Perspective

Dendrimers and supramolecular

Jean M. J. Fre´ chet*

Department of Chemistry, University of California, Berkeley, CA 94720-1460 ince their introduction in 1985 by Toma- high-generation dendrimers. Although the , and metals such as Ru(II) or Slia et al. (1) and Newkome et al. (2), majority of the dendrimers prepared to-date Os(II). Fig. 1A shows a very small bime- dendrimers have attracted much attention have been built of covalent bonds (3, 10), tallic dendrimer obtained with a modular because of their fascinating structure and many noncovalent dendrimers (3, 11) have strategy that has been used to prepare unique properties (3, 4). Dendrimers are also been prepared by a variety of self- many larger dendrimers with a variety of globular, size monodisperse macromole- assembly processes involving, for example, arrangements of the internal and periph- cules in which all bonds emerge radially hydrogen bonding (12) or supramolecular eral metal centers (17). These polynuclear from a central focal point or core with a coordination chemistry (13). complexes, which are redox-active and regular branching pattern and with repeat Relating the concepts of dendrimers and have luminescent properties, have been units that each contribute a branch point. (14) in this article suggested for use as photochemical mo- Not all regularly branched are requires more that just a consideration of lecular devices although many current dendrimers because properties of the den- molecules resulting from supramolecular structures are clearly not well suited for dritic state (4), such as core encapsulation construction. The unique layered architec- practical applications. Coordination (5, 6) and unusually low intrinsic viscosity in ture of dendrimers, their globular shape, chemistry has also been used to prepare a solution (7), are reached only when globu- highly controlled size, radially controlled great variety of other dendrimers or den- larity is achieved at a certain generation or chemical make-up, multivalent periphery, dritic hybrids such as the ‘‘lock and key’’ size threshold. Therefore, many low- variable inner volume, and controlled in- structure of Newkome et al. (25). The use generation dendrons or the early cascade tramolecular dynamics endow dendrimers of coordination chemistry to prepare den- molecules of Vo¨gtle and coworkers (8) are with unique features and provide them with drimers is synthetically accessible and, too small to exhibit the properties of den- the ability to morph into a variety of virtual with appropriate choices of metals and drimers, but they are frequently used as supramolecular arrangements in response ligands, can afford durable structures. Su- branched oligomeric building blocks in their to external stimuli. Unlike collections of pramolecular dendrimers containing both construction, and have a size relationship to small molecules, which might require su- metal centers and complementary func- dendrimers somewhat akin to that between pramolecular assembly to deliver function, tional moieties, as well as supramolecular oligomers and . dendrimers can simply use internal dynam- assemblies of nanocrystals and dendrim- Two distinct synthetic methodologies ics to arrange their multiple and intercon- ers, may well prove useful in areas such as have been used for the preparation of den- nected components in ways that minimize energy harvesting and conversion, signal- drimers: the divergent approach (1, 2), in free energy (15) and afford specific func- ing, and diagnostics. which growths starts at the core and pro- tions. Such intramolecular reorganizations Following the early work of Kato and ceeds radially outward toward the den- may lead to shape or volume changes, the Fre´chet(26, 27) and of Lehn and coworkers drimer periphery, and the convergent ap- creation of internal microenvironments, the (28) on the use of hydrogen bonding for the proach, (9, 10) in which growth starts at cooperative organization of surface or inner assembly of supramolecular struc- what will become the periphery of the den- functionalities, the concentration or exclu- tures, a remarkable family of dendrimers drimer proceeding inward. The two meth- sion of substrate from the molecular ‘‘cavi- was prepared by Zimmerman et al. (12) by odologies are complementary and neither is ty’’ of dendrimers, or the formation of de- using the H-bond-mediated self-assembly of generally better, the choice of synthetic ap- fined multimolecular assemblies. six Fre´chet-type polyether dendrons (9) fit- proach being usually justified by the features Supramolecular Assembly of Dendrimers ted with tetracarboxylic acid moieties at desired for the target , the chem- their focal point. Analogous but unsymmet- istry available for growth, and the specific The use of metal branching centers, such as rical dendritic structures were also obtained building blocks used in the construction of ruthenium and osmium, and multidentate by Freeman et al. (29) with the self-assembly the dendritic framework. In general, the ligands for the construction of early metal- of two types of convergent polyether den- convergent approach provides better overall lodendrimers centers was described a de- drons with complementary derivatives of structural control, in part as a result of its cade ago by Balzani and coworkers (16, 17) melamine and cyanuric acid at their focal enhanced potential for purification at inter- Since this early work, a large number of points (Fig. 1B). In this instance, however, mediate stages of growth, and, in part, as a self-assembled dendritic structures have the self-assembled structure had an even result of its innate ability to introduce dif- been prepared by using mainly metal lower stability than Zimmerman’s dendrim- ferentiated functionalities at the focal point complexes (Fig. 1A), hydrogen bonding ers as fewer H-bonds contributed to its B and the periphery of the dendrimer. In moieties (Fig. 1 ), or ionic interactions (Fig. assembly. Reinhoudt and coworkers (30) contrast, purity and structural uniformity 2) for the assembly. The topic of self- have combined palladium-centered coordi- are harder to maintain in the divergent assembly of dendrimers has been thor- nation chemistry and melamine-cyanuric approach, because the number of reactions oughly reviewed (11, 17–24). acid H-bonding to prepare a variety of me- that must be completed at each step of In their seminal work, Balzani and co- tallodendrimers. Although such structures growth increases exponentially requiring workers (16) demonstrated the formation are indeed beautiful, their synthesis is even large excesses of reagents, but the process is of dendritic polynuclear species by using, better suited not only for syntheses on a for example, 2,3-bis(2-pyridyl)pyrazine as larger scale but also for the preparation of bridging ligands, bipyridines as terminal *E-mail: [email protected].

