Dendrons/dendrimers: quantized, nano-element like building blocks for soft-soft and soft-hard nano-compound synthesis

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1 TUTORIAL REVIEW Soft Matter Dendrons/dendrimers: quantized, nano-element like building blocks for soft-soft and soft-hard nano-compound synthesis Donald A. Tomalia* Received 24th August 2009, Accepted 9th November 2009 First published as an Advance Article on the web 17th December 2009 DOI: /b917370f It was A. Lavoisier s original thinking in Traite Elementaire de Chemie (1789) followed by J. Dalton s seminal atom/molecular hypothesis (i.e., New System of Chemical Philosophy, 1808) that defined first principles for much of our contemporary small molecule chemistry. Dalton s concept, advocating atombased (elemental) building blocks ( nm) for the synthesis of well defined small molecules, has emerged as a fundamental theme over the past 200 years. It initiated fundamental concepts such as well defined mass combining ratios, stoichiometries, valency and compound formation which have defined the central dogma and underpinned the traditional fields of both organic/polymer and inorganic sciences. As such, these historical examples portend the significant role that similar well defined, quantized soft nanomatter, modules such as dendrons and dendrimers ( nm) might be expected to play in the emerging science of nano-syntheses. Dendrimers are well defined collections of atoms that may be viewed as core-shell type atom mimics (i.e., soft nano-element like modules). More than 12,000 published references in the dendrimer field have clearly demonstrated the ability to structure control important Critical Nanoscale Design Parameters (CNDPs) such as: (a) size, (b) shape, (c) surface chemistry, (d) flexibility and (e) architecture over a wide range of structures and compositions. These are features shared with elemental atoms and account for unique atom-like combining properties exhibited by dendrimers to yield well defined nano-module stoichiometries. We report first steps, including many literature examples that demonstrate the construction of well defined soft-soft and soft-hard matter nano-compounds. A variety of dendrimer surface reactions or guest-host assemblies have been shown to produce stoichiometric nano-compounds such as: (a) dendrimer-dendrimer, (b) dendrimer-protein (c) dendrimer-fullerene and dendrimer-metal nanocluster structures, to mention a few. These literature examples provide compelling evidence for the emergence of an active dendron and dendrimer module based synthetic nano-chemistry platform. The National Dendrimer & Nanotechnology Center, Department of Chemistry, Central Michigan University, Mt. Pleasant, MI 48859, USA. donald.tomalia@cmich.edu Donald A. Tomalia, PhD is Director of The National Dendrimer & Nanotechnology Center and Distinguished Professor/Research Scientist at Central Michigan University. Other positions currently held include Distinguished Visiting Professor, Columbia University; External Faculty, University of Wisconsin-Madison (School of Pharmacy); Advisory Boards, American Society of Nanomedicine and European Foun- Donald A: Tomalia dation for Nanomedicine and Faculty Member, Faculty 1000 Biology. He received his PhD from Michigan State University. Dr Tomalia serves as Associate Editor for Nanomedicine (Elsevier) and on the editorial advisory board of Bioconjugate Chemistry. His research interests include dendrons/dendrimers and a systematic framework for unifying and defining nanoscience. 1. Introduction Among the most important areas of mutual interest between physics and chemistry is the inextricable need to understand the structural and hierarchical implications of matter. Simply stated, the revolutionary introduction of atom and molecular theory by chemists such as A. Lavoisier (1789) and J. Dalton (1808) clearly set the stage for the evolution of a systematic understanding of the atomic elements, their chemical bonding and formation of molecular structure. Organizing atomic elements according to their periodic property behavior subsequently led to Mendeleev s Periodic Table in Unarguably the pioneering development of such an early systematic framework for understanding elemental and molecular matter in the chemistry field both inspired and synergized many subsequent breakthroughs in physics. Such seminal milestones included the discovery of the electron (J. Thompson, 1897), quantum theory (M. Planck, 1900), the nuclear structure of atoms (E. Rutherford, 1915), electron shells/structure of atoms (N. Bohr, 1915) and atom quantum mechanics (E. Schrodinger, 1926), just to mention a few. The historical succession of many such similar events has provided us with our present deeper understanding of atomic/molecular at the pico-and sub-nanoscale levels and has undeniably enriched both contemporary physics and chemistry as we know it today (Fig. 1) Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

2 All present day interdisciplinary nanoscientists are now faced with similar challenging issues. These contemporary issues will require new and different thinking as one ponders the emerging rules, principles and hierarchical roles for traditional pico-(elemental) and sub-nanoscale (molecular) entities as they are used for the bottom up construction of more complex synthetic nanostructures. In pursuit of this daunting task, much can be learned from the many successful strategies provided by Nature. Using traditional pico- and sub-nanoscale entities (i.e., small molecules, monomers, oligomers) as systematic building blocks, Nature has demonstrated an exquisite array of strategies for routinely constructing precisely defined soft matter, nano structures with dimensional enhancements of larger. Such soft nanostructures include: (a) poly(peptide) based proteins, (b) poly(nucleic) acid based DNA/RNAs, as well as combinations of (a) and (b) to yield more complex (c) nano-capsid assemblies able to encapsulate genetic materials and produce viruses, to mention a few. It has recently been proposed that historical first principles and step logic used in the development of traditional chemistry be invoked as a template and strategy for the evolution of a new nano-periodic system and central dogma for nanoscience. 2 Briefly stated, this concept proposed the following: (a) creation of a nanomaterials roadmap focused solely on well defined (i.e., >90% monodisperse), (0-D) and (1-D) nanoscale materials (b) these well defined materials were divided into hard and soft nanoparticles, broadly following compositional/architectural criteria for traditional inorganic and organic materials (c) a preliminary table of hard and soft nano-element categories consisting of six (6) hard matter and six (6) soft matter particles was proposed, (Fig. 2 and 19). Elemental category selections were based on atom mimicry features and the ability to chemically combine or self assemble like atoms (d) these hard and soft nano-element categories produce a wide range of stoichiometric nanostructures by chemical bonding or non-bonding assembly. An abundance of literature examples provides the basis for a combinatorial library of hard-hard, hardsoft and soft-soft nano-compounds, many of which have already been characterized and reported. However, many such predicted constructs remain to be synthesized and characterized, 2 (e) based on the presumed conservation of critical module design parameters (i.e., CADP/CMDP/CNDP) (Fig. 3), many new emerging nano-periodic property patterns have been reported in the literature for both the hard and soft nano-element categories and their compounds. 2 This review focuses on dendrons and dendrimers, recently proposed as an important soft matter, nano-element category for defining a new nano-periodic system. 2 Since the discovery of dendrimers several decades ago, 3 8 significant evidence clearly shows that these nano-materials react and self-assemble as discrete, quantized nano-units. These well defined collections of covalently bonded atoms exhibit many features normally Fig. 1 A chronological list of proponents and opponents of traditional atomistic, elemental concepts, the Mendeleev periodic table of the elements and traditional chemistry central dogma. This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

