Merging Macromolecular and Supramolecular Chemistry Into Bioinspired Synthesis of Complex Systems

Home , DuPont Central Research, Giulio Natta, Helmut Ringsdorf, Karl Ziegler, Paul Flory, Supramolecular polymer

Review

DOI: 10.1002/ijch.202000004 Merging Macromolecular and Supramolecular Chemistry into Bioinspired Synthesis of Complex Systems

Virgil Percec*[a]

Abstract: A brief and personalized historical review that after and influenced these developments as well as the describes the merger of macromolecular and supramolecular experience of the author during his stays at the Hermann chemistry to generate the new field of bioinspired synthesis Staudinger House that hosts the Institute of Macromolecular of complex systems is presented. Historical scientific events Chemistry from the University of Freiburg are also part of that took place during the days of Hermann Staudinger and this review. Keywords: macromolecular and supramolecular chemistry · self-assembly · supramolecular dendrimers · helical chirality · polyphenylacetylene

1. Introduction last graduate student of Staudinger, they provided me mentor- ship both for my new life in Germany and in US. 1.1 The Hermann Staudinger House at the University of At that time HSH was the leading educational Institution Freiburg was for Many Years my First Home! in the world of Macromolecular Science. The next few generations of German academics were either graduate In 1981 I defected the country I was born and educated. The students, doing habilitation or being postdocs in the HSH. At Hermann Staudinger House (HSH) that hosts the Institute of that time almost every top scientist in the field would pass by Macromolecular Chemistry at the University of Freiburg was Freiburg for a seminar. Special connections with industry, the first Institution to provide me a new home. Professors H.-J. BASF, BAYER and HOECHST, to mention just few leading Cantow and G. Wegner were its two directors at that time. German companies that ultimately, I ended consulting for, Together with Professor Helmut Ringsdorf (Figure 1),[1a] the made HSH the ideal place where the young generation of future scientists would learn everything about macromolecular chemistry and the real scientific life in a very accelerated way. One month later, a letter from Professor J. P. Kennedy invited me to join his laboratory at the University of Akron. This was an old invitation that dated back to the days of my PhD when I was not allowed to travel even to Eastern countries. Professor Cantow advised me to stay in Germany. When I asked what do you think I would I do in Germany, he stated that most probably I would become a Professor by next year. However, when I decided to go to US the German community continued to provide me with advice and help. The most memorable event in Akron was soon after my arrival when Herman Mark came to give a plenary lecture for the anniversary of the Institute of Polymer Science. I reintroduced myself to him reminding him that I was an undergraduate student in Iasi when he visited to receive a Doctor Honoris Causa. I also mentioned that I defected the country. He shook my hand and said: “Of course I remember you Virgil. Welcome to this country! Now you are one of ours.” I will never forget his cordial welcoming sentence. How could he remember one of

[a] V. Percec Roy & Diana Vagelos Laboratories, Department of Chemistry and Figure 1. Virgil Percec (far left) next to Helmut Ringsdorf, the last Laboratory for Research on the Structure of Matter, University of PhD student of Hermann Staudinger, H.-J. Cantow and Martin Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United Moeller (in the middle) during the IUPAC Symposium in Amherst, States [1a] USA, in 1982. E-mail: [email protected]