4782–4787 ͉ PNAS ͉ April 16, 2002 ͉ vol. 99 ͉ no. 8 www.pnas.org͞cgi͞doi͞10.1073͞pnas.082013899 Downloaded by guest on September 26, 2021 Fig. 1. (A) Self-assembled metallodendrimer. (B) Self-assembly of dendrimer by hydrogen-bonding.

more demanding than that of covalent an- spherical assemblies that mimic the shape other types of external environments, in- alogs, and the molecules remain little used. and architecture of certain types of viruses. cluding surfaces. A third type of self-assembled dendrimer Aida and coworkers (34) have used an anal- results from ionic interactions as exempli- ogous strategy involving weak metal–metal Shape and Conformations of Dendrimers fied by the lanthanide-core dendrimers of interactions to effect the hierarchical self- There has been significant and exaggerated Kawa and Fre´chet (31) (Fig. 2). In this organization of small dendrimers into lumi- controversy about the shape of dendrimers, approach, convergent polyether dendrons nescent superhelical fibers (Fig. 3). With a and the placement of their chain ends either with a carboxylic acid focal point are assem- rigid dendronized polymer consisting of a at the ‘‘periphery’’ of the globular macro- bled around a central trivalent lanthanide poly(phenylene ethynylene) backbone sub- molecule or back-folded within its building cation via metathesis by using, for example, stituted with Fre´chet-type polyether den- blocks. Indeed, a variety of calculations Er(OAc)3, Tb(OAc)3, or Eu(OAc)3.Inthis drons, evaporation of the solvent led to the and measurements have suggested back- case the dendrons perform the function of formation of very large donut-shaped as- folding of the chain ends whereas others shielding the lanthanide from one an- semblies (35). Given their sizes, optical and have ascertained their peripheral arrange- PERSPECTIVE other. This site-isolation (vide infra) elimi- electronic properties, such assemblies could ment (36). nates the self-quenching between metal at- well find display, storage, or other applica- Many dendrimers have been shown to be oms, enabling the use of such structures for tions in micro- and nanoelectronics. flexible, whereas a few of the largest seem to optical amplification, an area of practical Overall, it is clear that truly supramolecu- be fairly rigid. In general, it may be said that significance for fiber optics communication. lar dendrimers and dendritic systems can be true dendrimers—such as those that exhibit Among the numerous other self-assem- obtained by a variety of approaches, but the an unusual intrinsic viscosity to molecular bling dendritic systems that have been de- supramolecular character of dendrimers ex- weight relationship (7)—are globular mac- scribed, those involving the columnar as- tends far beyond their preparation. The romolecules that acquire significant rigidity SPECIAL FEATURE sembly of dendrons or of dendronized following paragraphs will therefore examine only at high generation. Small dendrimers, polymers are particularly intriguing. In their characteristics and properties of dendrimers and especially those that involve long and seminal work Percec et al. (32, 33) have used that result from intramolecular dynamics flexible connectors between branch points, van der Waals interactions and H-bonding and interactions involving the various build- are generally quite malleable and may even to self-assemble functionalized polyether ing blocks of dendrimers with solvents or collapse into high-aspect ratio ovoids or dendrons into cylindrical columnar or