3 Fig. 2 An illustration of hierarchical dimensions influenced by the traditional elemental periodic system and the proposed nano-periodic system, respectively. Fig. 3 Concentric hierarchical levels used to illustrate conservation of critical module design parameters (i.e., sizes, shapes, surface chemistries, flexibilities and architectures) as a function of hierarchical levels (i.e., CADP/CMacDP and dimensions (meters)). associated with traditional elemental atoms (i.e., atom mimicry). As such, dendrimers behave much as soft particle nano-elements to produce well characterized core shell (tecto)dendrimers (i.e., dendrimer-dendrimer type nano-compounds. 55,56 Similarly, reactions with fullerenes have been reported to produce stoichiometric dendrimer-fullerene type nano-compounds: 9 whereas, dendrimers bearing either surface or interior ligation sites reacted with metal salts to produce stoichiometric dendrimer-metal ligation type nano-compounds. 10,11 Some of these constructs could be further reduced to yield core-shell; dendrimer-metal nanocluster type nanocompounds. These results optimistically portend the extension of this concept to a wide variety of other well defined soft particle nano-elements (i.e., proteins, DNA/ RNA, viral capsids, etc.), as well as hard particle nano-elements (i.e., metal oxide nanocrystals, metal chalcogenide nanocrystals, etc.). These nano-element categories are proposed as a first step toward understanding their chemical bonding/self assembly features as well as associated nano-periodic property patterns. It is hoped that a deeper understanding of these issues will begin to more clearly define a central dogma for the new emerging area of synthetic nano-chemistry while unifying the general field of nanoscience. 2. Historical evolution of a central dogma for traditional chemistry Slightly more than 200 years ago (1808) traditional chemistry was in nearly the same stage of development that we find 458 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

4 nanoscience (technology) today. Traditional chemistry in the early 19th century was in its early stages of evolution from alchemy. From the perspective of a chemist, emergence of a central dogma for traditional chemistry began in the late 18th 19th century following the seminal contributions of Lavoisier and Dalton. Their introduction of atomic and molecular hypotheses set into motion a series of significant developments which are briefly summarized in (Fig. 1). These early developments led to the evolution of the Mendeleev Periodic Table and ultimately our contemporary understanding of atomic, molecular and chemical theory. Critical parameters that allowed this important progress evolved around the robust, reproducible features exhibited by the atomic elements such as; well defined (a) atomic masses, (b) reactivities, (c) valency, (d) stoichiometries, (e) mass combining ratios, and (f) bonding directionalities, to mention a few. The well defined nature of all these picoscale, atomic parameters is inextricably associated with the precise structures defined by the primordial self-assemblies of electrons with nucleons. 1 As we described earlier, 3,5 such picoscale structure control allows one to define certain important Critical Atomic Design Parameters (CADPs) of atoms as a function of features such as: (a) size, (b) shape, (c) surface chemistry, (d) flexibility (polarizability) and (e) architecture. From the perspective of a physicist/quantum chemist, the linear combination of atomic orbitals leads to molecular level structure. These structures consist of molecular orbitals that conserve many of these well defined atomic features, however, in completely different hierarchical forms (i.e., new emerging molecular properties and structures). 12 As such, one can now describe sub-nanoscale, molecular structures as a function of Critical Molecular Design Parameters (CDMPs) (a)-(d); wherein, (a)-(d) are as described above. In general, molecular size is determined by the elemental composition (i.e., atomic number), the number of elemental modules comprising the molecular structure as well as bonding directionality. Molecular shape and architecture is defined by elemental valency and bonding directionality (i.e.,valence shell electron pair repulsion theory, (VSEPR)). Molecular level surface chemistry is of course determined by a wide range of familar parameters, namely; molecular composition (i.e., molecular modules and functional groups), molecular architecture and steric environment, to mention a few. 8 Molecular flexibility is largely determined by the elemental composition of the molecular structure (i.e., inorganic versus organic structures), bonding types (i.e., p versus s bonding) and spacial placement of functional groups, etc. As a consequence of quantized and exquisitely defined features exhibited by the atomic elements and their compounds it soon became apparent to Mendeleev and others that such a continuum of systematic picoscale building blocks and their compounds produced a wide range of periodic property patterns. These periodic property patterns subsequently defined the grand vision of the famous Mendeleev Periodic Table which is routinely used to describe, predict and understand the central dogma for traditional chemistry as we know it today. 2.1 In quest of a central dogma for synthetic nano-chemistry In this quest one must ask several critical questions. Firstly, can one use historical first principles invoked for traditional chemistry to produce synthetic nanoscale structures, particles and architectures? Can one expect the conservation of critical hierarchical design features from the atomic to the nanoscale level (i.e., CADPs/CMDPs/CNDPs) as described in (Fig. 3)? In principle, Nature has demonstrated this notion with the numerous examples of bottom-up nano-structural control observed in the production of well defined macromolecules such as; proteins, DNA/RNA and viral capsids, etc. These nanomodules are exquisitely controlled as a function of: (a) size, (b) shape, (c) surface chemistry, (d) flexibility and (e) architecture. Can appropriate strategies and processess be developed for the production of synthetic materials with structural control of Critical Nanoscale Design Parameters (i.e., CNDP s) at the nano-level? Finally can such well defined systems be used to initiate first steps for the development of a central dogma for the new and emerging field of synthetic nano-chemistry? If such CNDP control could be garnered for a structural platform or dimensional continuum of nano-modules, would they behave systematically? Could they be treated as so called nano-elements? With properly designed nano-module surface chemistry, would it be possible to chemically bond or assemble these nano-modules to produce combinatorial libraries of so-called nano-compounds/ assemblies, with reproducible valencies, stoichiometries and mass binding ratios? Finally, will these proposed nano-elements and nano-compounds/assemblies exhibit systematic, nano-periodic property patterns? These questions are answered and the affirmative results are presented in the following sections. As such, a deep and broad understanding has developed in the area of dendrimer synthesis based on their intrinsic core-shell architectures, quantized sizes, shapes, surface chemistries and flexibilities. These collective data have provided a systematic pattern of structure control, based on bottom-up nano-synthesis, that provides an optimum model for extending these principles to other important soft and hard nano-matter modules. These unifying principles and concepts have been recently described elsewhere Structural control of critical nanoscale design parameters (CNDPs) in dendrimers and dendrons Dendrimers and dendrons are an important subclass in the fourth major polymer architecture category referred to as dendritic polymers. 7 Although random hyperbranched polymers (HBPs) are an important sub-class within this fourth major dendritic category of polymeric architecture, (HBPs) are not considered good examples of well defined nanoscale building blocks. Structural control is a strict requirement for suitable building block candidates for this nano-periodic system. It is widely recognized that (HBPs) are highly polydispersed as a function of both mass as well as isomeric structures. Hierarchically, dendrons and dendrimers are collections of atoms with relative molar masses of daltons and hydrodynamic dimensions ranging from 1 30 nm. These materials may be synthesized with a wide range of elemental compositions. More importantly, unlike traditional polymers and random hyperbranched polymers, dendrons and dendrimers may be routinely synthesized while maintaining precise structural control over their Critical Nanoscale Design Parameters This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