Isr. J. Chem. 2020, 60, 1–20 © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 These are not the final page numbers! �� Review the many underdraduate students when he passed though the Research published more papers in JACS per year than lab I was in? This was Herman Mark, the gentleman who Harvard together with Caltech. Not only that they pioneered could build with no money the first school of Polymer Science the field of polymers but also organometallic, metathesis, in US. I felt very bad when few years later he called my office fluorine, supramolecular chemistry to name just a few. I could and invited me to become an Editor of the Journal of Polymer not turn down when several years ago the German community Science. I turned him down saying that I think I am too young asked me to edit a book[1] dedicated to the 60th anniversary of to invest my time in editorial work. When several year later he the Nobel Prize of Hermann Staudinger (Figure 3). called again, I accepted. On March 1, 1982 I joined the I searched through his life and all places he has been Department of Macromolecular Science of Case Western educated or was a faculty, Halle, Strasbourg, Karlsruhe, Reserve University in Cleveland as a faculty. During late Zurich, Freiburg, and to my surprise nobody turned down my 1982, early 1983 when Professor Wegner decided to build the invitation to contribute to this book. As a consequence, the Max Planck Institute for Polymer Research in Mainz and be one volume book became two volumes. In addition, with this its first Director HSH asked me to consider replacing him. occasion I learned about Staudinger more than he would have This was the equivalent of following in the footsteps of liked anybody to know about him except for himself. This book Hermann Staudinger. It was a very hard call for me to turn contains as much as needed to learn everything about down and therefore, I did it as polite as I could: “I had six Staudinger. For these and many other reasons Hermann months during which time I changed between four different Staudinger House was, is and will remain a very special place Departments and Universities located in three different for me. Early polymer studies done before or in parallel by countries located on two different continents. Therefore, I Berzelius, Svedberg, Carothers, Ranby, Flory, Mark, Mora- would prefer to spend some time in one place in order to wetz, Pedersen and many other who contributed to the restart my research activities.” HSH was very friendly at my development of the field of polymer or macromolecular reply and offered me a visiting professor with support for me science were discussed in historical articles and books.[2] I find and my graduate students from US. In the summer of 1984 particularly interesting that even the Nobel Lecture of when I needed more laboratory space at CWRU I was back in Pedersen on supramolecular chemistry discusses polymer Freiburg with three of my graduate students: Brian C. Auman chemistry work done at DuPont Experimental Station.[2j] In (Figure 2), Jose M. Rodriguez-Parada, both now at the Central order to follow in more details the history events discussed Research, Experimental Station of DuPont, known for many here I recommend at least references 1a,b, 2a,f,h and 24d to be years as one of the three Industrial American Universities, the consulted. other two were Bell Labs and IBM, and Timothy D. Shaffer, now at Central Research of Exxon. Soon after I became a faculty, I was invited to consult for DuPont Central Research. 2. How Would Polymer Science be Today if Karl I did it for about 30 years. However, I never visited them for Ziegler Would Have Decided to Pursue in the the consulting fee but for the intellectual challenge of discussing with its top scientists. 1920th–1930th Living Anionic Polymerization I never let my colleagues from Case Western Reserve Rather than Ziegler-Natta Polymerization of University know that in fact I was going to DuPont to take Ethylene? classes at the DuPont Industrial University while I was being paid as a consultant. There were days that DuPont Central In the 1920th to 1930th Karl Ziegler demonstrated that alkyl

Professor Virgil Percec was born and educated in Romania. In 1981 he defected his native country and after short postdoctoral stays at the Hermann Staudinger House of the University of Freiburg and University of Akron he joined Case Western Reserve University on March 1, 1982 as an Assistant Professor. He was promoted to Associate Professor in 1984, to Professor in 1986 and to Leonard Case Jr Chair Professor in 1993. In 1999 he joined University of Pennsylvania as P. Roy Vagelos Chair and Professor of Chemistry. He serves as Editor and on the Editorial Boards of 24 journals, co-authored 775 peer reviewed publications, 60 patents, edited 20 books and gave over 1250 invited, plenary and endowed lectures. He has 3 Doctor Honoris Causa and received numerous awards. Of interest for the readers of this publication are the ACS Award in Polymer Chemistry (2004), Staudinger Medal from ETH (2005), H. F. Mark Medal and Award from the Austrian Institute for Science and Technology (2008), Honorary Member of the Israel Chemical Society (2009), Inaugural ACS Lecture and Award Kavli Foundation Innovations in Chemistry (2011), foreign member of the Royal Swedish Academy of Engineering Sciences IVA (2013), “Petru Poni” Medal of the Romanian Chemical Society (2014), Humboldt Award for Senior US Scientists (1997, 2011), NSF Award for creativity in Research (1990, 1995, 2000, 2015) and the C. Simionescu ACS Award and Medal in collaboration with the Romanian International Chapter for Excellence in Macromolecular Chemistry (2015). He is most known for his work on the elaboration of the stereoisomers of polyarylacetylenes, molecular, macromolecular and supramolecular liquid crystals with complex architecture, discovery and development of Ni-catalyzed Suzuki cross-coupling, borylation and mixed-ligand concepts, discovery of self- assembling dendrimers, elaboration of bioinspired synthesis of complex systems and synthetic cell biology, living polymerization methods for arylacetylenes, for radical and for condensation polymerizations.

