yielding a fiber or string- plays a chemically diverse surface allowing it to interactlike object. These systems have also been termed sup- with its environment in a specific and sophisticated wayramolecular polymers [4]. Nature utilizes many different (actin–myosin interactions are responsible for muscleone-dimensional supramolecular polymers, for example contraction and cell division amongst other things). Theactin filaments and microtubules. These fibers illustrate ability to prepare this type of advanced polymer that cansome 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 anunderstanding of the types of weak interactions normallyinvolved in their synthesis. A stable well-defined nano-*Corresponding author. Present address: Department of Materialsstructure can only form if it has a significant thermo-Science and Engineering, Northwestern University, 2225 North Campus

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: j-hartgerink@northwestern.edu (J.D. Hartgerink), final supramolecular product should represent the globalzoubarev@scs.uiuc.edu (E.R. Zubarev), s-stupp@northwestern.edu (S.I.

thermodynamic minimum for a given set of self-assem-Stupp).1 bling subunits. Therefore, the interactions between theTel.: 11-847-491-5952; fax: 11-847-491-3010.2Tel.: 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.PI I : S1359-0286( 01 )00019-5

5 (2001) 355–361356 J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science

Fig. 1. (a) An actin filament decorated with myosin heads. (b) Terech’s monomolecular thread prepared using metal ligation. (c) Meijer’s helical fiberformed 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 objectsthe self-assembling process. Most studies of molecular in a rapid and facile way.recognition are based on a specific type of non-covalentinteractions, i.e. hydrogen bonding [9–11], metal–ligandcoordination [12–14], or aromatic p–p stacking [15–17],since their geometry is often predictable. This review 3. Hydrogen bondingfocuses on recent application of these forces to preparediscrete 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. RecentlyMeijer 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 whichone-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

21simple ligand (ethylhexanoic acid) to bind Cu ions. This chains which can be modified to allow solubility in bothforms a sandwich-like structure composed of two copper organic solvents and water. The subunits dimerize inions coordinated by four alkylacid ligands. These hydrogen bonding permissive solvents and these pairs aresandwiches are able to stack upon one another in such a then able to stack upon one another in non-polar solventsway that the copper ion from one pair can favorably such as dodecane to form columnar aggregates. Meijerinteract with an oxygen of an adjacent copper–ligand takes this system to a higher level of sophistication bysandwich. Although a given bimetallic tetracarboxylate linking two of the ureidotriazine units to one another via acomplex is relatively rigid, inter-complex interactions are flexible spacer and using a chiral solubilizing chain.more flexible and allow for curvature of the ‘monomolecu- Together this forces the columnar aggregates to adopt alar thread’. Terech’s organometallic wires illustrate one of helical conformation in solvents that promote hydrogenthe great attractions of self-assembling systems in that bonding and pair stacking. The helical columns thussimple subunits of proper chemistry and geometry may formed have a diameter of 1.5 nm and have a con-

5 (2001) 355–361 357J.D. Hartgerink et al. / Current Opinion in Solid State and Materials Science

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 fixation of these structuresthrough internal cross-linking of the butadiene core. The

Although aromatic p–p stacking interactions are much authors performed cryo-transmission electron microscopyweaker than metal–ligand coordination or hydrogen bond- experiments which clearly demonstrated that the cylindri-ing, their utilization for construction of one-dimensional cal morphology remains intact upon the conversion ofensembles can be very successful as well. Nolte and these supramolecular objects into covalent macromoleculesco-workers [*21] have recently reported on the self-assem- (Fig. 2a). The molecular weight of the resultant polymerbly of chiral disk-shaped molecules that spontaneously can be as high as one billion daltons which is nearly threeorganize into helical superstructures exclusively via p–p orders of magnitude higher than that of typical syntheticstacking interactions. These molecules have a central polymers. This particular system proves yet another timephtalocyanine ring with four crown ether substituents that supramolecular chemistry can be used very effectivelyattached to its periphery. The crown ether moieties, in turn, for the preparation of structures and materials inaccessiblebear 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 planeof each disk is rotated by 6.58 along the stack axis with 6. Multiple non-covalent interactionsrespect to adjacent neighbors. The self-assembling processthen brings the system to the next hierarchical level when All the systems described above involve one primarytwo or more right-handed one-dimensional objects wrap type of non-covalent interaction. This general featurearound each other to produce left-handed superhelical makes the quest for even more sophisticated systems quitestructures (Fig. 1d). Perhaps, the most interesting finding obvious. That is the synthesis of self-assemblers thatmade by authors is related to blocking of ‘helicity transfer’ would be driven to aggregate through different types offrom the peripheral chiral tails to the central aromatic core. interactions simultaneously. Recently such a system wasThis was achieved by adding potassium ions prior to reported by Fenniri et al. [*26]. The authors synthesized aaggregation of disk-like molecules. Strong complexation molecule which has complementary hydrogen bonding

1between the crown ether moieties and K ions prevents sites analogous to those existing in natural nucleobasesstaggering orientation of molecules which instead pack (guanine and cytosine) and attached a chiral amino acid onexactly one on top of the other in an ‘eclipsed’ (face-to- its periphery. They also introduced a hydrophobic methylface) fashion. As a result, the fibers adopt a cylindrical group on the outside of the nucleobase-like moiety in ordermorphology and the helicity disappears almost completely to reduce the competition of water molecules for thein 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 foundsional objects can be tuned in a controlled way by simply that the self-assembling process in water proceeds throughchanging the strength and directionality of non-covalent two consecutive steps: first the molecules organize intointeractions. rosettes and then these macrocycles stack into one-dimen-

sional objects or nanotubes (Fig. 2b). The formation ofrosettes 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 first example of