5 including: nanoscale: (a) sizes, (b) shapes, (c) surface chemistries, (d) flexibilities/rigidities and (e) architecture. 3,5 3.1 Dendrimer synthesis: divergent and convergent methods In contrast to statistical, polydisperse traditional polymers, dendrimers are unique, monodisperse, macromolecular core shell structures. They possess three basic architectural components, namely; (I) a core, (II) an interior of shells (generations) consisting of repeating branch-cell units, and (III) terminal functional groups (the outer shell or periphery). In general, dendrimer synthesis involves either divergent or convergent covalent assembly strategies that require construction components and synthetic pathways generally as outlined in Fig. 4. Simply stated, the divergent strategy involves the controlled, iterative assembly of XZ 2 type monomers (i.e., referred to as branch cell monomers); wherein, the co-reactive nature of X and Z allows controlled covalent assembly of these XZ 2 monomers to produce precise radial shells (i.e., referred to as generations). This dendritic growth may be visualized as growing a molecular tree with mathematically defined branching and attached leaves (Z) (i.e., molecular surface) growing radially from a sapling to a mature tree at higher generations. The convergent strategy involves controlled, iterative assembly of XZ 2 type monomers, wherein, the Z and X components are co-reactive and protect/ deprotect schemes are used to build the dendrons, generation by generation. In essence one is starting with the leaves of a tree and amplifying the branching to produce a molecular tree with a root (i.e., focal point X) and leaves (Z) as shown in Fig. 4. In general, dendrimers produced by the convergent strategy are nearly defect free compared to the divergent approach (Fig. 4 and 5) which usually lead to low defect levels in the early generations and become more substantial at higher generations. A comparison is made of convergent Yamamoto-type dendrimers with Fig. 4 A hierarchical assembly scheme illustrating the options for constructing dendrimers by either divergent (Tomalia-type) or convergent (Frechet-type) synthetic strategies. 1 Fig. 5 The influence of core information and generational growth on dendrimer shape and size, respectively. Meijer-type dendrimers synthesized by the divergent strategy as shown in Fig. 6 and 7. Within each of these major approaches, there may be variations in methodology for branch-cell or dendron construction, (i.e., supramolecular assembly, 16 click chemistry, 17 etc.). Many of these issues, together with experimental laboratory procedures, have been extensively reviewed elsewhere Quantized, aufbau component relationships to produce core-shell, soft nano-matter dendrimer structures The aufbau steps required for the divergent assembly of dendrimers may be thought of as quantized, core information driven monomer polymerization events required to produce these discrete nanoscale core-shell structures. As such, dendrimers may be viewed as nanoscale processing devices; wherein, their precise sizes and shapes are directed and controlled as illustrated in Fig. 5. Each architectural component manifests a specific function, while at the same time defining important periodic properties for these nanostructures as they are grown generation by generation. For example, as illustrated in Fig. 5 the core may be thought of as the molecular information center from which size, shape, directionality and multiplicity are expressed via the covalent connectivity to the outer shells. 3,5 Within the interior, one finds the branch cell amplification region (Fig. 8) which defines the type and amount of interior void space that may be enclosed by the terminal groups as the dendrimer is grown to a surface congested level (Fig. 10). Branch cell multiplicity (N b ) determines the density and degree of amplification as an exponential function of generation (G), Fig. 9. The interior composition and amount of solvent filled void space determines the extent and nature of guest-host (endo-receptor) properties (i.e., for encapsulation of metals, pharma or small guest molecules) that are possible with a particular dendrimer family and generation, (Fig. 25). Finally, the surface may consist of either reactive or passive terminal groups that may perform a variety of functions. With appropriate function, they serve as a template polymerization region; wherein, each generation is amplified and covalently attached to the precursor generation (Fig. 8). Secondly, the surface groups may function as passive or reactive gates controlling entry or departure of guest molecules from the dendrimer interior. These three architectural components essentially determine a rich range of nano-physicochemical properties, as well as the overall sizes, shapes, reactivity and 460 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