Fig. 2. Schematic representation of self-assem- bled ionic dendrimer. Fig. 3. Organization of self-assembled dendrimers into supramolecular fibers.

Fre´chet PNAS ͉ April 16, 2002 ͉ vol. 99 ͉ no. 8 ͉ 4783 Downloaded by guest on September 26, 2021 Fig. 4. Dendritic ‘‘unimolecular micelle’’ used for the slow release of indomethacin.

flattened pancake-like shapes once solvent considerations will usually disfavor the indomethacin, within their collapsed inte- is evaporated after spreading on a surface. mixing of chain-ends with dissimilar inner rior as a model for a slow-release drug- The question of the existence of a ‘‘cavi- building blocks. In the case of dendrimer delivery agent (41) (Fig. 4). ty’’ within dendrimers has also been raised monolayers, molecular interactions be- frequently. Indeed, molecules have been tween the various components of the den- Site Isolation and Dendritic encapsulated in noncovalent fashion within drimer and with the surface also affect Encapsulation dendrimers but this does not mean that their shape (44–46). Numerous biological systems make use of dendrimers have a permanent and rigid the concept of site isolation in which an cavity. Most dendrimers are flexible enough Dendritic Unimolecular Micelles active center or catalytic site is encapsu- to accommodate inclusion guests—indeed Specially designed dendrimers with a hydro- lated, frequently within a protein, leading to solvent molecules are generally thought to phobic interior and a hydrophilic periphery properties that would not be encountered in freely penetrate dendrimers—but they are are not only capable of molecular inclusion the bulk state. The inherent topological also capable of rearranging themselves with but they can also solubilize hydrophobic features of a dendrimer in which a core is significant volume collapse when solvent is molecules, such as pyrene in aqueous solu- surrounded by a branched shell that carries removed. This collapse may leave guest mol- tion, to an extent at least equal to traditional peripheral functionalities may, of course, be ecules trapped inside the dendrimer, espe- micelles while not displaying any critical used to similarly encapsulate functional core cially if favorable interactions exist, as in micelle concentration (37–41). In contrast moieties and to create specific site-isolated some ‘‘dendritic micelles’’ (37–41),orifthe to classical micelles that are thermodynamic nanoenvironments (6), thereby affecting dendrimer structure has been rigidified to aggregates of amphiphilic molecules and molecular properties. However, for all but prevent their escape as in the ‘‘dendritic therefore dynamic assemblies of small mol- the largest and most rigid dendrimer struc- box’’ of Meijer and coworkers (42, 43). ecules, these ‘‘unimolecular micelles’’ are tures, the inherent ability of the various Overall, and as might be expected, free static and retain their cohesion regardless of structural subunits of a dendrimer to un- energy reigns supreme, and dendrimers concentration. Similarly, dendritic mole- dergo molecular motions and intramolecu- react to their environments to minimize cules with a polar interior and a nonpolar lar self-organization requires a careful their free energy. In a good solvent, a periphery behave as unimolecular reverse design of both the encapsulated and encap- dendrimer may be fully extended, reach- micelles capable of extracting and concen- sulating components. ing a volumetric maximum and an almost trating polar molecules from their solution Following the early demonstration of en- spherical shape. In the absence of solvent, in nonpolar solvents (44). The shape of such capsulation by Hawker et al. (5), who used a the volume of a dendrimer collapses while molecules, dissolved in a solvent that solvatochromic probe placed at the focal its final shape is determined by its flexi- matches the polarity of their periphery, is point of a homologous series of Fre´chet- bility, the interactions of its various com- expected to be spherical with chain-ends type dendrons, a number of researchers, ponents (core, building blocks, chain- extended toward the solvent and an interior using the distinct properties of the den- ends), and the interactions with its near that may be collapsed to minimize the un- drimer architecture, have placed active sites neighbors. Similarly, the location of chain- favorable interactions that might result from that have photophysical, photochemical, ends (peripheral or back-folded) in all but solvent penetration. electrochemical, or catalytic functions at the the most rigid structures is dictated by free As a result of their inherent stability, core of dendrimers. For example, there have energy. If the chain-ends possess favor- unimolecular micelles may be used to been numerous reports of dendrimer- able interactions (e.g., H-bonding or encapsulate guest molecules with a simple encapsulated porphyrins designed to mimic ␲-stacking) with the inner building blocks, precipitation approach. For example, we some of the features found in cytochromes. back-folding may be expected to occur, a have used dendritic molecules with a hy- Both the redox potential and the accessibil- phenomenon that may be exacerbated or drophobic interior and an oligoethylene ity of the porphyrin cores are greatly mitigated by solvent. In the absence of a glycol periphery to entrap significant affected by their environment and the char- favorable enthalpic contribution, entropy amounts of a hydrophobic drug, such as acteristics and size of the encapsulating