Figure 2. Virgil Percec (right) together with his first US graduate student, Brian C. Auman, holding the photo of Staudinger in the HSH in Freiburg, July 1984.

chains of polystyrene and polybutadiene with the reactive organometal end still intact thus demonstrating the absence of chain transfer and termination. These oligomers were the forerunners of the living anionic polymerization. Was Michael Szwarc aware of Ziegler experiments when he discovered in 1956 the living anionic polymerization of styrene via single electron transfer from naphthalene lithium to styrene followed by the dimerization of the styryl radical anion to provide living anionic polymerization in two directions?[4] Most probably not, since at my invitation as editor of the Journal of Polymer Science, the single electron transfer initiation and polymerization process story was told by Szwarc to have been inspired from his visit to the laboratory of Samuel Weissman.[4c] In the early 1950th Karl Ziegler[5a] developed the organometallic- mixed (organoaluminum/titanium compounds known as heter- ogeneous, or homogeneous catalysts with other metals than Figure 3. The two volumes of the book Hierarchical Macromolecular titanium) catalysts, to become later known as Ziegler-Natta Structures: 60 Years after the Staudinger Nobel Prize.[1] catalysts, and produce ultrafast high molecular mass, high density polyethylene. In 1952 Ziegler disclosed this process to Montecatini, and Giulio Natta[5b] a consultant for Montecatini, lithium derivatives were more reactive than the corresponding applied Ziegler’s catalytic system to the polymerization of Grignard reagents.[3] In 1927 Ziegler added stilbene to phenyl- alfa-olefins including propene. Isotactic, syndiotactic and isopropyl potassium to observe a sharp change in the color of atactic names were coined by Rosita Beaty, the wife of Giulio the reaction mixture from red to yellow. This was, most Natta, to describe what organic chemists would name probably, the first addition of an organo alkali metal across a homochiral, heterochiral and racemic, respectively (Figure 4). carbon-carbon double bond. In 1936 Ziegler generated long-

and Alan MacDiarmid discovered soon the extremely high conductivity of polyacetylene films obtained after doping. This provided the explosive research activity on conductive polymers. In the year 2000 Heeger, MacDiarmid and Shirakawa were awarded the Nobel Prize for the Discovery and Development of Conductive Polymers.[8]