6 Fig. 6 (a) Yamamoto-type [core: p-phenylene]; (G ¼ 4);{dendri-poly(phenylazomethine)} (DPA) dendrimers, (b) MALDI-TOF of the G4; DPA dendrimer. 13 Copyright: 2001 American Chemical Society. flexibility of dendrimers. It is important to note that dendrimer diameters increase linearly as a function of shells of generations added; whereas, the terminal functional groups increase exponentially (Fig. 9) as a function of generation. This dilemma enhances tethered congestion of the anchored dendrons, as a function of generation, due to the steric crowding of the end groups. As a consequence, lower generations are generally open, floppy structures; whereas, higher generations become robust, less deformable spheroids, ellipsoids or cylinders 23 depending on the shape and multiplicity of the core. 4. Proven structural control of Critical Nanoscale Design Parameters (CNDPs). Newtonian quantized: (a) sizes, (b) shapes, (c) surface chemistry, (d) flexibility and (e) architecture of interest to nanoscientists In this section, we focus on experimentally proven examples that illustrate structural control of Critical Nanoscale Design Parameters (CNDPs) when synthesizing dendrons/dendrimers. This brief overview illustrates examples of atom mimicry based on the synthetic ability to control: (a) sizes, (b) shapes, (c) surface chemistry, (d) flexibility and (e) architecture at the nanoscale level. It is apparent, that both the core multiplicity (N c ) and branch cell multiplicity (N b ) determine the precise number of terminal groups (Z) and mass amplification as a function of generation (G). One may view those generation sequences as quantized polymerization events that adhere to the dendritic aufbau mathematics described in Fig. 9. The assembly of reactive monomers, 5,24 branch cells 5,25,26 or dendrons 16,20 around atomic or molecular cores to produce dendrimers according to divergent/convergent dendritic branching principles has been well demonstrated (Fig. 4). This systematic filling of nano-space around cores with branch cells in generational growth stages (branch cell shells) produces discrete, quantized bundles of mass that are mathematically predictable. 5,28 Predicted molecular weights are routinely confirmed by mass spectroscopy 14,29,30 (Fig. 6 and 7) and other analytical methods. 27,31,32 Predicted Fig. 7 (a) Meijer Type [core:diaminobutane]; (G ¼ 4);{dendri-poly(propyleneimine)-(NH 2 ) z }(PPI) dendrimers illustrating perfect structure and defective structures observed by mass spectrometry, (b) Deconvoluted ESI-MS data showing masses for perfect structures and defective structures for PPI dendrimers; G ¼ Copyright: Wiley-VCH Verlag GmBH & Co. KgaA. This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

7 4.1 Quantized sizes-control of monodisperity Fig. 8 Tomalia Type (G ¼ 4.5); {dendri-poly(amidoamine)- (CO 2 Me) Z };(PAMAM) dendrimers Three-dimensional projection of dendrimer core-shell architecture for G ¼ 4.5 poly(amidoamine) (PAMAM) dendrimer with principal architectural components (I) core, (II) interior and (III) surface. 15 numbers of branch cells, terminal groups (Z) and molecular weights, as a function of generation, are as described in Fig. 9. It should be noted, that the molecular weights approximately double as one progresses from one generation to the next. The surface groups (Z) and branch cells (BC) amplify mathematically according to a power function; thus, producing discrete, monodisperse structures with precise molecular weights. These predicted values are routinely verified for convergent synthesized dendrimers by mass spectroscopy (Fig. 6). However, for divergent synthesized dendrimers, minor mass defects are often observed for higher generations as congestion induced de Gennes dense packing and nano-steric effects begin to occur 5,33 (Fig. 7). The bottom-up synthesis of dendrons/dendrimers provides one of the most precise and tunable strategies know for constructing a systematic continuum of reproducible soft matter nanoscale structures. Size and structure control observed for dendron/ dendrimer synthesis rival that expected for proteins and DNA/ RNA. In fact, dendrimers are often referred to as artificial proteins Based on the close mimicry of globular protein size scaling and their homogeneity (monodispersity), they are often used as protein replacements/substitutes in many nanomedicine applications. 35,37 Dendrimer mass and size uniformity has been exhaustively demonstrated by ESI/MALDI-TOF mass spectrometry, 30 gel electrophoresis, 31,32,38 electron microscopy (TEM), 39 (Fig. 11), atomic force microscopy (AFM) 40 and other methodologies, to mention a few. Within a specific dendrimer family, it is possible to produce a systematic, reproducible continuum of nano-sizes and precise masses as a function of generations (see Fig. 9, 10 and 11). It should be noted, that dendrimer mass approximately doubles, generation to generation, with a remarkable uniformity of mass distribution over five generations exhibiting polydispersities ranging from Quantized shapes (dendrons/dendrimers) Several simple parameters may be used to design and control covalent dendron/dendrimer shapes. As described in Fig. 5, the multiplicity as well as the shape of the core can be selected to produce a desired shape (i.e., spheroidal, ellipsoidal, cylindrical, etc.). For example, covalent 1-D cylindrical dendrimers are readily synthesized with shape control by dendronization or initiating dendron growth from multiple sites along the backbone Fig. 9 Mathematical expressions for calculating the theoretical number of surface groups (Z), branch cells (BC), and molecular weights (Mw) for [core: 1,2-diaminoethane];(G ¼ 0 7);{dendri-poly(amidoamine)-(NH 2 ) z } (PAMAM) dendrimers as a function of generation. Approximate hydrodynamic diameters (Gen ¼ 0 7) based on gel electrophoretic comparison for the corresponding PAMAM dendrimers. 462 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

