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TUTORIAL REVIEW

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From structure to function via complex supramolecular dendrimer systems Hao-Jan Sun, Shaodong Zhang and Virgil Percec* This tutorial review summarizes strategies elaborated for the discovery and prediction of programmed primary structures derived from quasi-equivalent constitutional isomeric libraries of self-assembling dendrons, dendrimers and dendronized polymers. These libraries demonstrate an 82% predictability, defined as the percentage of similar primary structures resulting in at least one conserved supramolecular shape with internal order. A combination of structural and retrostructural analysis that employs methodologies transplanted from structural biology, adapted to giant supramolecular assemblies was used for this process. A periodic table database of programmed primary structures was elaborated and used to facilitate the emergence of a diversity of functions in complex dendrimer systems via first principles. Assemblies generated by supramolecular and covalent polymer backbones were critically compared. Although by definition complex functional systems cannot be designed, this tutorial hints to a methodology based on database analysis principles to facilitate design principles that may help to mediate an accelerated emergence of chemical, physical and most probably also societal, political and economic complex systems on a shorter time scale and lower cost than by the current methods. This

Received 18th July 2014

tutorial review is limited to the simplest, synthetically most accessible self-assembling minidendrons,

DOI: 10.1039/c4cs00249k

minidendrimers and polymers dendronized with minidendrons that are best analyzed and elucidated at molecular, supramolecular and theoretical levels, and most used in other laboratories. These structures

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are all interrelated, and their principles expand in a simple way to their higher generations.

Key learning points (1) Definitions of quasi-equivalent self-assembling minidendrons, minidendrimers, covalent and supramolecular polymers dendronized with self-assembling minidendrons, complex systems, and first principles. (2) Discovery and prediction of programmed primary structures via accelerated synthesis mediated by structural and retrostructural analysis of their selforganized periodic and quasi-periodic arrays. (3) Transplant and adaptation of structural analysis methodologies from structural biology to synthetic supramolecular assemblies. (4) Supramolecular vs. covalent polymer backbones in self-assembly and the limitation of polydispersity in self-organization. (5) Accelerated emergence of functions in complex systems from programmed primary structures via first principles.

1. Introduction Dendrons, dendrimers and dendronized polymers constructed from chemically dissimilar fragments such as aliphatic, fluorinated or oligooxyethylenic combined with aromatic provide the simplest class of self-assembling dendritic building blocks frequently referred to as amphiphilic. They self-assemble and self-organize into complex supramolecular dendrimers by similar principles to those of natural viruses and other complex Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA. E-mail: [email protected]

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biological systems. Viruses are the simplest self-assembling, self-nucleating and self-checking complex biological systems. This tutorial review discusses accelerated methodologies developed to discover and predict programmed primary structures that self-assemble into 2D and 3D complex supramolecular dendrimers that are subsequently used to design functions via first principles. Due to the limited space allocated to a tutorial review we will discuss mostly first generation self-assembling dendrons, dendrimers and dendronized polymers denoted minidendrons, minidendrimers and polymers dendronized with minidendrons. Minidendrons have been used as models or maquettes for the elaboration of novel complex architectural motifs from larger generations of dendritic building blocks.1

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The role of these minidendrons is analogous to that of simple peptides used to understand the molecular engineering involved in the assembly of more complex proteins, or of maquettes used by sculptors and architects to appreciate various aspects of full size objects. Due to their lower molar mass and faster dynamics minidendritic building blocks have been influential in the discovery of most of the fundamental concepts of supramolecular dendrimer chemistry that apply to higher generations. Therefore, we consider that they are a valuable educational tool for the entire field of complex supramolecular dendrimer systems. A complex system, as defined by Ottino, ‘‘is a system with a large number of elements, building blocks, or agents, capable of exchanging stimuli with one another and with their environment. The interaction between elements may occur only with immediate neighbors or with distant ones; the agents can all be identical or different; they may move in space or occupy fixed positions, and can be in one state or multiple states. The common characteristic of all complex systems is that they display organization without any external organizing principle being applied. In most elaborate examples, the agents can learn from past history and modify their states accordingly. Adaptability, and robustness are often the byproduct. Part of the system may be altered, and the system may still be able to function. . . Complex systems cannot be understood by studying parts in isolation. The very essence of the system lies in the interaction between parts and the overall behavior that emerges from the interactions. The system must be analysed as a whole’’. Classic examples of complex systems include highways, the internet, power grids, metabolic pathways, social and political organizations, financial systems, and many physical, biological, and chemical systems. Ottino also underlines ‘‘that complex is different from complicated. Mechanical watches are examples of complicated systems. However, the pieces of complicated systems can be understood in isolation, and the whole can be reassembled from its parts’’.2

Dr Hao-Jan Sun received his BS degree in Chemical Engineering at National Tsing-Hua University, Taiwan, in 2005 and his PhD degree in polymer science at the University of Akron in 2012. His research topic was phase behavior and Janus hierarchical supramolecular structures based on geometrically and chemically asymmetric building blocks. Hao-Jan then joined the laboratory of Professor Virgil Percec as a postHao-Jan Sun doctoral fellow at the University of Pennsylvania. His research interests are in the structural analysis of chiral supramolecular structures, sugar-containing Janus dendrimers, reversible complexed/decomplexed supramolecular structures, and dendronized p-conjugated molecules as building blocks for organic solar cells and photovoltaic applications.

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Therefore, this tutorial review will discuss the emergence of complex dendrimer functional systems from quasi-equivalent dendritic building blocks that exhibit self-control.

2. Viruses as models for the self-assembly of complex systems Tobacco Mosaic Virus (TMV) is one of the simplest complex biological systems. It is self-assembled from 2310 identical proteins jacketing a single strand of helical RNA (bottom of Fig. 1a and b).3 TMV is self-assembling, self-nucleating and self-checking. All information necessary for self-assembling TMV is available in its parts.4a TMV is the best understood biological system that provides a model for the elaboration of the molecular principles involved during the self-assembly of non-biological supramolecular analogs. A brief account on the discovery of selfassembling dendrons and dendronized polymers is available.4d The first attempt to mimic TMV with self-assembling dendronized polymers was elaborated by the Percec laboratory in the late 1980s.5 Icosahedral viruses are assembled from quasiequivalent proteins that jacket a nucleic acid (top of Fig. 1a).3 Quasi-equivalence is a concept introduced by Caspar and Klug to explain the self-assembly of icosahedral viruses from a single quasi-equivalent protein which self-controls its conformation in order to assemble in both pentagons and hexagons (top of Fig. 1a). As defined by Caspar and Klug quasiequivalence refers to the purposeful switching between more stable, unsociable, and less stable, associable, quasi-equivalent conformations of identical proteins during the self-assembly of icosahedral viruses. This concept was transplanted by Percec laboratory6 to the field of self-assembly in 1998 and will be detailed later.

Dr Shaodong Zhang is currently a postdoctoral research associate at the University of Pennsylvania in the laboratory of Professor Virgil Percec where he works on supramolecular architectures from self-assembling dendrons and dendrimers, with particular interest on biomimetic materials self-assembled from amphiphilic Janus dendrimers. He obtained his Diploˆme d’Inge´nieur from ENSIACET (Toulouse in 2009) Shaodong Zhang before completing his PhD degree on the application of ionic liquids to polycondensation reactions under the supervision of Professor Alain Fradet from Sorbonne University-UPMC in Paris in 2012.

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3. Accelerated synthesis, discovery, and prediction by structural and retrostructural analysis In the late 1980s the Percec laboratory4a,b started to elaborate an accelerated rational design strategy for the discovery of programmed primary structures of quasi-equivalent self-assembling building blocks such as dendrons and dendrimers that were subsequently employed to predict the 3D structures that are responsible for the creation of functions in complex biologicallike systems.4e Emergence of functions from programmed primary structures via their secondary, tertiary and quaternary structures is known as ‘‘first principles’’. Fig. 2 outlines this accelerated synthetic methodology via the structural7 and retrostructural analysis of periodic and quasi-periodic arrays generated by self-assembling dendrons and dendronized polymers.4,11 Through ‘‘generational’’ (design and synthesis by increasing the generation number) and

Virgil Percec was born and educated in Romania (PhD, 1976). He defected from his native country in 1981 and after short postdoctoral appointments at the Universities of Freiburg, Germany, and Akron, US, he joined the Department of Macromolecular Science at Case Western Reserve University in Cleveland as an Assistant Professor in 1982. He was promoted to Associate Professor in 1984, to Professor in Virgil Percec 1986, and to Leonard Case Jr. Chair in 1993. In 1999 he moved to the University of Pennsylvania as P. Roy Vagelos Chair and Professor of Chemistry. Percec research interests are at the interface between organic, bioorganic, supramolecular, polymer chemistry, catalysis, liquid crystals and nanoscience, where he contributed 700 refereed publications, 80 patents, over 1100 endowed, plenary and invited lectures, and edited 18 books. His list of awards includes Honorary Foreign Member to the Romanian Academy (1993), Humboldt Award for Senior US Scientists (1997 and 2012), NSF Research Award for Creativity in Research (1990, 1995, 2000), PTN Polymer Award from the Netherlands (2002), the ACS Award in Polymer Chemistry (2004), the Staudinger–Durrer Medal from ETH (2005), the International Award of the Society of Polymer Science from Japan (2007), Doctor Honoris Causa from Universities of Iasi, Romania and Athens, Greece (2007), the H. F. Mark Medal from the Austrian Research Institute for Chemistry and Technology (2008), Honorary member of the Israel Society of Chemistry (2009), the Inaugural ACS-Kavli Foundation Innovation in Chemistry Lecture and Award (2011), Honorary Professor of the Australian Institute for Bioengineering and Nanoscience (2012), and Foreign Member of the Royal Swedish Academy of Engineering Sciences (2013). He serves on the Editorial Boards of 21 international journals.

