Topics in Current Chemistry,Vol. 217 © Springer-Verlag Berlin Heidelberg 2001 This review will focus on recent progress in supramolecular dendrimer chemistry. We have chosen to present several representative examples that illustrate the diverse ways in which dendrimers can be used to create supramolecular systems. The early focus is on host-guest chemistry where molecular recognition may occur within the dendrimer interior or at its sur- face.Interior binding may be directed,for example, by a specific group at the dendrimer core, or it may be a nonspecific hydrophobic effect (e.g., dendrimer as unimolecular micelle). Mo- lecular recognition at the “surface”is distinguished by the large number of end-groups and the potential for multivalent interactions. The nanoscopic size and recognition abilities of dendrimers make them ideal building blocks for self-assembly and self-organization systems.The review will focus on ways in which dendrimers may be formed by self-assembly and ways in which preformed dendrimers may interact with one another. Two types of self-organizing systems will be illustrated: liquid crys- talline dendrimers and dendrimers organized at interfaces. Keywords. Dendrimer, Complexation, Binding, Encapsulation, Nanosphere, Self-Assembly, Hydrogen Bonding 1Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 1.1 Definitions and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . 96 2 Host-Guest Chemistry Involving Dendrimers . . . . . . . . . . . . . 98 2.1 Unique Structures for Surface and Internal Complexation . . . . . . 98 2.2 Nonspecific Internal Binding . . . . . . . . . . . . . . . . . . . . . . 98 2.3 Directed Internal Binding . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3.1 Hydrogen Bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3.2 Apolar Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.4 Topological Complexation . . . . . . . . . . . . . . . . . . . . . . . . 104 2.5 Surface Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3 Self-Assembly of Dendrimers . . . . . . . . . . . . . . . . . . . . . . 106 3.1 Concept and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . 106 3.2 Hydrogen Bond Mediated Self-Assembly . . . . . . . . . . . . . . . . 106 3.3 Self-Assembly Using Pseudorotaxane Formation . . . . . . . . . . . 107 3.4 Metal Mediated Self-Assembly . . . . . . . . . . . . . . . . . . . . . 108 Supramolecular Chemistry of Dendrimers Steven C. Zimmerman, Laurence J. Lawless Department of Chemistry, University of Illinois, 600 South Mathews Ave, Urbana, Illinois 61801, USA E-mail: sczimmer@uiuc.edu 4 Self-Organization of Dendrimers . . . . . . . . . . . . . . . . . . . . 112 4.1 Concept and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.2 Liquid Crystalline Phases . . . . . . . . . . . . . . . . . . . . . . . . 112 4.3 Interfacial Organization . . . . . . . . . . . . . . . . . . . . . . . . . 113 5 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 1 Introduction 1.1 Definitions and Scope The field of dendrimer chemistry is rapidly advancing, and there continues to be a need for literature reviews. Our laboratory published two reviews on the supramolecular chemistry of dendrimers just four years ago [1, 2]. In the in- terim, numerous important reports have appeared, and therefore this is an appropriate time to update our earlier review. Thus, this chapter will focus primarily on work reported in 1999 and the first half of 2000. Because several specialized reviews on the topic of supramolecular dendrimer chemistry have appeared recently (see below), this review will present a broad overview of the field. The concepts will occasionally be illustrated with selected examples from earlier literature. This chapter will not cover the history of the field, methods of synthesis,or the structure and properties of dendrimers except as it is relevant to their supramolecular chemistry. Readers who are interested in these or more general aspects of dendrimer chemistry are directed to the out- standing book by Newkome et al. [3]. General reviews and those dealing with specific aspects of supramolecular dendrimer chemistry also have been pub- lished recently by Astruc et al. [4], Smith and Diederich [5], Emrick and Fréchet [6], Frey and Schlenk [7], Hawker [8], Inoue [9], Majoral and Caminade [10], Baars and Meijer [11], Moore [12], Müllen et al. [13], Newkome et al. [14], Schlüter and Rabe [15], Stoddart et al. [16], Tomalia et al. [17],Vögtle et al. [18], and many others. Many of the terms that are used in this review are not well defined in the lit- erature and their usage varies among authors. We use the term “self-assembly” to denote the process by which collections of molecules are formed [19]. These collections may contain a very small or very large number of molecules, but or- der should exist due to a “pre-programmed” atomic level recognition process. Thus, the chemist determines the ultimate structure. Self-organization refers to an identical process but where order arises spontaneously due to the inherent desire for molecules to order themselves into the lowest thermodynamic state, for example in the formation of liquid or molecular crystals and the formation of micelles and liposomes. 