4784 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.082013899 Fre´ chet Downloaded by guest on September 26, 2021 auxiliary acid acceptor such as solid potas- sium carbonate. In a more recent example we have demonstrated a similar synergistic combination of catalytic and pumping ac- tions with a dendrimer designed with a reversed polarity gradient (50) surrounding a photocatalytic core. A different type of encapsulation, involv- ing the formation of metal within dendrimers, has been used to prepare inorganic–organic composite structures that are also useful in catalytic applications (51). The initial driving force for encapsu- lation of the metals in poly(propylene imine) dendrimers with inert or noncom- plexing peripheral groups usually involves complexation of a metal with reactive inner tertiary amine functionalities present in the dendrimer framework itself. This is followed by chemical reduction within the Fig. 5. Dendritic manganese por- dendrimer to afford the final dendrimer- phyrin oxidation catalyst. encapsulated zerovalent metal nanopar- ticles. In this application, the dendrimers layer. In other systems, encapsulation of reactors’’ in which catalytic action is com- serve both as templating hosts for the prep- photoactive units in dendritic shells leads to bined with rapid and directional transfer of aration of the catalytic nanoparticles and as enhanced luminescence behavior and re- reagents and products (49, 50). For exam- nanoporous stabilizers preventing their ag- duced self-quenching (6, 18, 22, 31, 47). ple, a dendrimer with a nonpolar aliphatic gregation. Crooks et al. (51) have shown that In an early report of dendrimer-mediated periphery and polar inner functionalities substrates can readily penetrate the den- catalysis, Moore and coworkers (48) have (Fig. 6) can be used to catalyze the E1 drimers to access the catalytic sites and used a manganese porphyrin (Fig. 5) and elimination of a solution of a tertiary alkyl undergo simple reactions such as hydroge- iodobenzene to effect the shape-selective halide (49) in a nonpolar aliphatic solvent. nations. In this application, dendrimer en- epoxidation of alkenes. In this case, den- As the alkyl halide has some polarity, it capsulation can lead to materials with sub- drimer encapsulation of the active - becomes concentrated within the polar den- stantial activities, as the surface of the metal like site contributed to both its enhanced drimer as the system minimizes its free nanoparticles remains largely unpassivated stability and selectivity. energy. The polar medium within the den- whereas the dendrimer layers themselves PERSPECTIVE In all catalytic systems, turnover is an drimers favors the formation of polar tran- can also contribute a sieving or gating effect important issue requiring good mass trans- sition states and intermediates, and an equi- on approaching substrates. fer for the substrate and rapid removal of librium is established in which some free the product from the catalytic site to avoid alkene is formed. As a result of its low From Dendritic Antennae to Monolayers inhibition of catalytic activity. Given that the polarity and the existence of a gradient of The highly compact and globular shape of size of dendrimers is roughly comparable to polarity between the dendrimer interior and dendrimers, coupled to their uniform size, that of many proteins, and that, just like its exterior, the alkene product is rapidly restricted interpenetration, plurifunctional