4. Helical Stereoisomers of Polyphenylacetylene Merged Macromolecular with Supramolecular Figure 4. The macromolecular chemist and organic chemist defini- Chemistry tions used for stereospecific polymers. During the early 1970th my PhD mentor asked me to overcome the insolubility and intractability of polyacetylene Due to its simplicity, the birth of Ziegler-Natta catalysis, by the synthesis of substituted polyacetylenes. I decided that stereoregular polymers and stereospecific polymerization poly(1-alkyne)s containing alkyl substituents that were already generated instantaneously a tremendous industrial and societal investigated by Natta[9a] and Ciardelli[9b] were not the most impact all over the world. This work also generated most suitable candidates since they were unstable both in the probably the most rapid Nobel Prize recognition in 1963, presence of light, oxygen and at higher temperature than that within less than 10 years from the discovery, to Ziegler and of a refrigerator. Therefore, phenylacetylene and its homo- Natta. Living anionic polymerization was ultimately discov- logues were expected to provide soluble and stable substituted ered by Michael Szwarc in 1956.[4] Block copolymers and polyacetylenes. Immediately I made the models for all cis- chain ended functional polymers were generated from day cisoidal, cis-transoidal, trans-cisoidal and trans-transoidal one. However, its impact on society seems to be less than the stereoisomers of polyphenylacetylene (PPA) and few other one of Ziegler-Natta polymerization even after living proc- aryacetylenes and became very disappointed. These models esses were elaborated for any propagating growing species and showed that none of these PPA were going to be highly classes of monomers. However, no one can predict what would conjugated. At best some of them may exhibit some have been the outcome of polymer science if Ziegler would conjugation and a helical backbone conformation. My main have decided to pursue the living anionic polymerization question was how to transform a failure into a success. My rather than the Ziegler-Natta polymerization, or maybe even decision was very simple. I must learn everything about all both. stereoisomers of PPA and other arylacetylenes and hopefully some interesting functions other than conductivity will emerge. There was some literature already on PPA that was quite confusing. For example, the same Ziegler-Natta catalyst would 3. Ziegler-Natta Polymerization in the Early generate either cis- or trans-PPA. How and why? In addition, 1970th no method to determine the cis- or trans-content and the structure of these isomers was available. Would cis-trans Due to the magic industrial developments produced by the thermal isomerization of PPA in solution and in solid state be Ziegler-Natta polymerization of ethylene and propylene, in the possible? If yes, under what conditions? early 1970th chemists started to investigate the Ziegler-Natta All these questions were answered in a first publication polymerization of acetylene and substituted acetylenes. The that from behind the Iron Curtain took quite some time to get main reason for this interest was the potential conductivity of approved to be submitted for publication to an American the conjugated polyacetylene. In 1958 Natta laboratory journal.[6b] Cis-trans thermal isomerization occurs both in reported the synthesis of insoluble trans-polyacetylene by solution and in solid state. In both cases this isomerization is Ziegler-Natta polymerization of acetylene.[6] Shirakawa and accompanied by an intramolecular electrocyclization that can Ikeda reported the synthesis of both cis- and trans- cleave the chain by aromatization and release of the 1,3,5- polyacetylene.[7a,b] Both isomers of polyacetylene are insoluble triphenylbenzene (Figure 5b).[6b,10,11,12] and intractable. This insolubility creates numerous synthetic It has been shown that if the heat of polymerization is not and practical limitations. In 1974 Ito, Shirakawa and Ikeda removed during the polymerization process, it induces the cis- reported the discovery of a method to prepare films from the trans thermal isomerization during polymerization. NMR and insoluble polyacetylene by Ziegler-Natta polymerization.[7c] IR methods were developed for the quantitative determination During a visit to Tokyo Institute of Technology, my colleague of the cis-trans content of PPA of both the insoluble cis- Alan MacDiarmid, saw the polyacetylene film of Shirakawa cisoidal and for the soluble cis-transoidal stereoisomers. and invited him to Penn to investigate its electrical Methods for the synthesis of all cis- and trans-stereoisomers properties.[8a] Alan J. Heeger together with Hideki Shirakawa of PPA with predetermined cis- and trans-contents were