8 Fig. 10 Molecular simulations for [core: NH 3 ];(G ¼ 0 5); {dendri- poly(amidoamine)-(nh 2 ) n } (PAMAM) dendrimers and a generational comparison of hydrodynamic diameters. of a linear polymer. 23,41 Iterative monomer additions to produce generational growth will then produce precise amplifications of these programmed shapes. The rigidity/flexibility of these shapes may be controlled and tuned by appropriate selection of branch cell monomer symmetry, compositions and arm lengths (flexibility). Pioneering work by Rudick and Percec 42 demonstrated that quantized shape design of dendrons as a function of their generation level produced predictable hierarchical patterns of periodic nano-object shapes that could be defined as solid angle projections (a 0 ) of the dendron onto a plane (Fig. 12). The (a 0 ) angle is defined as the projection of the solid angle of the dendron onto a plane, and can be determined in all cases according to (a 0 ) ¼ 360/u, where u is the number of dendrons in a column stratum or supramolecular sphere. Increasing the branching via a change Fig. 12 Hierarchical control of self-assembly via molecular solid angle. 44 in sequence or increase in generation number of taper-like dendrons increases the (a 0 ) and the fraction of the disk occupied in columnar self assembly. At a certain threshold only unimolecular disks are formed. Above this threshold, further branching results in deformation of the disk into a conical segment with diminished (a 0 ). Beyond this point, increased branching increases (a 0 ) and the fraction of a sphere formed. Ultimately, a unimolecular sphere should result. A wide variety of periodic and quasi-periodic lattices can be formed by simply tuning the dendron shape parameters as described in Fig Quantized surface chemistry Fig. 11 (a f) Transmission electron micrographs (TEMs) of Gen 5 10 PAMAM dendrimers. Sample (f) contains three molecules of Gen 10 dendrimer for comparison. Bar length ¼50 nm. 39 Copyright: 1998 American Chemical Society. More than 1000 different surface reactions have been reported for dendrons/dendrimers. Essentially, all mechanistic reaction types (i.e., covalent, ionic, radical, etc.) have been reported. Several examples of these reactions are illustrated in Fig. 14. Both sub-nanoscale, as well as nanoscale reagents (i.e., proposed nano-elements) have been used in these surface reactions. The surface valency and stoichiometry are mathematically quantified by relationships described in Fig. 9 (i.e., Z ¼ N c N bg ). Generally, these valencies and stoichiometric binding ratios are operational for all generations preceding serious onset of de Gennes type dense packing congestion. Surface congested generations (i.e., > G ¼ 4 for poly(amidoamine) (PAMAM) dendrimers) usually exhibit lower than theoretical stoichiometries even with small sized reagents. Large sized reagents (i.e., >1 nm) may lead to less than ideal stoichiometries even at low generations due to steric effects. These unique steric effects are referred to as nanoscale sterically induced stoichiometries (N-SIS). 33 This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

9 Fig. 13 Periodic and quasi-periodic lattices formed via the self-assembly of Percec-type dendrons. 43 The use of dendrimers as nanoscale scaffolding for MRI contrast agents was first reported by Wiener et al. in and generated tremendous interest and activity which has been reviewed extensively elsewhere. 46,47 It involved conjugating metal specific (i.e., gadolinium) chelating groups (i.e., DTPA or DOTA) to the terminal groups of Tomalia type PAMAM dendrimers to produce a continuum of very precisely sized nanoparticles with well defined nano dimensions (Fig. 15) below. These surface saturated, dendrimer-metal chelates were well characterized examples of: [dendrimer (core)-ligated metal (shell) nano-compounds]. The stoichiometries of these nanocompounds were defined accordingly as: [dendrimer]:[ligated metal] Z, where: Z ¼ N c N bg. These core-shell nano-compounds Fig. 15 A Tomalia type PAMAM dendrimer series (i.e., [core: 1,2-diaminoethane]; (G ¼ 1 8); {dendri-poly(amidoamine)-(metal ligation sites) Z } dendrimers) illustrating the core-shell topology, naked dendrimer scaffolding diameters (nm), number of terminal groups (Z) and relaxivity values (R 1 ) as a function of generation. Fig. 14 Options for modifying amine-terminated dendrimer based nano scaffolding by utilizing classical subnanoscale and nanoscale reagents. 464 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

10 manifested enhancements in relaxivity properties (i.e., R 1 )as a function of the dendrimer generation level and the stoichiometry of dendrimer: metal. Furthermore, the features of these soft particle-hard particle (i.e., [S-1:H-1] nano-compounds) fit the proposed criteria for nano-compounds described elsewhere 2 by possessing a core derived from an [S-1] type dendrimer nanoelement and shells derived from well defined nanoscale collections of ligated metals (i.e., [H-1] type metal cluster nanoelements). Finally this series of [core-shell nano-compounds] fulfilled additional criteria that were predicted for these entities 2 by exhibiting unique emerging nano-periodic property patterns as evidenced by their unprecedented high relaxivity values (i.e.,r 1 ) as a function of dendrimer generation level. Empirical formulae for members of this core-shell nano-compound series may be written as follows: [G ¼ 1 8]@[M] NcNbG. 4.4 Quantized interior chemistry Metal complexations with dendrimers containing nitrogen type ligation sites have been known since the phenomenon was first observed in the earliest reported examples of the dendri-poly- (amidoamine) (PAMAM) series. 6 More recently considerable attention has been focused on the use of certain rigid (i.e., less flexible) Yamamoto-type (i.e., dendri-poly(phenylazomethine) (DPA) dendrimers as nanoscale templates for assembling very well defined metal based nano-cluster 11 and metal oxide nanoparticles. 10 In contrast to the more flexible/less rigid nitrogen containing PAMAM or PPI type dendrimers, the Yamamoto-type dendrimers have been shown to complex with a variety of metal salts and assemble them in a very precise, shell by shell, sequential manner as shown in Fig. 16. Empirical formulae describing members of this core-shell nano-compound series may be written as follows: [M] NcNb G 4]; where: N c N b G 1 ¼ 4, 12, 28 and 60, respectively. The generational shells 1 4 are saturated from the core outwardly to sequentially produce stoichiometric, dendrimerligated metal nanoassemblies. These nanoassemblies exhibited well defined, mass combining ratios (i.e., dendrimer-ligated metal salt masses) reminiscent of traditional small molecule compounds. It is notable that these nanoassemblies consisted of discrete nanomodule components (i.e., dendrimers and ligated metal atom collections), each of which were of nanoscale dimensions. Later it will be shown that these ligated metal domains may be transformed into precise metal nano-clusters or metal oxide nanocrystals, respectively, that remain associated as guests within their dendrimer hosts in stoichiometric proportions to produce unique core-shell nano-compounds. 5. Heuristic atom mimicry of dendrimers: nano-level core-shell analogs of atoms A heuristic comparison of the core shell architectures that are present in dendrimer-based nanoscale modules and picoscale atoms was made as early as ,28,49 This comparison was used to point out the unique similarities that exist between aufbau components in atoms (i.e., nucleons and electrons) and those that are involved in dendrimer constructions (i.e., cores and branch cell monomers). Remarkable analogies were also noted between recognized but dimensionally different parameters shared by both systems such as; (a) electron shells vs. monomer shells (generations), (b) electron shell vs. monomer shell aufbau filling patterns (i.e., mathematically defined), (c) electron shell vs. monomer shell saturation levels, (d) atomic weights vs. dendrimer molecular weights as a function of shell level and saturation level, and (e) atomic (elemental) reactivity versus dendrimer reactivity as a function of shell saturation level. We have referred to these remarkable similarities between picoscale (atomic elements) and nanoscale dendrimers as atom mimicry, keeping in mind that picoscale structures are best described by non-newtonian physics, whereas, the dendrimer structures are expected to adhere to and be described by Newtonian physics. Furthermore, it appears that a very interesting size continuum exists in the transition from picoscale (atomic) structures to nanoscale dendrimer structures as illustrated in Fig Chemical bond formation/valency and stoichiometric binding ratios with dendrimers to form nano-compounds Fig. 16 A schematic representation of the stepwise complexation of SnCl 2 or FeCl 3 with a Yamamoto-type dendrimer. 48 Using first principles and step logic invoked by Dalton (i.e., Philosophy for a Chemical System (1808), as briefly stated below (Fig. 18), it was possible to experimentally demonstrate that certain quantized nano-modules (i.e., dendrimers, fullerenes, metal nano-clusters or metal oxide nanocrystals) could be chemically combined or assembled to produce stoichiometric nanocompounds/assemblies possessing well defined mass combining ratios. 2,50 Furthermore, both the quantized nano-modules (i.e., nano-elements) and their resulting nano-compounds were found to exhibit new emerging properties as well as interesting new nanoperiodic property patterns. 2 Both soft matter and hard matter categories of these quantized nano-modules (i.e., referred to as nano-elements), have been proposed based on selection criteria This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