96 S.C. Zimmermann · L.J. Lawless There continues to be debate about the exact structure of dendrimers, in par- ticular whether they are fully extended with maximum density at the surface or whether the end-groups fold back into a densely packed interior [1,2]. Recently, experimental evidence has been obtained in support of both compact folded and extended structures. For example, Amis et al. has reported [20] the synthe- sis of seventh generation poly(amidoamine) (PAMAM) dendrimers with par- tial deuteration of the peripheral layer (CD 2 CDHCONHCH 2 CH 2 NH 2 ). Contrast matching experiments (in CD 3 OD) using small angle neutron scattering allowed the radius of gyration to be determined which was similar to that of the whole dendrimer. This finding is consistent with localization of the terminal groups near the surface of the dendrimer. Wooley et al. have synthesized two fifth- generation Fréchet-type dendrimers with 19 F at the core, one with a 13 C label in the third generation layer, the other in the fifth generation (peripheral) layer [21]. Solid state rotational-echo double-resonance (REDOR) NMR experiments indicate a similar distance between the core and the third- and fifth-generation labels consistent with a fold-back of peripheral groups. As seen in Fig. 1, the structure of some dendrimer repeat units, for example, the 1,3-diphenylacetylene unit developed by Moore [22], must by their very na- ture fold back on themselves. Parquette and coworkers [23, 24] have designed and synthesized a new class of dendrimers, which are designed to fold back via hydrogen bonding and adopt defined chiral ordered structures.With many den- drimers it is likely that no single structure is adopted but rather different struc- tures depending on the nature of branching units and its environment. Thus, in referring to surface and internal recognition events, we note that the “surface” refers to the end-groups and the interaction being discussed might actually oc- cur on the inside of the dendrimer. Likewise,“internal” refers to the core or the subunits that interconnect the core and end-groups, and this recognition could occur at a solvent exposed surface if the end-groups fold back. Supramolecular Chemistry of Dendrimers 97 Fig. 1. a Moore-type dendrimers consist of phenyl acetylene subunits.At the third generation different arms may occupy the same space and the fourth generation layer potential overlaps with the second generation layer. b Parquette-type dendrons are chiral, non-racemic, with in- tramolecular folding driven by hydrogen bonding a b 2 Host-Guest Chemistry Involving Dendrimers 2.1 Unique Structures for Surface and Internal Complexation The unique structure of dendrimers provides special opportunities for host- guest chemistry (Fig. 2). The multiple end-groups allow multiple complexation events to occur simultaneously at these sites, which can lead to special types of interfacial molecular recognition. For example, dendrimers are especially well equipped to engage in multivalent interactions.At the same time,one of the ear- liest proposed applications of dendrimers was as container compounds wherein small substrates are bound within the internal voids of the dendrimer [25]. Ex- perimental evidence for unimolecular micelle properties was established many years ago both in hyperbranched polymers [26] and dendrimers [27, 28]. 98 S.C. Zimmermann · L.J. Lawless Fig. 2. Schematic showing the three main parts of a dendrimer,the core,end-groups,and sub- units linking the two 2.2 Nonspecific Internal Binding This nonspecific approach to binding is nicely illustrated by the coating of poly(propylene imine) (PPI) dendrimers with a hydrophilic outer layer by Mei- jer and coworkers (see dendrimer 1) [29]. With basic amines and a somewhat hydrophobic interior, dendrimer 1 dissolves in water and binds rose Bengal (2) and 4,5,6,7-tetrachlorofluorescein (3), with association constants (K assoc ) of 5 ¥ 10 5 M –1 and 3 ¥ 10 4 M –1 , respectively. The importance of the acid-base asso- ciation was supported by the pH effect on binding. Finally, SAX measurements showed localization of the guest molecules on the dendrimer interior. A dendrimer-like inverted unimolecular micelle was recently described by Sun and coworkers [30]. Using the Bingel-Hirsch type addition reaction to C60 (sixfold), the straightforward synthesis of 4a–c was achieved. Sonicating this compound in dodecane with an aqueous lithium chloride solution led to incor- poration of a portion of both water and metal ions on the inside of 4.As would be expected, the amount of aqueous ion incorporated was dependent on the length of the hydrophilic block (i.e., 4a Æ b Æ c). The authors also showed that the micellar structures could be used as “nanoreactors” to produce silver nanoparticles of relatively uniform sizes. Supramolecular Chemistry of Dendrimers 99 In a related study, Crooks and coworkers [31] showed that inverted micelles could be produced by a self-assembly process. Thus, a fourth generation PAMAM dendrimer was shown to readily dissolve in 1% dodecanoic acid-toluene to a degree that suggested nearly complete formation of surface ion pairs (i.e., ammonium ion-carboxylate pairings; see 5 in Fig.3). The IR was consistent with this suggestion. Similar structures have been prepared by covalent modification and shown to encapsulate guest molecules. Beyond avoiding the need for cova- lent chemistry and its attendant purification difficulties, the self-assembly ap- proach is reversible. Thus, addition of acid leads to protonation of the PAMAM dendrimer, which in turn causes it to migrate to an aqueous layer. The authors not only demonstrate the reversible transport and encapsulation of methyl orange (6) into the self-assembled inverted micelles – they also show that cat- alytically active Pd nanoparticles can be prepared within the micelles. There is considerable interest in the use of dendrimers as unimolecular mi- cellar carriers of water insoluble drugs or for targeted delivery of drugs using the peripheral groups for tissue or cellular specificity. The simple binding ex- periments that have been reported to date strongly support the utility of den- drimers as unimolecular micelles. Little effort has focused on the capacity of dendrimers. It is likely that the capacity will be considerably lower than that of liposomes. Wendland and Zimmerman have shown that dendrimers may be 1 100 S.C. Zimmermann · L.J. Lawless Fig. 3. Ionic assembly of PAMAM dendrimer and decanoic acid (5) studied by Crooks and co- workers. In water the assembly is capable of complexing methyl orange (6) Scheme 1. Wendland and Zimmerman process for “coring”dendrimers.Cross-linking with the ring closing metathesis reaction is followed by basic hydrolysis/alcoholysis which removes the core unit 5 6 “cored,” which may open the way to increasing their carrying capacity [32]. As shown in Scheme 1,the ring closing metathesis (RCM) reaction of dendrimers 7 and 8 occurs with the commercially available Grubbs’ catalyst 9, giving nearly full cross-linking of the peripheral homoallyl groups. The core is then removed under basic conditions to give “cored”dendrimers 10 and 11.The coring process can leave different functional groups behind. An interesting example of metal ion sensing by a multi-chromophoric den- drimer was reported by Balzani et al. [33]. The dendrimer studied, 12, contains a trimesic acid core,a bis(ethylamino) spacer,then two lysine layers,and 24 dan- syl units as the end groups. In 5:1 acetonitrile-dichloromethane solution con- taining tributylamine, 12 showed strong fluorescence quenching upon addition of Co 2+ and Ni 2+ whereas no change was seen when a control compound (N- butyl 5-dimethylamino-1-naphthalene sulfonamide) was subjected to the same conditions.This result,combined with the results of other experiments,suggests that two or more sulfamide anions cooperate in the metal ion binding. Signifi- cantly, at stoichiometric metal ion concentrations, a single ion is found to quench the fluorescence of nine chromophores.This type of signal amplification is particularly useful for sensing applications. Supramolecular Chemistry of Dendrimers 101 12 2.3 Directed Internal Binding The incorporation of host or guest molecules at the core of a dendrimer allows the binding to be directed specifically at the core. Early examples showed that hosts that use either hydrogen bonding interactions or hydrophobic complexa- tion led to specific guest binding. Of course the host-guest designation is arbi- trary, but compounds traditionally considered guests have recently been at- tached to dendrimer cores. 