Figure 5. Intramolecular electrocyclization followed by chain cleavage of cis-transoidal and cis-cisoidal stereoisomers of PPA is eliminated by dendronizing PPA (a). The helix-coil transition accompanied by electrocyclization (b) is eliminated and replaced by an unprecedented helix- helix cis-cisoidal to cis-transoidal transition that provides a molecular machine (c, d, e). Obtained by combining redrawing and rearranging parts of Figure 4 with Figure 5d from ref. [18b] with part of Scheme 1 from ref. [18a]. Reproduces with permission from ref. [18a]. Copyright 2005, American Chemical Society. Reproduces with permission from ref. [18b]. Copyright 2008, American Chemical Society. developed. The cis-cisoidal PPA was shown to be highly to mimic and elucidate helical chirality based biological crystalline and insoluble forming columnar hexagonal crystals events.[15] Chiral stationary phases for the separation of from highly compressed helical structures resembling stacks of enantiomers by HPLC,[16] chiral memory effects,[17] contact 1,3,5-triphenylbenzene. The cis-transoidal PPA was only semi- lenses,[14c,e] and molecular machines interfaced with the real crystalline and soluble and provided a helical conformation life[18] are only few of the many applications that evolved from that represents an elongated form of the compact cis-cisoidal this very active new field of research.[14a,15,19] After the PPA helix (Figure 5). Thermal isomerization both in solution Romanian revolution from 1989 the author was elected as a and in solid state of cis-cisoidal and cis-transoidal PPA Honorary Foreign Member of the Romanian Academy. In provides trans-cisoidal PPA. The temperature at which this 1995, together with a group of scientists, he visited for the first isomerization is performed determines the extent of intra- time Romania and the laboratory in which the helical stereo- molecular electrocyclization and formation of different extents isomers of PPA and intramolecular donor-acceptor complexes of 1,3,5-triphenylbenzene (Figure 5).[6b,10–12] were pioneered (Figure 6). All these conclusions were supported by experiments performed also with the stereoisomers of polypentadeuterophenylacetylene[11] that contained only one proton in the 1H-NMR spectrum, and of other poly(arylacety- 5. From Stereoisomers of PPA to Intra- and lene)s including with electron acceptor side groups.[13] Simpler Inter-Molecular Donor-Acceptor Interactions methods for the synthesis of the stereoisomers of PPA and of other acetylenic monomers including by living polymeriza- Before joining Freiburg, I spent several years using donor- tions were elaborated.[14] Since secondary helical conformation acceptor (DA) non-bonding interactions to mediate the represents one of the most common structural events in copolymerization mechanism and the stereochemistry of the biological systems, the helical cis-conformers of PPA became resulting copolymers[20a,b,c] and to design experiments to one of the most common synthetic helical polymers employed investigate both intramolecular and intermolecular donor-

Figure 6. My first visit back to the laboratory where the helical stereoisomers of PPA and the intramolecular donor-acceptors complexes were designed and synthesized, together with a group of polymer chemists: June 19–20, 1995. Top from left to right: J. Put (Vice-President DSM), M. Sawamoto (Kyoto U), D. A. Tirrell (U Mass), K. Müllen (Director MPI, Mainz), V. Percec (CWRU), S. Kobayashi (Kyoto U). Down from left to right: B. M. Novak (UC Berkeley), C. Pugh (U Michigan, Ann Arbor), K. Matyjaszewski (Carnegie Mellon, U), E. W. Meijer (Eindhoven U). The 75th anniversary of my PhD mentor was also celebrated on this occasion.

acceptor interactions.[20d,e] Cantow’s laboratory in Freiburg was R. Todd Lecture, “Chemie in Vergangenhjeit und Gegenwart.” interested in using non-bonding interactions to mediate the Delivered on the occasion of the “Goldenes Doktordiplom”, design of structure and the properties of complex polymer University of Frankfurt, October 16, 1981. This statement was systems. Therefore, intermolecular DA interaction became a confirmed by the work of J.-M. Lehn. This concept led to the new program in his lab. This work culminated in the molecular development of a universal methodology to co-assemble and design of intermolecular self-organization of amorphous self-repair highly ordered helical supramolecular electronic polymers that could be monitored by an unprecedented organic materials[23] starting from molecular and macromolec- kinetically controlled first order phase decomplexation-recom- ular inactive components (Figure 7). Additional bioinspired plexation transition in the self-organized state.[21] concepts based on this process are in progress in our lab. This first order phase transition that corresponded to the decomplexation-complexation process was employed to deter- [22] mine the equilibrium constant of self-assembly. This work 6. Crown-Ethers and Podants as Receptors to on DA interactions was inspired by the following statement of Lord A. R. Todd, cited on the first page of reference 21b: Mediate Self-Assembly by Molecular Recognition “Apart from consideration of the hydrogen bond, we organic of Supramolecular 2D Assemblies Including chemists have really paid little attention to linkages other than Liquid Crystals purely covalent. I believe that it will be the duty of organic chemists in the future to study the weak, non-bondind The extremely simple and efficient synthesis of functional interactions which are of enormous importance in the large crown-ethers (CE),[24] cryptates[25] and podants[26] provided a natural macromolecules. Such studies will lead to a blossom- powerful tool to mediate self-assembly by precise molecular ing of organic chemistry in the future.” From Lord Alexander recognition. While original experiments were directed with