11 Fig. 17 An example of atom mimicry. A comparison of core-shell structures representing picoscale atoms and nanoscale dendrimers, as well as the continuum of sizes that prevails over the two dimensional ranges that are controlled by quantum mechanics and Newtonian physics, respectively. described elsewhere 2 (Fig. 19). Furthermore, these twelve soft and hard nano-elements, designated [S-n] and [H-n], respectively, have been reported to form a wide range of soft particle and soft-hard particle type nano-compounds. Both the nano-elements and their nano-compounds are widely recognized to exhibit new emerging properties and nano-periodic property patterns. 2 Leading references to these literature examples, designated by X in the combinatorial nano-compound library, (Fig. 19), are described in greater detail elsewhere. 2,51 54 This account will focus only on four selected examples of nano-compound formation designated by (*) that involve either reactions or self-assembly with dendrimers (Fig. 19). Combining dendrimers (i.e., [S-1] type nano-element categories with other dendrimers (i.e., [S-1:S-1] core-shell types 55 ), with fullerenes (i.e., [S-1:H-4] core-shell type) or with metal nanoclusters (i.e., [H-1:S-1] core-shell type) produced three unique coreshell nano-compound category types designated in Fig. 19. On the other hand, dendrimers have also been used as templates to produce precisely sized [H-3] type, metal oxide nanocrystals which have exhibited interesting quantum size effects as described in the next section. Fig. 18 Dalton s first table of elemental atoms and their conversion to compound atoms according to his atom/molecular hypotheses. Key components of traditional chemistry central dogma based on Dalton s hypothesis. Images reproduced with permission from Wiley-VCH Verlag GmbH & Co. KGaA Dendrimer-dendrimer; [S-1:S-1] core-shell type nanocompounds Saturated shell, nano-compounds (Fig. 20) are prepared by a twostep approach which involved; firstly, self-assembly of an excess of carboxylic acid terminated dendrimers (i.e., shell reagent) around 466 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

12 Fig. 19 Proposed hard and soft particle nano-element categories and combinatorial libraries of possible nano-compounds. Nano-compounds designated by [*] are described in the following section. Nano-compounds designated by [X] have been reported in the literature and described elsewhere. 2 Fig. 20 The saturated-shell-architecture approach to megamer synthesis. All surface dendrimers are carboxylic acid terminated. 56 a limited amount of amine terminated dendrimer (i.e., core reagent) in the presence of LiCl. This was followed by covalent amide bond formation between the core and dendrimer shell reagents using a carbodiimide reagent The resulting nano-compounds (i.e., saturated core-shell tecto (dendrimers), referred to as megamers), are prime examples of precise poly-dendrimer cluster structures. These structures may be mathematically predicted by the Mansfield-Tomalia-Rakesh equation Fig and have been unequivocally verified by experimental mass spectrometry, gel electrophoresis and atomic force field microscopy (AFM). 4,55,57,58, Dendrimer-fullerene; [S-1:H-5] core-shell type nanocompounds Stoichiometric dendrimer core-fullerene shell nano-compounds were readily formed by allowing a [core; 1,2-diaminoethane]; (G ¼ 4); {dendri- poly(amidoamine)-(nh 2 ) 64 }(PAMAM) dendrimer to react with an excess of buckminsterfullerene (C 60 ). 9 In the presence of an excess of (C 60 ), only thirty (C 60 ) moieties bonded to the dendrimer surface to produce a well defined, stoichiometric; dendrimer core: fullerene shell nano-compound (i.e., an [S1:H-5] core-shell type) as shown in Fig. 21. These structures were extensively characterized by MALDI-TOF, TGA, UV-vis and FTIR. Such nano-compounds exhibited new emerging fullerene like solublity and photo-properties by readily generating singlet ( 1 O 2 ) in either aqueous/organic solvents. However, they offered other unique features such as larger size and nano-container type properties that would normally be associated with the dendrimer core interior. 6.3 Metal nanocluster-dendrimer; [H-1:S-1] core-shell type nano-compounds Using a G ¼ 4; phenylazomethine dendrimer as a template, Yamamoto, et al. 11 demonstrated that Pt(IV) chloride salts could be sequentially assembled to produce four discretly different, yet precise, collections of ligated Pt salts within the interior of the dendrimer. Subsequent reduction of these ligated Pt(IV) arrays yielded Pt(0) nanoclusters consisting of very well defined numbers of Pt atoms. The size of these incarcerated Pt(0) nanoclusters (i.e., by TEM) was in good agreement with the number of Pt atoms present in the ligated metal precursors. For example, the [H-1:S-1] nano-compound series designated by; [Pt 12 ]@[G4;dendrimer], [Pt 28 ]@[G4;dendrimer] This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