enzymes, dendrimers are able to create a expelled from the dendrimer back into the character, and controlled arrangement of SPECIAL FEATURE special microenvironment within their nonpolar solvent. Overall, the reaction is functional groups, makes them ideal for structure, we have recently exploited this driven to completion by using as little as applications in energy harvesting and stor- feature of dendrimers to construct ‘‘nano- 0.01% of dendrimer in the presence of an age, or as functional surfaces or interfaces.

Fig. 6. A dendritic nanoreactor providing both catalysis and rapid mass transfer.

Fre´ chet PNAS ͉ April 16, 2002 ͉ vol. 99 ͉ no. 8 ͉ 4785 Downloaded by guest on September 26, 2021 rocenyl groups and biotin analogues. In the absence of avidin, an electrochemical signal is generated by the enzymatic activity of glucose oxidase. As the concentration of avidin in the electrolyte solution is in- creased, the electrochemical signal is de- creased because of the steric blockage by the avidin adlayer formed on the modified elec- trode. Once used, the biosensing device can Fig. 7. Shape change of alkyl-modified poly(propylene imine) dendrimer after spreading at air–water be regenerated by treatment with excess interface. biotin to desorb avidin from the biotinylated dendrimer surface. Dendrimer self-assembled monolayers, For example, dendrimers with different tionalities, or even through their single focal attached either covalently or ionically onto chromophores placed at their periphery and point (58, 59). In the latter case, surface- a silicon surface, have been used success- focal point have been use as light-harvesting binding is generally rather weak unless fully as resist materials for nanolithography antennae (52) in which geometry and chro- strong ionic (60) or covalent (61) linkages (60, 61) (Fig. 8). Following imaging that has mophore selection control intramolecular are used. The flexible nature of lower gen- used a scanning probe, appropriately de- energy transfer. In such applications, the eration dendrimers is frequently an asset signed dendrimer monolayers are capable of size of dendrimers is a clear asset as its range because molecular interactions can be max- withstanding the harsh conditions of an roughly matches the sort of distances over imized for strong binding by distortion of the aqueous fluoride wet-etching process and which energy transfer by the Fo¨rster mech- globular framework of the dendrimer. This both negative- and positive-tone images can anism can operate with high effectiveness. was demonstrated by Meijer and coworkers be obtained. This approach would still re- With appropriate design, the undesired in- with a study of functionalized dendrimers at quire significant process optimization and terchromophoric phenomena that might the air–water interface (45). This involved a extensive tip multiplexing (64) to become arise from interactions of close neighbors poly(propylene imine) dendrimer with practical. can be avoided, and extremely efficient chain-ends modified with long-chain alkyl Assembling Dendrimers into Megamers transfer of energy can be achieved. The substituents, which could only interact with concept is especially attractive for designs in the water surface through their hydrophilic It is appropriate to conclude this brief per- which multiple peripheral chromophores internal components and not through their spective on dendrimers and supramolecular funnel their energy to a central chro- hydrophobic chain-ends. As a result, the chemistry with a few words on megamers, mophore located at the focal point of the shape of the dendrimers changed from a molecules that are multimolecular assem- dendrimer, as demonstrated again recently sphere with extended chain-ends—the con- blies of dendrimers. It is clear that some of by Aida and coworkers (53), with a very formation favored in a nonpolar solvent—to the dendrimeric clusters, self-assembled large dendrimer containing an array of 28 a flattened conformation in which the hy- monolayers, or multilayer gels mentioned zinc porphyrin donor chromophores radially drophilic dendrimer interior maximizes its earlier constitute supramacromolecular as- emanating from a central free-base porphy- association with the water surface, while the semblies of dendrimers. Similarly, simple rin acceptor. These early mimics of natural hydrophobic end groups are forced upward covalent oligomeric species in which two or photosystems show great promise and their and away from the water surface (Fig. 7). three dendrimers are joined