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Tutorial Review

‘‘deconstruction’’ (design and synthesis by deconstructing a higher generation previously known or unknown dendron or dendrimer) approaches to constitutional isomeric libraries it was discovered that primary structures responsible for a particular 3D architecture could be predicted with more than 82% fidelity from a diversity of AB2,8–11 AB3,8–12 AB4,13 AB5,13 and hybrid ABy–ABn14 selfassembling dendrons, dendrimers and dendronized polymers.6,15 For simplicity primary structures are not shown in Fig. 2. However, secondary structures discovered by this methodology are shown in the top row of Fig. 2, tertiary structures with internal order in the second row and quaternary structures in the last row. This accelerated approach led to the elaboration of a ‘‘nanoperiodic’’ table database that correlates primary structures11,16 with 2D and 3D assemblies self-organizing in lamellar S(bilayer),14 p2mm simple rectangular columnar (Fr-s),9,14 c2mm centered rectangular columnar (Fr-c),9,12,14 p6mm hexagonal columnar (Fh),7–9 cubic Im3m (BCC),17 12-fold quasi-liquid crystalline (QLC),18 cubic Pm3n (Cub),7,19 and tetragonal P42/ mnm (Tet)20 periodic and quasi-periodic arrays with internal order (bottom row in Fig. 2). Porous or hollow and non-hollow helical columns as well as hollow or non-hollow helical icosahedral or spherical assemblies containing a supramolecular or covalent polymer in their center are shown in the second row of Fig. 2. Most remarkable was the recent discovery that these helical structures are homochiral regardless of whether they are assembled from achiral, racemic or homochiral building blocks (to be discussed later). Only some of these periodic arrays are encountered also in block copolymers. However, related periodic arrays from block copolymers do not exhibit internal order. In order to understand how the primary structure created by the ‘‘generational’’ approach determines the secondary structure and ultimately the mechanism via which these dendrons and dendronized polymers govern their self-assembly, Percec laboratory introduced the parameter a 0 , which is defined as the projection of the solid angle a of a dendron on a plane (Fig. 3).21 The solid angle (a) of a conical dendron (bottom row in Fig. 3) is defined as a = 4p/m, where m, determined by XRD, is the number of dendrons needed to construct one column stratum or supramolecular sphere (see formulae in Fig. 3 for different phases). The projection of the solid angle (a 0 ) of a conical dendron gives a planar angle defined as a 0 = a/2 = 2p/m = 3601/m. The planar angle, a 0 , of a tapered dendron (top row in Fig. 3) is also a 0 = 2p/m = 3601/m. The solid angle (a) of a conical or tapered dendron is therefore directly proportional to its projected planar angle (a 0 ). With the increase of the size of the branched groups at the dendron periphery or of the generation number of flat-tapered dendrons, a 0 increases until a threshold where one column stratum is formed by a single disclike molecule. Above this threshold, the quasi-equivalent dendron switches its conformation from tapered to conical shape with a decreased a 0 , and the resulting supramolecular architecture self-organizes in a cubic lattice. Further branching or higher generation number will again increase a 0 , ultimately resulting in a conical dendron becoming a unimolecular spherical dendron (bottom of Fig. 3).22 The solid angle a is therefore the primary determinant of both shape and dimensions generated

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Fig. 1 Models of icosahedral and rodlike viruses (a), and the mechanism of self-assembly of Tobacco Mosaic Rod-Like Virus (TMV) (b). Adapted with permission from ref. 3. Copyright 1982 The Nobel Foundation.

Fig. 2 Accelerated synthesis of constitutional isomeric libraries of quasi-equivalent self-assembling dendrons and dendrimers via structural and retrostructural analysis of their periodic and quasi-periodic assemblies with internal order.11 Adapted with permission from ref. 11. Copyright 2009 American Chemical Society.

during the self-assembly process. Other structural changes such as the volume of the functional group attached at the apex of the dendron and temperature can also be employed as efficient strategies to modulate the solid angle. Once the ‘‘generational’’ discovery strategy to constitutional isomeric libraries became less efficient,8–11,13,14 the Percec laboratory elaborated the ‘‘deconstruction’’ strategy (Fig. 4) to discover novel primary structures of self-assembling minidendrons to provide unprecedented 3D structures.23 Starting with any known or unknown self-assembling dendron or dendrimer, for example the third-generation (3,4BpPr-(3,4,5BpPr)2)12G3-X (middle structure in Fig. 4), each branch or fragment of dendron is removed to

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generate a diversity of novel primary structures that would not be accessible via the generational methodology. The primary structures resulting from this process were synthesized by the same iterative method used in the generational synthesis approach. A library of self-assembling minidendrons with unprecedented primary structures discovered by the deconstruction of (3,4BpPr(3,4,5BpPr)2)12G3-X, that emerge in a diversity of novel 3D structures, is in Fig. 4.23 Fig. 5 summarizes all the topologies of linear polymers dendronized with self-assembling dendrons produced in the Percec laboratory.4e,15 Dendrons were attached to the polymer backbone from their apex (Fig. 5a–d). The covalent attachment

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Fig. 3 The emergence of a single-sphere dendron from tapered or conical dendrons and the correlation with the projection of the solid angle (a 0 ). (a, solid angle; m, number of dendrons per column stratum or sphere; NA, Avogadro’s number = 6.022045  1023; D, experimental column diameter; a, cubic lattice parameter; t, average height of the column stratum; r, experimental density; M, molecule weight.) Adapted with permission from ref. 21. Copyright 2000 American Chemical Society.

of the dendrons to the backbone is either direct (Fig. 5a) or via a flexible spacer (Fig. 5b). The dendrons can also be attached to the polymer backbone via non-covalent bonding (Fig. 5c). Construction of supramolecular backbones via non-covalent bonds (Fig. 5d) represents another strategy. Alternatively, linear polymers were designed with dendrons attached from the dendron periphery either directly (Fig. 5e) or via a spacer (Fig. 5f). The last row in Fig. 5 summarizes the attachment strategies for twin dendrimers (Fig. 5g) and Janus dendrimers (Fig. 5h and i) to the polymer backbone, the latter being able to be attached to the backbone from their two different dendrons. In Fig. 6a the blue code outlines the self-assembly of hydrogenated twin-dendritic molecules (in dark blue), of the polymer dendronized with hydrogenated twins (in light blue), and their co-assembly. Twin dendritic molecules self-assembled into supramolecular columns, which subsequently self-organized into a 2D columnar hexagonal superlattice (Fh).1,24 Polymers attached to twin dendritic molecules self-assembled into a structure with an extended polymer chain coated with threecylindrical1 or four-cylindrical24 bundles of supramolecular columnar dendrimers, which self-organize into a thermotropic columnar nematic liquid crystal phase (NC). Some empty space (white color) was present in the four-cylindrical-bundle structure, which can be amended by co-assembly with twin dendritic molecules that fill the empty space.24 Co-assembly of twin dendritic molecules with the dendronized polymers also generated a densely packed columnar hexagonal 2D periodic array with the twin dendritic molecule-derived columns filling the cavity of the three-cylindrical bundle structure of the supramolecular polymer.1 In Fig. 6b the yellow code summarizes the self-assembly and co-assembly process of the fluorinated analogs to the hydrogenated dendrons.15 Both fluorinated twin dendritic molecules and semifluorinated Janus dendrimers also selfassemble into supramolecular columns forming a 2D columnar hexagonal superlattice (Fh). On the other hand, the Janus dendrimers change their conformation to tapered dendrons, and therefore form supramolecular columns with the diameter two times larger than that of the corresponding columns self-assembled by