Entropically driven formation of micelles in aqueous both H-bonded macrocycles and nanotubular objectssolutions [22–24] is one of the simplest and well-known spontaneously forming in water and is a particularlyexamples 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 toby Bates and co-workers [*25], who reported on worm-like interface with biological systems and the other to modifymicelles formed by diblock copolymer of ethylene oxide traditional synthetic polymers. The first example deals withand butadiene in water. These flexible cylindrical objects a system designed to promote the healing of damaged andhave a well-defined cross-section and lengths on the order diseased tissue [31]. Toward this end the one-dimensionalof microns. The structures can exist in a fully isolated state fibers are prepared via the self-assembly of biocompatiblein a dilute concentration regime due to their much greater peptide-amphiphiles (Fig. 2c). These amphiphiles have theamphiphilicity relative to conventional non-ionic surfac- geometry such that they will prefer to self-assemble into

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Fig. 2. (a) Bates’ giant worm-like micelles showing both the reduced (top) and covalently captured (bottom) forms. (b) Fenniri’s nanotube which displaystwo 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 nanofibers which can be reversibly self-assembled and covalently captured. (d) Stupp’s dendron rodcoil nanoribbon whichutilizes p–p stacking and hydrogen bonding during self-assembly.

cylindrical micelles as judged by the rules for amphiphileself-assembly described by Israelichvilli’s theory [32]. Theuse of a short peptide allows for rapid and facile synthesisusing standard solid phase methodology and incorporationof nearly any natural or unnatural amino acid allows for abroad range of chemistries to be displayed on the one-dimensional object’s surface. Initial studies have focusedon molecule 1 shown below.

The amino acid selection for the peptide-amphiphile 1provides for several important characteristics of the materi-al. First, the highly charged nature of the peptide allowsthe material to be readily dissolved in water at neutral pH.However, upon acidification of the solution, the net chargeof the molecule changes from 23 to neutral as several ofthe acidic groups are protonated. When this occurs, thecoulombic repulsion between molecules is eliminated andthe hydrophobic alkyl tails are able to aggregate to form acylindrical 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 fiber diameter is betweenassemble and disassemble based on the pH environment. 5 and 8 nm while the length can be in excess of a micron.

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Second, the tetra-cysteine sequence just before the hydro- initial observation suggested formation of a network whichphobic tail allows the self-assembled material to be can immobilize organic solvent in a highly effective way.covalently captured through the formation of intermolecu- Specifically, the ratio of solvent to DRC molecules can belar disulfide bonds. Covalent capture is an effective tool for as high as 7000:1. Transmission electron microscopy ofstabilization of preorganized self-assembled structures as the samples prepared from the DRC gels diluted in excessillustrated in the work of Bates [25] above and other dichloromethane revealed the presence of one-dimensionalexamples in the literature [33–37]. This effectively allows structures with uniform width of 10 nm and length on thethe 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 bimolecularmakes the crosslinked product stable at high pH where packing of DRC molecules which are |6.5 nm long inbefore crosslinking it would have disassembled. Given the their fully extended conformation. The morphology ofmolecular weight of the peptide-amphiphile and the length these structures was determined by atomic force micro-of the self-assembled fibers as imaged by transmission scopy experiments which showed that the strands have aelectron microscopy, the molecular weight of the polymer uniform thickness of 2 nm. Therefore DRC forms well-

7after crosslinking is |2310 Da. Because the tetra-cys- defined bimolecular ribbons which lay flat on the substrateteine region is centered in the peptide-amphiphile the used for imaging.formation of disulfide bonds only occurs within a single There are several important features of these sup-fiber and does not link multiple fibers to one another. Like ramolecular structures which distinguish them from typicalthe pH induced self-assembly, the covalent capture is also organogel fibers [39]. First, the width and the thickness ofreversible 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 diametersdissolved molecule to supramolecular fiber to high molecu- hundreds or even thousands of times greater than the sizelar weight polymer and back again at will, simply by of the fiber-forming molecules. The cross-section of DRCaltering 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 fibersa 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 stateand 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 fibers observed in mostrodcoil (DRC) which is composed of the hydroxyl-termi- other systems regardless of concentration. We believe thatnated dendron (generation 1), biphenyl-ester mid-section, the presence of two wedge-shaped dendritic segmentsand oligoisoprene tail [*38] located in the center of the nanoribbon prevents their

.Each block plays its specific role in the self-assembling

process. Phenolic and carbonyl groups of the dendron arestrongly driven to form hydrogen bonds in non-polarsolvents resulting in formation of head-to-head dimers.The biphenyl ester units can then stack the preformeddimers in at least one dimension via aromatic p-stackinginteractions. The oligoisoprene segment, on the other hand,is readily solvated by non-polar organic solvents and canremain rotationally free after the aggregation of moleculesthrough the rod-dendron portion takes place. This reducesthe loss of conformational entropy upon the aggregationand makes the self-assembling process thermodynamicallymore favorable. When the DRC is dissolved in aproticsolvents, a spontaneous gelation rapidly occurs and theorganic media transforms into birefringent gel at exceed- Fig. 4. Transmission electron microscopy image of DRC structures

formed in dichloromethane.ingly small concentrations of DRC (|0.2 wt.%). This

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bonded tapes based on cyclic secondary diamides. Chem Revaggregation in one direction (perpendicular to the plane of1994;94:2383–420.the ribbon), whereas the oligoisoprene coil segments

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