2.3.1 Hydrogen Bonding Remarkably few reports have appeared wherein specific recognition sites on the interior of dendrimers are used to direct internalization of guest molecules. Early work by Newkome et al. [34] on glutarimide complexation and studies by Zim- merman et al. [35] on amidinium binding showed that hydrogen bonding could occur on dendrimer interiors with similar binding constants to those observed in free solution.In the latter case,the dendrimer type and generation number did not affect the ability to complex a small guest, and the K assoc values were fully respon- sive to the solvent polarity. The results suggest that even large dendrimers can be filled with solvent and this controls the microenvironment at the core. Diederich has reported chiral, non-racemic “dendroclefts” where the dendrimer diminishes the degree of enantioselective binding of a -glucosides but increases the diastere- oselective binding [36].In this example,the dendrimer plays an integral role likely due to additional hydrogen bonding interactions possible between host and guest. Newkome and coworkers have synthesized a series of dendritic monomers, 13, 14,and15 containing one, three, and six 2,6-diamidopyridine units, respec- tively [37]. These were subsequently covalently linked to epichlorohydrin-acti- vated agarose and the surface-modified gel’s ability to bind amital (16) deter- 102 S.C. Zimmermann · L.J. Lawless 13 14 15 16 mined. In this case, the dendritic structure diminished the extent of amital up- take. Indeed, a 13-fold increase in uptake was observed for dendron (13) and a linear analog relative to the gel derivatized with 15.Although two proximal arms of 15 (and14) might simultaneously complex amital,thereby increasing its bind- ing efficiency,the authors propose that two adjacent arms in 14 and 15 self-com- plex. Thus, an energy price must be paid prior to binding. 2.3.2 Apolar Binding Kaifer and coworkers have extensively studied ferrocene-based dendrimers as macromolecular redox agents [38a]. Recently, these workers have synthesized Newkome-type dendrimers (e.g., 17 and 18) containing a single ferrocene unit at the focal point (Fig. 4) [38b]. Because ferrocene is known to be an excellent guest for b -cyclodextrin (19),the electrochemical potentials were determined in water with and without b -cyclodextrin present, and K assoc values for cyclodex- trin binding were measured as a function of generation number of the den- drimer.It was found that both the dendrimer and its binding to cyclodextrin af- fected the electrochemical properties of the ferrocene. Also, the affinity of the cyclodextrin for the ferrocene was reduced with the third generation dendrimer 18 showing the largest effect (K assoc = 50 M –1 ) and the first generation ferrocene, 17,(K assoc = 950 M –1 ) at the low end of the normal range for ferrocene-cy- clodextrin complexes.The electrochemical redox potentials of the ferrocene are clearly affected by both the dendrimer and its complexation to cyclodextrin. Supramolecular Chemistry of Dendrimers 103 Fig. 4. Kaifer’s third-generation Newkome-type dendrimer with a ferrocene core (18). Equa- tion showing ferrocene complexation (first generation, 17) into the secondary side of b -cy- clodextrin (19) 17 19 18 Shinkai and coworkers found [39] that Fréchet-type dendrimers with phloro- glucinol (20),porphyrin (21),and cyclotriveratrylene (22) cores (Fig.5) all bound C60 in apolar organic solvents.In each case,the K assoc values increased with gen- eration number. For example,in toluene with hosts 20a–c, the K assoc values were 5 (20a),12 (20b),and 68 M –1 (20c),respectively.Spectroscopic evidence was pre- sented indicating complexation at the core. For the cyclotriveratylene-based hosts 22a–c, the K assoc values in methylene chloride were 130, 190, and 300 M –1 , respectively.A Job plot indicates 1:1 stoichiometry. The results indicate that the electron-rich dendrons increase the binding to the core element,presumably by classical electron donor-acceptor interactions (i.e., electrostatic, polarization, and dispersion forces). 2.4 Topological Complexation There are several ways in which one could imagine topological complexation of molecules by dendrimers. One of the earliest proposals was that dendrimers with extremely densely packed end-groups might permanently encapsulate guests. Meijer et al. realized this process [40] in work that was previously re- viewed [1]. Mechanical complexation could also occur by catenane or rotaxane formation (see below). Pseudorotaxane formation has been used to self-assem- ble dendrimers and this work is discussed in Sect. 3.3. Vögtle et al. have described two types of chiral dendrimeric assemblies based on rotaxane and catenane topologies (Fig. 6) [41]. Both types of structures were made by chemoselective alkylation of the preexisting rotaxane (23, R = H) or 104 S.C. Zimmermann · L.J. Lawless Fig. 5. Shinkai’s dendritic hosts for C60. Three generations of Fréchet-type dendrons (a–c) attached to phloroglucinol (20), porphyrin (21), and cyclotriveratylene (22 – lacking OMe groups) core units [...]