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fluorinated or hydrogenated twin dendritic molecules. A selfrepairing process was observed when the Janus dendrimersconjugated polymer co-assembled with Janus dendrimers with molar ratios larger than 1 : 1.15

4. Selecting self-assembling dendrons The methodology outlined in Fig. 2 can be applied to any selfassembling primary structure. However, minidendrons containing dissimilar chemical fragments (Fig. 7) were selected as the simplest synthetic mimics of peptides and proteins,4e since their complex topology is expected to provide a more rapid discovery process than their linear topology. The apex of these minidendrons (X) was functionalized with –CH2OH,8 –CO2H,8 –CO2CH3,8 –NH2,1 –CO2M (M = Li, Na, K, Rb, Cs),12 electron-donor and acceptor compounds,28 crown-ethers –CO2CH2–15C5,4c,26 –CO2CH2–B15C5,4c oligooxyethylene –CO2(C2H4O)4H and oligooxyethylene-derived polymer backbone –CO2(C2H4O)1–4PMA and their complexes with metal salts. The strength of the supramolecular interaction provided by X mediates a tapered or conical conformation for the same dendron.8 The periphery of these minidendrons can be conjugated with hydrogenated groups –CnH2n+1 (Fig. 7a),4c,8,11,12,26 semi-fluorinated groups –(CH2)n(CF2)mF with n + m = 12 (Fig. 7b),15,27,28 and hydrophilic groups –(C2H4O)3CH3 (Fig. 7c).29,30 Additional constitutional isomeric libraries of AB2- and AB3-based dendrons with even more complex primary structures (Fig. 7e and f) were designed in attempts to discover novel supramolecular architectures.9,11,14 The structural diversity of the dendrons was further expanded to twin dendrimers, Janus dendrimers,15 AB4 and AB5 hybrid dendritic building blocks (Fig. 7d),13 willow-like dendrons and dendrimers,31 and other first-generation hybrid dendrons (Fig. 7g).32 Other laboratories discovered additional examples of self-assembling dendrons and dendrimers. Kim’s group reported self-assembling aliphatic amide dendrons and dendrimers (Fig. 7i).33 By using dendrons containing a six atoms spacer between the aromatic branching

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Fig. 4 The deconstruction strategy of third-generation dendron (3,4BpPr-(3,4,5BpPr)2)12G3-X (shown in the middle) led to the discovery of new selfassembling minidendrons, where X = –CO2CH3 for 6a and –CH2OH for 6b. In each step of the deconstruction (solid arrows), the fragment highlighted by the wedge of the corresponding colour (red or grey) is removed. Dotted arrows indicate construction. Reprinted with permission from ref. 23. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

points (Fig. 7j) and a combination of methods consisting of only non-oriented samples for XRD and TEM, the Mezzenga and ¨ter laboratories discovered several inverse34a,b 2D morphoSchlu logies. Periodic direct arrays similar to those reported from other laboratories,4e but without internal order, were recently reported on related molecules when the end moieties of the dendron and dendrimer were more rigid.34c Therefore, this work illustrates that depending on a combination of intrinsic rigidity and segmental composition, both direct and inverse morphology may arise.34a–c More complex supramolecular structures based on combinations of direct and inverse arrangements of self-assembling dendrons were also reported.32 Hult’s laboratory (Fig. 7k) provided useful building

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blocks for supramolecular structures that are commercially available.35 Amphiphilic dendrons from Fig. 7l with linear polyoxyethylene chains elaborated by the Wiesner laboratory36 exhibit an unexpected sequence of crystalline lamellar, cubic micellar, hexagonal columnar, continuous cubic, and lamellar 2D and 3D arrays.

5. Structural and retrostructural analysis methodologies The structural and retrostructural analysis involved in Fig. 2 was accomplished by a combination of complementary techniques

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Fig. 5 Topologies of covalent and supramolecular polymers dendronized with self-assembling dendrons. Dendron directly attached to the polymer backbone via apex (a), with a flexible spacer (b), attached via non-covalent interactions (c), supramolecular polymers dendronized (d), dendron directly attached to the polymer backbone via its periphery (e), via its periphery and a flexible spacer (f), covalent polymers dendronized with twin-dendrimers (g), and with Janus dendrimers (h and i). Reprinted with permission from ref. 15. Copyright 2012 American Chemical Society.

Fig. 6 Self-assembly of hydrogenated twin-dendrons, of polymers dendronized with hydrogenated twin-dendrons, and their co-assembly (all in blue) (a). Self-assembly of fluorinated twin-dendrons (in yellow), of semifluorinated Janus dendrimers (half in blue and half in yellow), and of polymers dendronized with semifluorinated Janus dendrimers (half in blue and half in yellow) (b). Notations: a1 = lattice dimension for the assemblies generated from twin dendritic molecules. Adapted with permission from ref. 1, 15 and 24. Copyright 1999 and 2003 Wiley-VCH Verlag GmbH & Co. KGaA. and 2012 American Chemical Society.

(Fig. 8), many of them transplanted from structural biology3 and adapted to large supramolecular assemblies,4e,7,19,29,39a,40,42 including differential scanning calorimetry (DSC) with different

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rates,41,43 thermal optical polarized microscopy (TOPM),43 experimental density (r20), circular dichroism (CD) in solution39a,c,43 and thin film,43 light scattering,6c temperature-variable small- and

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Fig. 7 Selected examples of self-assembling ABn-based (n = 2, 3, 4, 5) dendrons from the Percec laboratory (a–h) and other laboratories (i–l). (a) X = –CH2OH, –CH2Br, –CO2H, –CO2CH3, –NH2, –CO2CH2–15C5, –CO2CH2–B15C5, –CO2M, with M = Li, Na, K, Rb, Cs; (b) X = –CO2H, –CO2(C2H4O)4H, –CO2(C2H4O)1–4PMA, –CO2CH2–15C5, –CO2CH2–B15C5; (c) X = –OH, –Br, –COOH, –NH2; (d) X = –CO2CH3, –CH2OH, –CH2OAc–, –CO2H; (e) X = –CO2H, –CO2CH3, –CH2OH, –CH2Br. Structures selected from ref. 8, 9, 11–14 and 31–36.

wide-angle X-ray diffraction (XRD) experiments on powder and oriented fibers18–20,28a,39a,41,43 including helical diffraction theory,42 electron density maps and histograms,19a isomorphic replacement,19b solid state NMR,28,41,43 molecular dynamics simulation at the atomic level,37 computer simulation of the XRD by supramolecular models,43 transmission electron microscopy (TEM),7,17b cryogenic-TEM (cryo-TEM),29,30,40 electron diffraction (ED),7 scanning force microscopy (SFM),39a confocal microscopy,29,40 and micropipette aspiration experiments.29 Dendrons and dendrimers self-assemble into object-like assemblies such as globular, icosahedral, and helical rods (Fig. 2).7,19 These nano-objects self-organize into various 2D and 3D periodic and quasi-periodic arrays. The structural and retrostructural analysis employing this combination of complementary techniques provides details of the molecular arrangement and conformation of the primary structures within the 3D and 2D periodic arrays (Fig. 8). Fig. 8a and e show the bright field TEM images of a hexagonal array with p6mm symmetry and a cubic lattice with pm3% n symmetry,7 respectively. TEM is a useful tool to determine nanostructure

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since it provides both structural and morphological information simultaneously.7 The bright field images from Fig. 8a reveal the hexagonal arrangement of supramolecular columns arranged homeotropically (top)7 or planar (bottom)7 on a surface, while their corresponding electron diffraction (ED) patterns (insets) indicate the symmetry of the assemblies and therefore, the detailed molecular arrangement of supramolecular columns in the hexagonal periodic array.7 In Fig. 8e, the ED pattern (inset in the TEM image) suggests, in agreement with XRD, two possible cubic structures made of spheres and cylinders with identical symmetry (see models in Fig. 8f).7 The bright field TEM (Fig. 8e and f)7 and the electron density model (Fig. 8h) reconstructed from the XRD data from Fig. 8g demonstrate one of the two possible self-assembly models. Although complementary to XRD, TEM has limitations. First, the sample has to be a very thin monodomain (o100 nm) for structural data collection and electron diffraction must be performed on stained and unstained samples to determine the extent of degradation during staining and irradiation (see ref. 30 in ref. 7). It is usually difficult to control sample temperature and orientation in TEM.