Figure 7. Self-assembly, co-assembly and self-repairing of supramolecular assemblies and polymers mediated by donor-acceptor interactions. Reproduced with permission from ref. [53]. Copyright 2013, Wiley-VCH Verlag GmbH &Co. KGaA. main-chain and side-chain[27] liquid crystal polymers to see if transition to the next level of molecular and supramolecular liquid crystal phases could tolerate crown-ether (CE) recep- complexity. tors, subsequent experiments were employed to self-organize liquid crystal states via molecular recognition mediated with [28] CE and podants. Molecular recognition directed self- 7. The Discovery of Quasi-Equivalent assembly mediated by crown-ethers and podants provided the first examples of supramolecular polymers and dendrimers Self-Assembling Dendrons, Dendrimers, exhibiting self-regulated high ionic conductivity.[28d,l] Confor- Supramolecular Dendrimers and Polymers and mational, constitutional isomerism and quasi-equivalence were Self-Organizable Dendronized Polymers concepts employed to elaborate LC with complex architecture such as macrocyclics, hyperbranched and dendrimers exhibit- Aaron Klug’s work on the self-assembly of rod-like such as ing conventional LC phases.[29,30] The biphasic concept for the TMV and icosahedral viruses[38] inspired me in 1982 to search decoupling of the main-chain from the side groups in side- for a synthetic strategy to self-organize synthetic homologues chain LC polymers was also elaborated at this time. Living that self-organize similar architectures.[38,39] The history of my ring-opening polymerization of cyclic imino ethers,[31b] of first encounter with Aaron Klug and of the discovery of self- vinyl ethers[31,32] including cyclocopolymerization,[21] and poly- assembling dendrons, supramolecular polymers,[39] merization in LC state,[33] the discovery of LC polyethers supramolecular dendrimers, and self-organizable dendronized including LC polyethers based on conformational isomerism[34] polymers was published by invitation.[40] Figure 8 summarizes were extensively employed to provide a molecular engineering this discovery process.[19a,28b,c,39, 40,41,42,43] approach to main-chain[34] and side-chain LCP[28h–k,35] that Crown ethers, podants and oligomers made by living involved also a theoretical explanation of the correlation polymerization were again used to mediate the self-assembly between virtual, monotropic and enantiotropic phase transi- of dendrons and minidendrons into supramolecular polymers tions and of the corresponding synthetic strategies required to and columnar dendrimers containing an ionic channel along implement these transformations.[36] This already classic work their long axis of the column.[42] The strength of ionic will not be expanded in more details since it was extensively interactions was quantified and compared with that of the reviewed.[28h–k,28°, 37,40,41,42,43] The expertise accumulated in our contribution of covalent bonds.[24–26,42] According to our laboratory on LC and LC polymers (LCP) equipped us with knowledge this was the first and may remain the only the tools needed to approach in a very efficient way the quantitative comparison of a supramolecular backbone with a

Figure 8. Self-assembly and self-organization of dendrimers and dendronized polymers in supramolecular dendrimers or polymers. covalent backbone[41,42] in columnar assemblies generated by chiral both when self-assembled from crown-like[48] or from covalent and supramolecular backbones. Rapid progress on conical dendrons[49] (Figure 10). this work was facilitated by the expertise of our laboratory on the self-organization of conventional calamitic, columnar and of more complex liquid crystal phases..[19a,35,41–44] 9. Bioinspired Synthesis of Complex Functional Systems