together have combination with moieties capable of These findings correlate well with the earlier also been known for some time, as they are charge separation and electron injection work of Saville et al. (58, 59) on deuterated frequently obtained as products of coupling might contribute to lessen our dependence Fre´chet-type poly(benzyl ether) dendrons side reactions during the divergent synthesis on energy from fossil fuels. In more tech- and those of Tomalia and coworkers (56) of poly(amido amine) dendrimers. How- nological areas, such as nanoscale photon- and Hawker and coworkers (57) on end- ever, dendrimers can also be used as reactive ics, dendrimers show excellent promise be- modified poly(amido amine) dendrimers. building blocks for the rapid construction of cause, to be used for devices, the materials Because of their unique properties, den- larger structures possessing both complexity should have a well defined macromolecular drimer monolayers are finding a number of and dimensions beyond the dendrimer it- architecture with a large cross section for applications from surface-confined chemi- self. Tomalia et al. (65–67) have combined energy absorption, extremely high quantum cal arrays (54, 55) or affinity biosen- preformed poly(amido amide) dendrimers yields of , as well as good sol- sors (62, 63) to resists for nanolithography of different generations to obtain well ubility and processability characteristics. It is (60, 61). Kim and coworkers’ (62, 63) elec- defined core-shell-type megamers in clear that dendrimers have all of these assets trochemical biosensing device uses cyclic which the central, and usually larger, ‘‘core’’ and also have the built-in structural, chem- voltammetry to detect the avidin–biotin in- dendrimer is surrounded by a well defined number of smaller dendrimers (Fig. 9). Al- ical, and physical versatility that will enable teraction by monitoring the redox proper- ties of free glucose oxidase in a glucose- though much remains to be done to obtain the tuning of each of these properties for the containing electrolyte solution. Self- size-monodisperse megamers and avoid specific intended application. assembled monolayers of amine-terminated clustering into larger, ill-defined entities, The many unique structural features of poly(amido amine) dendrimers were pre- megamers and analogous assemblies such as dendrimers also make them attractive for pared on gold electrodes, and the periphery those obtained from nanocrystals and den- the modification of surfaces and interfaces was functionalized randomly with both fer- drimers are likely to draw much attention (44). A number of studies have explored the ability of dendrimers to form self-assembled monolayers. Although dendrimer molecules are significantly larger than the classical surfactants used for most monolayers, they can interact with surfaces through the co- operative effect of multiple peripheral (54, 55) or inner structural (45, 46, 56, 57) func- Fig. 8. Scanning-probe lithography on dendrimer monolayer used as resist.

4786 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.082013899 Fre´ chet Downloaded by guest on September 26, 2021 their various constituting blocks to minimize overall free energy even as their internal hierarchical order is preserved. Although a number of possible areas of application of dendrimers resulting from their unconven- tional supramolecular character has been outlined in the above text, there is little doubt that rich additional and more refined findings are likely to emerge within the next decade. Fig. 9. Assembly of a megamer from two different types of dendrimers. Thanks to all my excellent coworkers and collab- orators whose names appear in the references. in the coming years, as they may be expected concept of supramolecular chemistry far This research was supported by the Department of Energy (Basic Energy Sciences), the Air Force to provide access to new properties and beyond Lehn’s original definition. Den- Office of Scientific Research, and by the National phenomena. drimers come in many forms and sizes; a few Science Foundation (Division of Materials Re- As outlined in this article, dendrimers, are rigid whereas many others have the search). The Army Research Office (Multi- with all their interesting architectural fea- ability to react to their environment, mod- University Research Initiative program) is ac- tures and unusual properties, extend the ifying their shape and the arrangement of knowledged with thanks.

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