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Fig. 8 Structural analysis methods used for supramolecular complex systems in bulk (a to j) and in solution (k and l): TEM (a, e)7 and discrimination % by TEM (f);19a powder XRD (b),14 wide- (c)41a and small-angle (g)17a XRD from oriented fibers; 3D electron between the two possible models of pm3n density maps (d, h);7,39a SFM (i) and the corresponding histogram of the contour length distribution of supramolecular columns (j),6d cryo-TEM (k);40 confocal microscopy (l), (insertion shows a giant vesicle containing hydrophilic, green, and hydrophobic, red, dyes).29,40 Adapted with permission from ref. 6d, 7, 14, 17a, 19a, 39a, 40 and 41a. Copyright 1997, 2000, 2004, and 2013 American Chemical Society, 1997 American Association for the Advancement of Science, 1998 Wiley-VCH Verlag GmbH & Co. KGaA, and 2004 Macmillan Publisher Ltd. (Nature).

Besides, TEM provides only local identification and does not give average sample information. XRD, on the other hand, provides overall sample information in a wide diffraction angle and temperature range with a much simpler sample preparation procedure. Therefore, XRD together with ED maps is the most powerful structural determination technique for 2D and 3D periodic arrays, although TEM and electron diffraction data provide complementary information. Fig. 8b shows the 1D plot integrated from a powder XRD pattern of a 2D hexagonal lattice.14 The powder XRD is used to determine the symmetry and lattice parameters for 2D arrays and identification of known crystals. It does not provide orientation information of the underlying molecules and is not suitable for unknown crystalline and helical structure determination. Fig. 8c and g17a,41a are wideand small-angle XRD fiber patterns for hexagonal and BCC cubic phases, respectively. These experiments were performed with extruded fibers in order to induce preferred orientations.17a,41a In an extruded fiber, for example, the supramolecular columns

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align along the fiber direction and provide additional information such as lattice orientation, inter- and intra-columnar correlation, molecular tilt, p–p stacking distance, helical parameters, etc.42 Orientation provides a convenient way to determine the lattice parameters for unknown complex 3D arrays that are difficult to grow into large single crystals. If the supramolecular column is helical, the helical parameters can be determined from fiber XRD (see example in Fig. 9).42 Nevertheless XRD cannot provide information on the handedness of the helix, since right- or left-handed objects give identical XRD patterns. The diffraction pattern (reciprocal space) is a Fourier transform of the sample electron density (real space). Therefore, it is possible to reconstruct the real space electron density by reverse Fourier transform of the diffraction pattern. The electron density reconstruction is required for structure determination since it indicates how the molecules are arranged inside an object and objects in a lattice.7,18–20,39a However, the phase angle information is lost for each reflection in the XRD pattern during the data

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Fig. 9 Illustration of analysis methods for helical supramolecular dendrimers. (a) 51 single strand atomic helix and its structural parameters (a); simplified representation of fiber XRD by helical diffraction theory (b);42 example of wide angle XRD of an oriented fiber and the schematic of the helical structure of a helical supramolecular dendrimer (c);42 temperature dependence of the CD and UV spectra during helical supramolecular polymerization in solution (d).43 Adapted with permission from ref. 42 and 43. Copyright 2008 and 2014 American Chemical Society.

collection, and therefore, the reconstructed electron density map from reverse Fourier transform is not unique. All possible combinations of phase angles and electron density maps based on our knowledge of the molecules and their self-assembly behavior must be examined in order to determine the most probable electron distribution in the 2D or 3D lattice.4,19 Discrimination between various models is provided by the electron density histograms exhibiting the sharpest intramolecular microsegregation between the dissimilar chemical parts of the assembly.19 Fig. 8d and h shows examples of 3D reconstructed electron density maps for the hexagonal39a and cubic phases.7,19 Hollow channel-like supramolecular columns are apparent in the hexagonal array (Fig. 8d). In addition to TEM,7 other techniques are also applied for direct visualization of supramolecular objects. Fig. 8i shows the visualization of individual supramolecular columns by SFM.6a,c,d The sample was prepared with a very dilute solution (0.01–0.1 mg mL1) spin-coated on a pyrolytic graphite substrate to avoid aggregation of columns.6d The contour length of columns was measured and the polydispersity was determined from the contour length of each individual dendronized polymer. The GPC-like data obtained by this method agreed with those obtained from gel permeation chromatography (GPC) experiments (Fig. 8j).6d Amphiphilic Janus dendrimers self-assemble into various structures in water, buffer, and bulk.29,40 Nano-size vesicles were prepared by injecting a water-miscible solution of an amphiphilic Janus dendrimer into water or buffer, while giant vesicles are prepared by hydration of a thin film of the Janus dendrimer.29 In order to study the supramolecular assemblies in their unperturbed state, techniques such as cryo-TEM in vitrified water and confocal optical microscopy in water, both transplanted from biology, are used.29,40 Fig. 8k and l show the cryoTEM image of nano-size vesicles (glycodendrimersomes) and

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giant vesicles (on the scale of 10 mm) self-assembled from amphiphilic Janus glycodendrimers containing a hydrophobic (red to visualize the wall) or a hydrophilic dye (green to visualize the cavity) or a combination of both. The mechanical properties of the vesicle wall was determined by micropipette aspiration experiments performed on giant vesicles obtained by film hydration experiments.40 These experiments also discriminate between soft and hard vesicles.29,40 Fig. 9 summarizes the combination of methods used to study the helical supramolecular dendrimers. Fig. 9a shows a simplified single strand 51 helix model constructed by tilted repeat units, and its corresponding fiber XRD pattern is illustrated in Fig. 9b.42 The helical parameters are obtained by helical diffraction theory.42 In the XRD pattern, the equator reflections (L = 0, white ellipsoids) reveal the 2D projection arrangement of helical columns. The position and spacing of reflections on higher layer lines (red, yellow, and green ellipsoids) provide information about the helical pitch, the distance and the rotation angle between adjacent molecules, stacking distance along column axis, helix radius, and tilt angle. Fig. 9c shows an actual fiber XRD pattern obtained from the crownshaped (3,4Bn)dm8*G1-CTV in the 3D crystalline hexagonal columnar phase.43 The supramolecular column is a triple-121 helix with diameter of 34.3 Å (bottom model in Fig. 9c). Instead of diffused reflections commonly observed on layer lines of 2D helical structures, sharp reflections were identified in the pattern indicating strong intercolumnar correlations, that is, the helical columns generate 3D ordered hexagonal crystals that imply identical helical handedness within a single crystal domain according to the lattice symmetry.43 The handedness of supramolecular helical columns was determined in a solvophobic solvent43 or thin film (see examples in Fig. 20) by combining CD

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(Fig. 9d, top) and UV-vis (Fig. 9d, bottom) experiments. The R and S enantiomers showed opposite Cotton effects indicating opposite helical handedness. Oriented fiber experiments are used to determine the helical structure of supramolecular columns. However, as in the case of DNA results from these experiments rely on the quality of the oriented fiber and of the XRD. For example, three possible supramolecular columnar models of dendronized polymethacrylate

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(PMA), (4Bn-3,4,5Bn)12G1-4EO-PMA, obtained from oriented fiber XRD experiments are illustrated in Fig. 10. The polymer backbones are omitted for clarity. Strong off-meridional reflections observed in fiber XRD patterns suggest the taper-like dendrons are tilted at 40–501 to the column axis and therefore, exhibit a ‘‘pine-tree’’ model. Compared with 25 1C, it was found that the column diameter was reduced by about 2.4 Å at 60 1C, and the intra-columnar correlation also decreased. Experimental density measurements revealed that each unit cell contains eight molecules. One possible model involves nonhelical columns with 8-fold disk-like stacking (Fig. 10a), the other two are based on helical columns with 81 (Fig. 10b) or 84 (Fig. 10c) helical symmetry. However, the quality of the fiber XRD was not sufficient in this case to discriminate between these three models.44 Molecular dynamics simulations,29,37 and other theoretical38 work and discoveries53 were initiated by the novel giant globular or icosahedral and helical dendritic assemblies,7,18–20 sometimes as large as 1.73  106 g mol1, challenging the size of the ribosome.

6. Molecular design principles for the hierarchical control of internal structure, dimensions and stability of supramolecular minidendrimers

Fig. 10 Pine-tree models of the supramolecular structure of (4Bn-3,4,5Bn)12G1-4EO-PMA with nonhelical 8-fold stacked disks (a), helical 81 (b), and nonhelical 84 symmetry (c). Adapted with permission from ref. 44. Copyright 1994 American Chemical Society.