13 Fig. 21 Core-shell architecture of the PAMAM core:fullerene shell; [S-1:H-5] core-shell type nano-compound; where: (Z ¼ terminal NH 2 or NH, groups on the PAMAM dendrimer core component of the core-shell nano-compound). 9 and [Pt 60 ]@[G4;dendrimer] core-shell type nomenclature were extensively characterized and determined to exhibit precise stoichiometries as described in Fig. 22. The ability to precisely control these independently sized Pt(0) nanocluster cores within the G4; dendrimer shells provided discrete nano-cages that prevented metal nanocluster aggregation. Furthermore, it allowed the evaluation of these four discrete core-shell nanocompounds as catalysts in reactions involving four (4X) electron reductions of oxygen molecules. These catalytic reductions are of high interest in the development of optimized fuel cells. Quite remarkably it was demonstrated that these catalytic reductions are highly dependent on subtle metal nanocluster size differences. As such, a significant nano-periodic property pattern was observed within this nanocompound series. It was found that within this Pt(0) nanocluster size continuum (i.e., sizes ranging from 0.5 nm to 6.0 nm) it was observed that 3 nm Pt(0) nanocluster sizes offered optimum catalytic properties. 11 Fig. 22 (A) Sequential complexation of PtCl 4 with a Yamamoto-type dendrimer, 3, to produce Pt Pt and Pt [H-3:S-1] core-shell type nanocompounds, respectively, after reduction with NaBH 4. (B) (C) and (D) Histograms of Pt(0) nanocluster core size distributions in each nanocompound above with corresponding electromicrograms of these [H-3:S-1] core-shell type nanocompounds. 11 Reprinted by Permission of Macmillan Publishers Ltd, Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

14 Fig. 23 An illustration of the quantum size effect (Q-size) on semiconductor bandgaps for a series of well defined [TiO 2 ] n nano-crystals. The nanoparticle size can be precisely controlled in a dendrimer template and is influenced by the number of [TiO 2 ] n assembled in a dendrimer interior. This is an elegant synthesis strategy for producing well defined [H-3] type, metal oxide, nano-element particles. 11 Reprinted by Permission of Macmillan Publishers Ltd, Templated metal salt nanocrystal-dendrimer;[h-3]:[s-1] core-shell nano-compounds as precursors to well defined metal oxide nanocrystals (i.e., [TiO 2 ] n, where: n ¼ 6,14 and 30) Much as described above, Yamamoto, et al., 10 also demonstrated use of the rigid phenylazomethine dendrimers as templates for ligating discrete titanium salt domains within the dendrimer interior. Based on these precise assemblies, they served as precursors for producing very well defined [H-3] type metal oxide nanocrystals (i.e.,[tio 2 ] n, where; n ¼ 6,14 and 30). The precursor [Ti(acac)Cl 3 ] metal ligation complexes were either hydrolyzed or thermolyzed to produce the desired anatase or rutile forms of TiO 2,with concurrent destruction of the dendrimer template. A unique quantum size effect is observed as one decreases the TiO 2 nanoscale sizes within this series. Such controlled size reductions may be used to raise the conduction band while lowering the valence bands of the metal oxide nanocrystals as illustrated in Fig. 23 above. These quantum size (Q-size) effects produce a unique nano-periodic property pattern which is evidenced by a blue shift as the nanoparticle size decreases. 7. Nano-periodic chemical/physical property patterns 7.1 Periodic chemical reactivity/physical size property patterns Soft particle, dendrimer based, [S-1] type nano-elements are unique macromolecules that exhibit completely different Fig. 24 Comparison of surface area/head group (Z), refractive index, density (d) and viscosity (h) as a function of generation: G ¼ ,61 Copyright Wiley-VCH Verlag GmbH & Co. KGaA. physico-chemical properties (i.e., nano-periodic property patterns) compared to traditional polymers. This is largely due to congestion properties that emerge as a function of generational growth, as shown in Fig. 24, to produce unprecedented nanoperiodic property patterns that are intrinsic and uniquely characteristic of dendrimers. Plots of intrinsic viscosity [h], density(d), surface area per Z group (A z ) and refractive index, as a function of generation, clearly show intrinsic maxima or minima at generations ¼ 3 5 for this Tomalia-type PAMAM dendrimer series. These data corroborate computer-assisted molecular-simulation predictions, 5,62 as well as extensive photochemical probe experiments reported by Turro, et al. 61,63 66 Dendrimer based intrinsic viscosities [h] initially increase in a classical fashion as a function of molar mass (generation), but dramatically decline beyond a critical generation due to a congestion induced shape change. A dendrimer shape change occurs from an initial extended, compressible configuration in the early generations (i.e., G¼ 0 3) to more rigid globular shapes in the later generations (i.e., G¼ 4 10). In effect, at critical generations (i.e., G¼ 3 4 and >) the dendrimer acts more like an Einstein spheroid. Intrinsic viscosity is a physical property expressed in dl/g, which in essence is the ratio of volume to mass. As the generation number increases and transition occurs to a spherical shape, the volume of the spherical dendrimer increases in cubic fashion while its mass increases exponentially; hence, the value of [h] must decrease once a certain generation is reached. This prediction has now been widely confirmed for many different dendrimer families. 5,26,67 Dendrimer surface congestion may be appraised mathematically as a function of generation according to the following simple relationship: A z ¼ A D a r 2 N Z N c Nb G Where: A z is the surface area per terminal group Z, A D the dendrimer surface area, and N z the number of surface groups Z per generation. This relationship predicts the surface area per Z group at higher generations (G) and becomes increasingly smaller finally approaching the cross-sectional area or van der Waals dimension of the surface groups Z at higher generations. Congestion at these higher generations (G) is referred to as de Gennes dense-packing. 5 Ideal dendritic growth without branch defects is possible only for those generations preceding this dense-packed state. This critical dendrimer property gives rise to self-limiting dendrimer dimensions, which are a function of the branch cell segment length (I), the core multiplicity N c, the branch cell juncture multiplicity N b, and the steric dimensions of the terminal group Z. Dendrimer radius r in the above expression is dependent on the branch cell segment lengths l; wherein, large l values delay congestion. On the other hand, larger N c, N b values and larger Z dimensions dramatically enhance congestion. These congestion properties are unique for each dendrimer family; wherein, N c and N b determine the generation levels within a family that will exhibit nano-encapsulation properties. Higher N c and N b values predict that lower generation levels will produce appropriate surface congestion properties to manifest encapsulation features as in Fig. 25. This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