... experiment performed on a monolayer prepared on mica 4 .3 Interfacial Organization Müllen and coworkers have reported the synthesis of a series of relatively rigid polyphenylene dendrimers with nanoscopic sizes based on a clever divergent, Diels-Alder strategy [ 13] With two members of this class, 33 and 34 (Fig 13) , whose diameters are 5.5 and 3. 8 nm, respectively, they have examined their ability to form... highly oriented pyrolytic 114 S.C Zimmermann · L.J Lawless 33 34 Fig 13 Müllen and coworkers synthesized polyphenylene dendrimers 33 and 34 and examined their self-organization in monolayers on highly oriented pyrolytic graphite (HOPG) Supramolecular Chemistry of Dendrimers 115 35 Fig 14 Schlüter and coworkers synthesized dendritic rods (e.g., 35 ) and reported the self-organization of amphiphilic structures... 30 :1178 28 Hawker CJ, Wooley KL, Fréchet JMJ (19 93) J Chem Soc, Perkin Trans 1 21 :30 0 29 Baars M, Kleppinger R, Koch MHJ, Yeu SL, Meijer EW (2000) Angew Chem, Int Ed Engl 39 :1285 30 Fu K, Kitaygorodskiy A, Sun Y-P (2000) Chem Mater 12:20 73 31 Chechik V, Zhao MQ, Crooks RM (1999) J Am Chem Soc 121:4910 32 Wendland MS, Zimmerman SC (1999) J Am Chem Soc 121: 138 9 33 Balzani V, Ceroni P, Gestermann S, Gorka M,... Dalton Trans 37 65 34 Newkome GR, Woosley BD, He E, Moorefield CN, Güther R, Baker GR, Escamilla GH, Merrill J, Luftmann H (1996) Chem Commun 2 737 35 Zimmerman SC, Wang Y, Bharathi P, Moore JS (1998) J Am Chem Soc 120:2172 36 Smith DK, Diederich F (1998) Chem Commun 2501 37 Strumia MC, Halabi A, Pucci PA, Newkome GR, Moorefield CN, Epperson JD (2000) J Polym Sci, Part A Polym Chem 38 :2779 38 a Cardona... is carried out in the presence of 37 , similar arrays are observed but with larger spacings This result suggests that 37 is incorporated into the assembly most likely as a group linking the dendrimers This approach gives especially stable arrays of dendrimers, and the authors note that the result is some of the highest resolution images of dendrimers obtained to date Dendrimers containing one or more... Macromolecules 33 :6214 22 Moore JS (1997) Acc Chem Res 30 :402 23 Recker J, Tomcik DJ, Parquette JR (2000) J Am Chem Soc 122:10,298 24 Huang BH, Parquette JR (2000) Org Lett 2: 239 25 Maciejewski M (1982) J Macromol Sci Chem A17:689 Supramolecular Chemistry of Dendrimers 119 26 Kim YH, Webster OW (1990) J Am Chem Soc 112:4592 27 Newkome GRM, Baker GR, Saunders MJ, Grossman SH (1991) Angew Chem, Int Ed Engl 30 :1178... and 26b similarly formed self-assembled dendrimers, with the time to reach equilibrium being generation-dependent: 26a (ca 36 h), 26b (ca 48 h), and 26c (ca 72 h) 3. 4 Metal Mediated Self-Assembly There continues to be considerable activity in the area of metal-mediated selfassembled dendrimers Newkome has continued an extensive investigation of self-assembled dendrimers based on the Ru(II)-terpyridine... The widths for 30 a and 30 b were measured to be 20 ± 4 nm and 23 ± 4 nm, respectively Aida has continued his extensive studies of biomimetic self-assembled dendrimers with a timely report on the “dendrimer effect” in a non-heme metalloprotein mimic [58] The work is based on the report by Tolman et al [59] that copper complexes such as 31 a react with molecular oxygen to form complex 32 a (Fig 12) which may... Dendrimer 33 was found to form regions (50–100 nm ¥ 70–800 nm) consisting of parallel rows with a 5.9 ± 0.7-nm spacing In most cases, only a few percent of the surface was covered, but in 2 out of 11 tries the entire surface was covered by a rod-like structure With dendrimer 34 , 2-D crystals were obtained with each unit cell containing at least two dendrimers The rod-like structures formed from 33 are... [66] Some of these compounds (e.g., 35 ) form stable monolayers in Langmuir troughs In the case of 35 , it could be efficiently transferred to mica, 116 S.C Zimmermann · L.J Lawless 36 37 Fig 15 Abruña and coworkers self-assembled a dendritic network on highly oriented pyrolyt- ic graphite (HOPG) surfaces by treating 36 with Fe(II), with and without the linking unit 37 forming a monolayer that is stable . on a clever divergent, Diels-Alder strategy [ 13] . With two members of this class, 33 and 34 (Fig. 13) , whose diameters are 5.5 and 3. 8 nm, respectively, they have examined their ability to form. pyrolytic Supramolecular Chemistry of Dendrimers 1 13 Scheme 2 114 S.C. Zimmermann · L.J. Lawless Fig. 13. Müllen and coworkers synthesized polyphenylene dendrimers3 3 and 34 and examined their self-organization. the oxygenated core. The largest dendrimer, 31 d, failed to undergo conversion to 32 d presumably due to steric hindrance. 31 31 32 4 Self-Organization of Dendrimers 4.1 Concept and Definitions As