The primary structures of the dendrons and dendronized polymers determine their hierarchical internal structure, dimension and stability of the supramolecular structures assembled from them. Fig. 11 demonstrates the role of different molecular parameters of a dendronized polymethacrylate (PMA), as an example for a 2D columnar hexagonal (Fh) periodic array.45 The column diameter increased linearly from 61.9 Å to 70.0 Å when the alkyl chain length increased from n = 10 to 16 (Fig. 11a).

Fig. 11 Dependence of the supramolecular column diameter (a, Å) and the diameter of its constituent micro-segregated components on alkyl chain length (n in green, left), aromatic groups (Ar in red, middle), and oligooxyethylene segment length (m in blue, right) of the dendronized polymer (4Ar-3,4,5Bn)nG1-mEO-PMA, where Ar = Nf, Bn, and Bp, or no O-Ar (m, number of monodendrons per column stratum; a 0 , projection of solid angle). Adapted with permission from ref. 45. Copyright 1998 American Chemical Society.

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This increase occurs at the periphery of the columns (green region, Fig. 11a) while the regions closer to dendron apex were unchanged. Therefore, the number of dendrons per disk (m) remains constant in spite of their different alkyl chain length. The stability of the 2D Fh periodic array increased from 139 1C for n = 10 to 152 1C for n = 16. The change of aromatic region in the dendron produced a larger difference in both column diameter and stability since the aromatic structure affects the p–p stacking interactions in a stronger way than the aliphatic–aliphatic interactions.4e Fig. 11b compares the structure of the column and melting temperature of the periodic array generated by supramolecular columns containing benzyl (Bn), naphthylmethyl (Nf), and biphenylmethyl (Bp) aromatic groups, and in the absence of any aromatic group (red region). The column diameter increases with increasing rigid aromatic group length of the dendron. This decreases the solid angle and therefore, increases m. Comparing columns from dendrons with no aromatic group and with three benzyl groups, the isotropization temperature (Ti) of the latter increases by about 45 1C. This is contributed by the three benzyl rings of the dendron repeat unit which provides an effective p–p stacking force to stabilize the columnar structure. This p–p stacking interaction increases with increasing size of the aromatic group. Larger aromatic groups generate more stable 2D Fh arrays. The columns with Nf groups provide an additional increase in column stability of 48 1C, and the Ti for columns with Bp groups are stable up to 179 1C. Changing the number of oligooxyethylene repeat units (m) in the dendron core region affects the diameter of all three regions in the column (Fig. 11c, blue region). However, the diameter increased linearly with m from 0 to 2 and reached a plateau for m = 3 and 4. This is most likely due to the high flexibility of the oligooxyethylene units that also destabilizes the columnar structure. Interestingly, the column stability has a

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reverse trend compared to the diameter. Ti is around 120 1C for m = 0 and 1, and decreases linearly to around 100 1C for m = 4. Self-assembly is a result of cooperative non-covalent interactions, such as van der Waals forces, hydrogen bonding, electrostatic interactions, metal–ligand coordination, and p–p stacking known also as multivalency.4e,47 The concept of multivalency in self-assembly47 is seen in Fig. 12, which shows how the 2D Fh array was stabilized by cooperative interactions including covalent bonding, hydrogen bonding, p–p stacking, and ionic interactions.25,46 In Fig. 12a, both the dendronized PMA and the dendrons with –OH groups in their apex form columns with decreased stability due to the increase of the number of oligooxyethylene units (n). This is consistent with the results shown in Fig. 11c. The difference of Ti between the columns generated from polymers and monomers with all n was almost constant at around 40 1C, suggesting that the contribution of the covalent polymer backbone to the stabilization of the Fh phase is equivalent to ca. 40 1C. When LiOTf was complexed within the system, the salt formed an ionic liquid located at the center of the column due to the solvation of Li+ with the oligooxyethylene groups to provide a supramolecular polymer (top models in Fig. 12). The ionic interaction stabilized the Fh phase in a similar way to a covalent polymer backbone, but it destabilized slightly the 3D array of the dendrons with an –OH group in the apex. This led to a wider temperature range of the 2D Fh array as a function of Li+ molar ratio for all n values tested (Fig. 12b). The temperature range of the Fh phase reaches 40 1C at Li+ molar ratio of 0.4, indicating that the power of one covalent polymer backbone in stabilizing the columnar structure is equivalent to approximately 0.4 mole of Li+ per mole of dendron. Comparing the dendrons with –OH and methyl groups at the apex (Fig. 12c), the Ti of pure

Fig. 12 General molecular structure of dendritic monomers and dendronized polymers, and the top and tilt views of the supramolecular column (top). Dependence of the isotropic temperature of dendritic monomers (R = H) and of dendronized polymers (R = PMA) on the oligooxyethylene segment length (n) (a). Dependence of phase transition temperature on the molar ratio of LiOTf as a function of n (b), and as a function of head group (R = H, CH3, and PMA) (c, d). Adapted with permission from ref. 25 and 46. Copyright 1993 and 1994 Royal Society of Chemistry.

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(4Bn-3,4,5Bn)12G1-3EO-OH was found to be roughly equivalent to that of (4Bn-3,4,5Bn)12G1-3EO-CH3 complexed with 0.6 equivalents of Li+. This indicates that the strength of the hydrogen bonding formed with one –OH group in the column core is equivalent to 0.6 moles of Li+ per mole of dendron. Comparing with the result from Fig. 12a, it was concluded that hydrogen bonding is more powerful than the contribution of the covalent PMA backbone for the stabilization of the supramolecular columnar assembly. This is because the covalent polymer backbone is relatively rigid when compared with the more flexible hydrogen bonded supramolecular backbone structure. The dynamics of hydrogen bonding requires less entropic penalty when forming the supramolecular columns than required by a rigid polymer backbone and therefore leads to more energetically-favored columns. Also, in the case of (4Bn-3,4,5Bn)12G1-3EO-OH, complexation of 0.5 mol Li+ per mole dendron leads to an increase of Ti with 40 1C (Fig. 12c), which is equivalent to the contribution of a PMA backbone. From the slope shown in Fig. 12d, the influence of Li+ complexation on Ti is more significant for the dendrons than for the dendronized PMA. The increase of Ti after complexation with

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Li+ in dendronized PMA is within 10 1C for all Li+ concentrations, while the Ti increased from 10 1C to over 70 1C with 1.2 mol Li+ per mol for the dendron with –OH in the apex. In the case of (3,4,5Bn)12G1-3EO-OH (Fig. 12d), the PMA backbone is equivalent to 0.4 mol Li+ per mol in stabilizing the supramolecular columns. Also, from the intersection point in Fig. 12d, it is observed that one PMA repeat unit complexed with 0.2 mol Li+ per PMA mol repeat units (mru) is equivalent to the stabilization power generated by 0.6 molar ratio of Li+ alone. Finally, comparing the Ti for the dendrons with –OH in the apex from Fig. 12c and d before complexation with Li+, the dendron with three benzyl groups in the alkyl tails (Ar = Bn) exhibited a Ti 45 1C higher than that without benzyl groups (Ar = no O–Ar), indicating that the column stabilization power provided by the three benzyl groups through p–p stacking is about 45 1C which is consistent with the result shown in Fig. 11b. Fig. 13a–c summarizes the crystal melting temperature and the transition temperature between 2D Fh and isotropic phases of semifluorinated (n 4 0) and hydrogenated dendrons (n = 0) with different numbers of (CF2)n repeat units (n) containing

Fig. 13 Dependence of the phase transitions of periodic arrays assembled from supramolecular columns (3,4,5Bn)12FnG1-R (R = –4EO–OH and –COOH) and of dendronized polymers (3,4,5Bn)12FnG1-4EO-PMA on the number of fluorinated methylene units in the alkyl tails (n, a–c), of (4Ar-3,4,5Bn)10FnG1-R (R = –4EO-OH and –COOH) and of dendronized polymer (4Ar-3,4,5Bn)10FnG1-4EO-PMA on the number of fluorinated methylene units in the alkyl tails (n) and on the presence and absence of aromatic group (Ar, where Ar = –C6H4–CH2–(Bn), d–f). Adapted with permission from ref. 48. Copyright 1995 and 1996 American Chemical Society.