15 Fig. 25 Congestion induced dendrimer shape changes (I,II,III) with development of nano-container properties for a family of [core: 1,2-diaminoethane];(G ¼ 0 4); dendri-poly(amidoamine) (NH 2 ) Z },(PAMAM) dendrimers: N c ¼ 4; N b ¼ 2, where: Z-Z ¼ distance between surface groups as a function of generation. Clearly these fundamental dendrimer properties illustrate the unique and intrinsic nano-periodic property patterns manifested by this soft matter, [S-1] type nano-element category. Many other nano-periodic property patterns have been documented for the behavior, assembly and reactions of dendrimers with other dendrimers as well as with other well defined nano-element categories. For example, work on this soft matter, [S-1] type nano-element category 4,58,59 has demonstrated that mathematically defined, periodic size properties of spheroidal dendrimers can determine chemical reactivity patterns with other Fig. 26 (a) Symmetry properties of core-shell tecto(dendrimer) structures, when: r 1 /r 2 < (b) Sterically induced stoichiometry (SIS) defined shell capacities (N max. ), based on the respective core and shell radii, when: r 1 /r 2 < (c) Mansfield Tomalia Rakesh equation for calculating the maximum shell filling value (capacity) (N max. ), when: r 1 /r 2 > , Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010

16 Fig. 27 A Yamamoto-type poly(phenylazomethine) dendrimer series illustrating quantized, sequential dendrimer shell filling with metal salts using; [G ¼ 4]; dendri-poly(phenylazomethine) (DPA) dendrimers. 68 Copyright: 2006 Wiley-VCH Verlag GmbH & Co. KGaA. dendrimers. These reactivity patterns based on the relative sizes of a targeted dendrimer cores and dendrimer shell components strongly influence the assembly of precise dendrimer clusters (i.e., core-shell (tecto) dendrimers). Mathematical relationships (i.e., the Mansfield Tomalia Rakesh Equation) predict dendrimer cluster saturation levels (i.e., magic numbers for dendrimer shells) as a function of the core dendrimer size relative to the size of the shell dendrimers that are being used to construct the dendrimer cluster (Fig. 26). 4,59 These periodic property patterns and magic shell relationships are reminiscent of those observed for the self assembly of [H-1] type metal nanocrystals; wherein, the predicted number of touching spheroids surrounding a central core metal atom is 12 as shown below when r 1 /r 2 ¼ 1.00 (Fig. 26). 7.2 Atom mimicry and nano-periodic property patterns observed for Yamamoto-type dendrimers The importance of controlling the CNDPs related to flexibility/ rigidity was clearly demonstrated with Yamamoto-type dendrimers. Based on the rigidity features and mathematically quantized ligation sites present in Yamamoto-type dendrimers, it was possible to quantitatively document an amazing sequence of metal dendrimer shell filling events. These metal-shell filling events are heuristically reminescent of traditional electron shell filling events observed for elemental atoms. It was shown in this present case that quantized amounts of metal salts will first ligate closest to the core at the lowest generation level to produce a saturated generational shell with well defined and perfect stiochiometry (i.e., 4x@G ¼ 1), based on ligation sites present. Subsequent addition of metal reagent led to a stepwise filling of the next highest generational shell until it reached a shell saturated state (i.e., 8x@G ¼ 2) and higher generation saturation states as shown in Figs 27 and First steps towards a central dogma for synthetic nano-chemistry? Dendrimer based nano-chemistry As stated earlier (Fig. 1) the central dogma for traditional soft matter chemistry emerged from the first initatives of Lavoisier and Dalton in the early 19th century and was initially focused on the simple combinatorial bonding of atoms to form small molecules (i.e., monomers, branch cell monomers), much as illustrated below (Fig. 29). Synthetic soft matter chemistry throughout the 19th and 20th century witnessed steady progress toward more complex molecular structure and architecture, including dendrons and dendrimers. Fig. 29 illustrates the aufbau process for the bottom-up construction of such well defined nanoscale structures (i.e., dendrons/dendrimers) that one might refer to as soft matter nano-elements. 2 Essentially all other proposed hard-soft nano-element categories (Fig. 19) evolve from an analogous aufbau strategy that allows the control and conservation of critical heirarchical design parameters from the atom to the nanoscale level (i.e., CADP/CNDP). Vivid examples of such aufbau processes for two hard matter nanoelement categories (i.e., [H-1] and [H-2] types) were described Fig. 28 A comparison of stepwise and random ligation processes that are observed for PtCl 4 complexation with a rigid Yamamoto-type poly- (phenylazomethine) dendrimer and a flexible Tomalia type poly(amidoamine) (PAMAM) dendrimer, respectively. 11 This journal is ª The Royal Society of Chemistry 2010 Soft Matter, 2010, 6,

17 Fig. 29 Approximate nanoscale dimensions as a function of hierarchical building blocks (i.e., atoms, monomers, branch cells, dendrimers and megamers) and presumed conservation of critical hierarchical design parameters. earlier, see Fig. 22 and 23. In each case, metal atoms were precisely controlled and assembled to produce both [H-1] type metal nano-clusters or [H-3] type metal oxide nanocrystals by using soft matter [S-1] type nano-element (i.e., dendrimer structures) as templates. Nature has already presented very exquisite evolutionary aufbau strategies for synthesizing proposed soft matter nano-element categories such as (a) proteins [S-4], (b) viral capsids [S-5] and (c) DNA/RNA[S-6] (see Fig. 19). Clearly a deeper understanding of the critical aufbau processes leading to each of these well defined nano-element categories, as well as Fig. 30 A chronological overview of traditional disciplines, structural complexity and quantized building blocks relative to traditional and nanoperiodic systems. 472 Soft Matter, 2010, 6, This journal is ª The Royal Society of Chemistry 2010