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–OH, –CO2H, and PMA backbone at the apex. The number of carbons in the alkyl tails was kept constant with m + n = 12 for all molecules. Therefore, the chain length varies very little between molecules, resulting in a small variation (less than 10 Å) of the column diameter. Without the PMA backbone, the hydrogenated dendrons (n = 0) show no 2D Fh phase (Fig. 13a and b). For the compounds with –OH at the apex (Fig. 13a), the stability of the crystalline phase (melting temperature, Tm) decreased first by introducing four CF2 units in the alkyl chains, and then increased with the increasing number of CF2 units. The 2D Fh phase started to appear at four CF2 units with an isotropization temperature (TFh–i) at about 0 1C. It was observed that TFh–i was proportional to the number of CF2 units. This suggests that, similar to the aforementioned interactions, the fluorophobic effect generated by CF2 repeat units can also stabilize the supramolecular columns. Although both Tm and TFh–i increased with the increasing n, the rate change, i.e. slope, of TFh–i was higher than that of Tm, which resulted in a wider range of temperature for the 2D Fh phase with an increasing number of CF2 units. For the case of (3,4,5Bn)12FnG1-CO2H (Fig. 13b), the slope of TFh–i was lower than that of Tm, resulting in a narrower range of the Fh phase with an increasing number of CF2 units. By introducing the covalent PMA backbone at the apex, the supramolecular columnar LC structure was generated even with the hydrogenated compound (n = 0) (Fig. 13c). With further incorporation of CF2 groups, the crystalline phase was suppressed and a glassy state was observed at low temperature. Although the glass transition temperature (Tg) was raised by increasing the number of CF2 units, the slope was much lower

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than that of the crystalline melting. The Fh phase was therefore stable within a much wider range of temperatures in the case of the semifluorinated dendronized polymers. Similarly, Fig. 13d–f compares the thermal stability of each phase for hydrogenated (n = 0) and semifluorinated (n = 6) dendrons with different head groups, shorter chain length (m + n = 10), and with or without benzyl (Bn) groups in tails. In all cases, the fluorophobic interaction helped to stabilize the Fh phase and increased TFh–i. This effect was more significant for the compounds with benzyl groups in the alkyl chains. Comparing the semifluorinated dendrons and dendronized PMAs with and without the three benzyl groups in each dendron unit (red and green in Fig. 13d–f), the p–p stacking helped to raise TFh–i by 80 1C and 120 1C for the dendrons with –OH and –CO2H in the apex, respectively, and by 90 1C for the dendronized polymers. When the crown-ether fragments of the tapered dendrons were complexed with Na+, they also self-assembled into supramolecular columns that in turn self-organized to form 2D Fh arrays.4c,27 Fig. 14 summarizes the dependence of the thermal stability of the 2D Fh phase on the structures attached at the apex and at the periphery of the dendrons. The Fh supramolecular architecture generated by (3,4,5Bn)12G1-15C5 was stable below 27 1C,4c but the thermal stability was enhanced by either replacing 15C526 with an aromatic crown-ether B15C549 or replacing (3,4,5Bn)12G1 with wider flat-tapered dendrons. For the same crown-ether (B15C5 or 15C5), the wider tapered dendron (4Bn-3,4,5Bn)12G1 generated a more stable Fh than that derived from (3,4,5Bn)12G1.4c The size of (3,4,5Bn)12G1 could also be enlarged with semifluorinated dendrons (3,4,5Bn)12FnG1

Fig. 14 Thermal transitions of the 2D periodic arrays generated from supramolecular columns assembled from various dendronized crown-ethers complexed with NaOTf. Adapted with permission from ref. 4c and 27. Copyright 1996 American Chemical Society and 1996 Wiley-VCH Verlag GmbH & Co. KGaA.

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(n = 4, 6, and 8).27 By increasing the number of CF2 units the thermal stability of Fh phase gradually increased up to 105 1C.

7. From structure to function

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7.1 Mediating chemical reactivity, backbone conformation and 3D shape Percec’s laboratory designed synthetic analogs of quasi-equivalent proteins by conjugating a conical dendron (3,4,5Bn)212G2 with styrene (S) and methacrylate (MA) to generate the dendronized monomers (3,4,5Bn)212G2-CO2-S and (3,4,5Bn)212G2-CH2-MA (Fig. 15).6a The dendronized monomers were subsequently polymerized by radical polymerization initiated with AIBN in ideal dilute solution and in self-assembled states of a concentrated solution or in bulk. At low degrees of polymerization (DP) the resulting dendronized polymers exhibited a spherical shape with the polymer backbone adopting a random-coil conformation (Fig. 15a) regardless of the ideal solution or self-assembled state polymerization. By increasing the DP, the quasi-equivalent dendritic units changed from a spherical to a columnar structure with an extended polymer backbone incorporated in the center of the column. This phenomenon is unprecedented considering that

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the backbone of a conventional polymer adopts an extended conformation at low DP and a random-coil conformation at high DP. In the self-assembled state these dendronized monomers generate a supramolecular reactor in which the polymerizable groups jacketed by the dendritic coat create an extremely high local concentration of the monomer. As a consequence the rate of polymerization is dramatically increased, yielding columnar rigid polymers with Kuhn segment length of about 500 Å6c and unprecedentedly high molar mass, Mn, of 40 000–3 500 000 (Fig. 15a), in several minutes.6a–c The transition between spherical (Fig. 15b) and columnar (Fig. 15c) dendronized polymer shape with increasing DP was shown by XRD and was directly visualized by SFM demonstrating the quasi-equivalence of the dendritic side-groups (Fig. 15).6a However, in ideal solution, the rate constants of propagation, bimolecular termination and chain transfer decrease by increasing the DP to the point that a self-interruption of the polymerization occurs at the time when the polymer adopts a spherical shape.6b This is also unprecedented since in traditional polymerizations the reactivity of the growing species is chain length (DP) independent. Therefore, the monomers dendronized with self-assembling dendrons mediate the chemical reactivity of the growing species. Under these polymerization conditions the resulting polymers display molecular weight distributions as narrow as those obtained by conventional living polymerization methods (Fig. 15a).

Fig. 15 Supramolecular shape change during radical polymerization of conical dendronized monomers illustrating the quasi-equivalence concept (a), and the SFM images of spherical (b) and cylindrical (c) assemblies. Reprinted with permission from ref. 6a. Copyright 1998 Macmillan Publishers Ltd. (Nature).

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7.2

The limitations of covalent polymers during self-assembly

Quasi-equivalence of self-assembling dendrons was further investigated with an oxazoline polymerizable group attached to a minidendron.50 The dendronized monomer (3,4Bn)14G1-Oxz was polymerized by living cationic ring-opening polymerization to different DPs to yield polymers with narrow molar mass distribution (Fig. 16a). The transition of the polymer shape from spherical to columnar was also induced by increased DPs. The scale atop Fig. 16b shows the percentage of a sphere and demonstrates that an entire sphere can be co-assembled from small fragments of dendronized polymers. As demonstrated by XRD 70 repeat units of poly[(3,4Bn)14G1-Oxz] form a single sphere,50 which can also be self-assembled from fragments, such as a quarter (25%), half (50%), and a third (33%) of a sphere. However, as shown in the shaded area of Fig. 16b, a biphasic mixture of both spherical and cylindrical shapes is observed in the range of DP = 30 to 75. Although the polymers obtained by cationic living ring-opening polymerization exhibited narrow molar mass distribution Mw/Mn = 1.09–1.02 (Fig. 16a), they also contain a mixture of polymers with different DPs rather than a single polymer chain. The molar mass distribution of the polymers explains why Cub lattices coexist with Fh lattices in this range of DPs. On the other hand, when DP o 30, the polymer mixtures were only composed of fractions that self-assembled into a spherical fragment, and they can co-assemble to form solely supramolecular spheres. This experiment demonstrates the limitations of covalent polymer backbones generated via the most sophisticated living polymerization methods on the mechanism of self-assembly. Supramolecular polymer backbones are not affected by this limitation since they are dynamic structures.

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7.3

Ordered ionic conductors

Synthetic ionic conductors were designed in order to estimate the role of 3D and 2D order vs. complete disorder on their ionic conductivity (Fig. 17).49 An efficient strategy for their assembly involved the use of the tapered self-assembling minidendrons with ion-selective crown ether49 or ion-active but non-selective oligooxyethylene units attached at their apex (Fig. 17a). When the crown-ether and the oligooxyethylene were complexed with an alkali metal salt containing Li+, Na+, and K+, these dendritic molecules self-assembled into supramolecular columns that self-organize into 3D (k) and 2D (Fh) hexagonal columnar periodic arrays. At higher temperatures the supramolecular columns form completely disordered isotropic liquids. As demonstrated by Fig. 17b and c, crown-ethers or oligooxyethylenes generate the center of the column while the dendron and its aliphatic tails radiate toward the periphery of the column. The complexation with metal salts enhanced the stability of the 2D Fh array, provided a valuable mechanism for its design and enhanced the conductivity of ordered ionic conductors. When complexed with appropriate amounts of cations (e.g., 0.6 Na+ mol mol1), these minidendrons can be engineered to form 2D Fh arrays with DC conductivity higher than that of their 3D array. Also a higher slope of the dependence of the ionic conductivity on temperature is observed in the 2D than in the 3D or even in the disordered array of supramolecular columns.49 This demonstrates that the order and motion available in the 2D array are more favorable to ionic conductivity than the completely disordered isotropic liquid and the 3D ordered arrays which lack mobility. The tapered minidendron can also be functionalized with one single polymerizable group on its periphery (Fig. 17a), and the thermal

Fig. 16 Dependence of shape of supramolecules self-assembled by the dendronized polymer poly[(3,4Bn)14G1-Oxz] on its degree of polymerization (DP) observed during the living cationic ring opening polymerization of its monomer. Selected GPC traces for poly[(3,4Bn)14G1-Oxz] (a), and its weight fraction as a function of the theoretical DP = [M]0/[I]0 (b). The red line represents the threshold for spherical supramolecules, and the shaded area shows the range of DPs where a biphase was observed by XRD. Adapted with permission from ref. 50. Copyright 2001 American Chemical Society.

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Fig. 17 Ionic conducting columns self-assembled by dendronized crown-ethers, oligooxyethylene and their polymers. Molecular structures (a); top view (b) and tilt view (c) of the ionic conducting column; (d) dependence of log s (S cm1) on temperature T (1C) and 1/T (1/K) during the first heating DSC scan shown on the bottom. Adapted with permission from ref. 49. Copyright 1993 Royal Society of Chemistry.

stability of the 2D Fh periodic array was considerably enhanced after polymerization. 7.4

Nanomechanics and molecular machines

When polyarylacetylenes, such as polyphenylacetylene (PPA), are dendronized with self-assembling dendrons they form helical columns that self-organize into 3D or 2D Fh arrays.51 PPAs dendronized with chiral, nonracemic dendrons adopt a preferred helical handedness, which was confirmed by CD spectroscopy (Fig. 18c). The helical columnar structure is persistent in solid state. Conventional synthetic and biological polymers undergo a helix–coil transition that in the case of cis-cisoidal and cis-transoidal PPA is accompanied by an irreversible intramolecular electrocyclization followed by chain cleavage.51 This electrocyclization transforms the helix–coil transition from a reversible process into an irreversible process. The corresponding dendronized PPA generates helical columns that eliminate the intramolecular electrocyclization since they undergo an unprecedented reversible and reproducible helix– helix transition upon heating and cooling (Fig. 18a). This helix– helix transition was accompanied by a small decrease in column diameter and a significant increase in column length upon heating. A reverse trend is seen upon cooling (Fig. 18a). These dendronized PPAs provide thermoreversible nanomechanical functions that exhibit macroscopic output and were interfaced with the real world.52 As demonstrated in Fig. 18b, the oriented fiber made of dendronized PPAs lifts a dime of 250-times its own weight when it was heated from 20 1C to 80 1C.52 Depending on the length of the peripheral alkyl tail of dendrons, the total extension of the fiber can be tuned to fulfil different mechanical requirements (Fig. 18d). Polymers dendronized with Janus dendrimers demonstrated the opposite behaviour, expanding their length upon cooling and compressing their length upon heating.15 7.5

Supramolecular electronics

Semifluorinated tapered minidendrons functionalized with a variety of electroactive donor (D) or acceptor (A) groups at their apex self-assemble and co-assemble into helical columns (Fig. 19a).28a When an A or D-containing a semifluorinated dendron and a complementary A- or D-containing polymer were blended in a 1 : 1 ratio of donor/acceptor units, the electron

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Fig. 18 Molecular machine self-organized from dendronized helical polyphenylacetylenes. Illustration of the helix–coil transition and its transformation into a helix–helix transition that mediates expansion and contraction of the helical structure with temperature (a); expanded images collected by a digital camera at 25 1C and at 80 1C of the oriented fiber (b); variable-temperature CD spectrum (c); comparison of the fiber length change from optical microscopy and column diameter from the fiber XRD for the library of the polyphenylacetylenes with different peripheral alkyl chain length in the dendron (m) (d). Adapted with permission from ref. 52. Copyright 2008 American Chemical Society.

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Fig. 19 Schematic illustration of complex electronic supramolecular materials mediated by dendrons containing donor (D) and acceptor (A) groups, and their co-assembly with complementary amorphous polymers containing D and A side groups (a). The different systems form hexagonal columnar (Fh), centred rectangular columnar (Fr-c) and simple rectangular columnar (Fr-s) arrays; a and b are lattice dimensions. The self-repairing process of backfolded (brown) electronically active supramolecular helical pyramidal columns self-assembled by semifluorinated minidendron attached to the acceptor groups (b). Adapted with permission from ref. 28a and c. Copyright 2002 Macmillan Publishers Ltd. (Nature), and 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

donor–acceptor complexes (EDA) also formed supramolecular columns that self-organized into either Fh or Fr-c periodic arrays with alternating stacking of donors and acceptors. The optoelectronic elements of these columns reside in the center of the columns and therefore they are becoming ordered and are protected from moisture by the fluorinated coat.28a Donor, acceptor and donor–acceptor complexes of dendrons and dendrons mixed with complementary polymers generated hole and electron mobilities that were enhanced by 3 to 5 orders of magnitude over that of the parent electroactive component in the non-assembled state. This enhancement is due to proper arrangement of the electroactive component in highly ordered columns.28 On the other hand, back-folded structural defects from undesirable packing of the apex functionalized with acceptors on the donor part of the dendron were observed by solid state NMR and were shown to ‘‘self-repair’’ under slow heating to the isotropic liquid state and subsequent cooling to the 2D ordered state (Fig. 19a).28a

7.6

Homochiral self-sorting

Hat-shaped dendronized cyclotriveratrylenes (CTV) with chiral alkyl chains on their periphery ((3,4Bn)dm8*G1-CTV) are capable of forming helical supramolecular columns self-organizable in 3D hexagonal crystals (Fig. 20).43 All samples with different chiral compositions (enantiomerically pure, racemic by mixing, and racemic by synthesis) or even achiral compounds formed 3D hexagonal crystals consisting of homochiral columns with

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different degrees of perfection.43 Higher enantiomeric purity afforded higher order crystals. Due to the weak intra-columnar and intramolecular interactions, the helical columnar assemblies generated from a mixture of two enantiomers were able to diffuse between columns during thermal annealing and produce homochiral crystal domains with perfect 3D order. This process occurs when the hat-like dendronized CTV undergoes crown inversion and adopts a temporary disc-like conformation as shown by solid state NMR. This represents the first example of chiral self-sorting in supramolecular crystals.43 After annealing, the crystals were supramolecular conglomerates analogous to the small molecular crystalline conglomerates discovered by Pasteur during the mid-19th century.43 Fig. 20b illustrates this chiral selfsorting mechanism. Fig. 20a compares the fiber XRD patterns of the racemic mixture before and after thermal annealing. The much stronger intensity and larger number of reflections after annealing are clear evidence for the formation of enantiomerically pure crystal domains. The solution and thin film CD experiments (Fig. 20c) showed similar spectra, suggesting that identical supramolecular structures were generated in solution and in bulk. Temperature-dependent CD measurements in solution combined with theoretical fitting were also applied to obtain the thermodynamic parameters of the cooperative helical supramolecular polymerization such as the elongation temperature (Te) and enthalpy (he) of the chiral supramolecular assemblies (Fig. 20d). Identical Te and he values for the two enantiomers and racemic by mixing enantiomerically pure samples confirmed the

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Fig. 20 Illustration of homochiral columns constructed by chiral self-sorting supramolecular helical organization of hat-shaped molecules (S), (R)-(3,4Bn)dm8*G1-CTV; comparison of wide angle XRD patterns before and after thermal annealing (a); demonstration of chiral self-sorting mechanism (b); thin film (25 1C) and solution (0 1C) CD spectrum of S (red) and R (blue) enantiomers (c); the degrees of aggregation and fitting with the cooperative helical supramolecular polymerization model (d). Adapted from ref. 43. Licensed under CC BY 4.0.

results from XRD that all samples generated enantiomerically pure helical columns. Unexpectedly, enantiomerically pure supramolecular columns were also assembled from achiral building blocks.43 These results suggest mechanisms for the origins of homochirality in biological systems. 7.7 Thermodynamically controlled crystallization of helical supramolecular columns Complex supramolecular helical columns from a series of dendronized perylene bisimides (PBI) with different chain length and spacer length, (3,4,5Bn)nG1-m-PBI, were studied for possible applications in organic electronics (Fig. 21).41 They contain a PBI core, which is an excellent n-type organic semiconductor. The two dendrons attached on each side of PBI can be tuned to engineer their self-assembled 2D and 3D structures. In the molecular structure, n indicates the number of carbons in the alkyl chain while m indicates the number of methylenic units in the spacer between the dendron and the PBI core. Electron mobilities higher than that of amorphous silica have been reported for m = 1 and n = 12. However, the result was not reproducible because this molecule has difficulty crystallizing and in addition forms a diversity of polymorphic

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2D and 3D periodic arrays. DSC analysis with repeated heating and cooling rates ranging from 40 1C min1 to 0.2 1C min1 were required to discover many, otherwise invisible, polymorphic crystalline structures.41 The experiments reported in these publications were performed with 100% pure samples and are recommended to all practitioners of supramolecular structural analysis in bulk state, since lower purity can yield different co-assemblies. Therefore, it is important to search for the formation of a highly ordered 3D crystalline structure generated by fast crystallization that is suitable for practical applications. This ideal 3D structure requires 3D helical columns with well-defined inter-columnar correlation and uniform 3.5 Å p–p stacking distance between PBIs within the column. A fast crystallization rate requires a thermodynamically controlled crystallization with low supercooling (o10 1C) that is independent of heating and cooling rate. In other words, the ordered crystal structure should be able to form without long annealing or slow cooling. In this study, various helical columnar crystal structures were identified for different members in the series (bottom models in Fig. 21). This was a very challenging endeavor since theoretically 3D crystals form by a kinetically controlled process. In summary, the dendronized

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Fig. 21 Transformation of the kinetically controlled crystallization of supramolecular electronics assembled from dendronized perylene bisimides (PBIs) (3,4,5Bn)nG1-m-PBI with m = 0, 1, 2, 3, 4 and n = 6 to 12 into thermodynamically controlled crystallization. Adapted with permission from ref. 41a. Copyright 2013 American Chemical Society.

PBI form dimers or tetramers in their column. For m = 0, 2, 3, 4 and n = 12, the crystallization is kinetically controlled and the p–p stacking distance is not uniform. For m = 3, and n = 8, 9, optimized crystal structures can be obtained but a long time annealing at high temperature is required (a kinetically controlled process). Similarly, for m = 1, and n = 12, 11, annealing is required for optimized crystal structure. However, it was discovered that when m = 1, and n o 11, the dendronized PBIs self-assemble into supramolecular columns possessing uniform p–p stacking distance via thermodynamically controlled crystallization. Since crystallization is by definition a kinetically controlled process the discovery of the thermodynamically controlled crystallization of supramolecular columns is both fundamentally and technologically important.

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7.8

Aquaporin mimics

Dipeptides conjugated with self-assembling dendrons form dendritic dipeptides39a that self-assemble into hollow helical columns that self-organize into a 2D Fh structure with intracolumnar order (Fig. 22a to e).39a–c The supramolecular structure of the assemblies generated from these dendritic dipeptides is similar to a b-barrel, and functions as an Aquaporin (AQP) mimic. When these hollow columns are reconstituted in phospholipid liposomes, they mediate the transport of water via a Grotthuss-type mechanism without eliminating H+ transport across the liposomes (Fig. 22f).39a,b However, these hydrophobic porous columns do not allow the transport of Na+, Li+, and Cl ions. The stability of these AQP mimics in phospholipid

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Fig. 22 Molecular models of the helical porous columns self-assembled from the dendritic dipeptide (4Bn-3,4Bn-3,5Bn)12G2-CH2-Boc-L-Tyr-L-AlaOMe (a–e), top view TEM and its Fourier transform together with electron diffraction (f), side view AFM (g) and proton transport through the helical pores reconstituted in phospholipid vesicles (h), vesicles without (left) and with (right) helical porous dendritic dipeptide. Adapted with permission from ref. 39a and b. Copyright 2004 Macmillan Publishers Ltd. (Nature), and 2007 American Chemical Society.

membranes is mediated by the aromatic part of the selfassembling dendron via the principles described in Fig. 11b. These dendritic dipeptides are also models of chiral selection in primitive biological systems.39c

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Biological membrane mimics

Percec’s laboratory discovered that amphiphilic Janus dendrimers self-assemble into vesicles, denoted dendrimersomes (Fig. 23).29,54

Fig. 23 Dendrimersomes and glycodendrimersomes self-assembled in water from amphiphilic Janus dendrimers with different topologies (three examples in the bottom row) and selected examples of hydrophilic and hydrophobic dendrons and carbohydrates used as building blocks.29,40,54,55

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Fig. 24 Cryo-TEM images of onion-like dendrimersomes self-assembled from (3,5)12G1-CH2-L-Ala-(3,4,5)-3EO-G1-(OCH3)3 (structure shown in bottom left side of Fig. 23), in water at concentrations of (a) 0.025 mg mL1, (b) 0.1 mg mL1, (c) 0.2 mg mL1, (d) 0.5 mg mL1, (e) 1 mg mL1, (f) 2 mg mL1 and (g) 2.5 mg mL1. The 3D surface plots shown at the bottom of each panel were generated by transforming the gray scale intensity, or luminance of each pixel in the image into an effective height, with lower (darker) gray scale values being interpreted as greater heights. Reproduces with permission from ref. 30. Copyright 2014 PNAS.

By contrast with liposomes assembled from phospholipids, and other vesicles, dendrimersomes are easily prepared by simple injection of their solution in a water-soluble solvent into water or buffers. The resulting dendrimersomes are monodisperse, impermeable, stable in various media over time, and exhibit excellent mechanical properties.29,54 When conjugated with different carbohydrates in the hydrophilic part, these Janus glycodendrimers self-assemble into vesicles with carbohydrates on their outer surface, denoted glycodendrimersomes.40,55 By performing agglutination assays with biomedically relevant carbohydrate-binding proteins known as lectins, the glycodendrimersomes showed specific and potent bioactivity, demonstrating that glycodendrimersomes provide an efficient mimic of the glycan ligands of biological membranes.40 The study of different topologies of amphiphilic Janus glycodendrimers shows that with the multivalent glycan ligands extending out of the vesicle surface, the glycodendrimersomes formed by twinmixed amphiphilic Janus glycodendrimers exhibited the highest bioactivity.55 These results open pathways to programmed glycan ligands on the surface of biological membrane mimics assembled from amphiphilic Janus glycodendrimers. By screening the amide- and peptide-bonded amphiphilic Janus dendrimers, dendrimersomes with concentric multibilayer structure denoted onion-like dendrimersomes were discovered (Fig. 24).30 The resulting onion-like dendrimersomes have identical spacing between each two bilayers. By simply changing the final concentration of the Janus dendrimers, the dimension and the number of the bilayers of the dendrimersomes can be predicted. Numerous new medical

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applications will derive from these new biological membrane mimics.

8. Concluding remarks When we were invited by the guest editors of this special issue to write a Tutorial Review on ‘‘Complex Dendrimer Systems’’ we were faced with the 265 pages and 1380 references of the last review on this topic published in 2009 in Chemical Reviews that is cited as ref. 4e in this tutorial. The immediate conclusion was that it is impossible in a Tutorial Review to cover most of the aspects even on a very limited and restricted number of topics. Therefore, we decided that the only option was to self-restrict to the first generation self-assembling dendrons defined as minidendrons, minidendrimers, and polymers dendronized with self-assembling minidendrons, the last helping to bridge and compare the efficiency and limitations of covalent and supramolecular chemistry. We were delighted to realize while organizing this Tutorial Review that in many cases the principles involved in the discovery and prediction of the primary structures of selfassembling minidendrons, minidendrimers, and polymers dendronized with minidendrons can be transplanted without special additional structural analysis effort to their higher generations (Fig. 2 and 3). Very few of the assemblies reported in Fig. 2 and from other laboratories were first discovered in higher generations and subsequently in the first generation derived assemblies. Therefore, we believe that this Tutorial Review provides the tools and the main principles involved

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during the transition from primary structure to function in complex dendrimer systems. Since all complex systems emerge via similar principles,2 related periodic table database methodologies to the one reviewed here can be elaborated for all of them. Finally, we apologize to the authors that we have nonintentionally or intentionally omitted from this Tutorial Review, due to the length restrictions of this article type.

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Acknowledgements Financial support by the National Science Foundation (DMR1066116, DMR-1120901 and OISE-1243313), the Humboldt Foundation, and the P. Roy Vagelos Chair at Penn and careful proofreading of the revised manuscript by Benjamin E. Partridge are gratefully acknowledged.

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From structure to function via complex supramolecular dendrimer systems.

This tutorial review summarizes strategies elaborated for the discovery and prediction of programmed primary structures derived from quasi-equivalent ...
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