8. From Helical Columnar to Helical Spherical We define “bioinspired synthesis” as the methodology that Assemblies and from Structural to Retrostructural involves in the first step the discovery of an achiral, racemic Analysis or homochiral programmed primary structure, of a molecule or macromolecule that self-organizes into secondary, tertiary and Spherical assemblies were discovered in our laboratory almost ultimately into the quaternary structure that encodes a simultaneously with columnar assemblies.[39] However, while particular function. The first step of this methodology is columnar assemblies and even supramolecular polymers were accomplished by scanning through a rationally designed well known since the discovery of columnar liquid crystals by library. After the structural and retrostructural analysis of the the self-assembly of discotic molecules by Chandrasekhar in supramolecular structure generated from the first primary 1977[45] and even much earlier such as the 1952 example of structure discovered and the elucidation of the self-organiza- supramolecular polymer of diisobutylsilanediol,[46] and more tion mechanism a second library containing minimum recently even from liquid crystal polyethers,[34m,n,°] spherical variations of the primary structure already discovered is assemblies were not known. Therefore, it took about 10 years screened in order to discover and ultimately predict additional to elucidate by a combination of X-ray synchrotron experi- primary structures that provide the same function. Complex ments on single domains, combined with electron density systems were discussed and defined in previous maps, transmission electron microscopy (TEM) and isomor- publications.[41,42] For this discussion it is sufficient to mention phous replacement, the structure of the pm3n lattice, known that according to their definition complex systems cannot be also as the Frank-Kasper A15 phase (Figure 9).[47a,b,c] designed and engineered since they evolve, emerge and adapt. In order to understand the mechanism of self-organization Figure 11 illustrates the structural and retrostructural analysis of this lattice from supramolecular spheres, after the distorted concept and methodology. So far, a series of generational columnar model was eliminated,[47] retrostructural analysis of libraries[50] and one deconstruction library[51] were investigated the monodisperse quasi-equivalent spheres forming the A15 by this methodology. phase was elucidated. The supramolecular spheres can be

Figure 9. The electron density maps of the 3D and of the two cross-sections of the A15 phase of monodisperse supramolecular dendrimers or polymers. Designed by combining fragments of Figures 8 and 9, both in black and white, from ref. [47a] with Figure 6 from ref. [47b]. Reproduced with permission from ref. [47a]. Copyright 1997, American Chemical Society. Reproduced with permission from ref. [47b]. Copyright 1998, American Association for the Advancement of Science.

Figure 10. Self-organization of conical and crown-like conformations of dendrimers into chiral spheres and their A15, sigma and liquid quasicrystal assemblies. Reproduced with permission from ref. [52c]. Copyright 2011, Wiley-VCH Verlag GmbH &Co. KGaA.

Aside from the A15 phase originally discovered from soldiers” and “majority rules” are not being employed by supramolecular spheres assembled from conical dendrons, biology were also addressed with these tools (Figure 13).[53,54g,i] A15 generated from crown-like dendrons as well as A15 phases assembled from hollow spherical reactors and from vesicular spheres were discovered[48,49] In addition to the A15 phase a tetragonal and a LC quasicrystal lattice were 10. Supramolecular Spherical Assemblies from discovered.[52,53] Mimics of Aquaporin, AQP (Figure 12a,c,d) Self-Organizable Dendronized Crown-Ethers, and hollow spheres (Figure 12d,e)[54,49a] were also discovered Ion-Pairs, Ionic Liquids by this methodology.[12] A most unusual supramolecular column assembled from A large diversity of functions can be incorporated in the supramolecular spheres was also observed for the first time.[54h] spherical assemblies described above by dendronizing with Fundamental questions such as why the classic “sergeant and self-assembling dendrons the apex of the dendron with different functionalities such as crown ethers, ion-pair, ionic liquids,

dendrimers, etc. When crown-ethers are at the apex, mono- conditions narrow molar mass polymers can be obtained by disperse spherical supramolecular polymers containing uncom- conventional polymerization in dilute solution (Figure 15).[56] plexed or complexed crown-ethers in their core can be When the polymerization is performed in self-assembled generated by self-assembly.[55] These systems can also undergo state, the concentration of the monomer increases dramatically a transition from supramolecular sphere to supramolecular by comparison with its concentration in dilute solution since column. In this case the complexed system can transit from the monomer self-assemble in a microreactor located at the closed ionic reservoir to ionic channel and therefore these center of a supramolecular sphere or column. In both situations systems can behave as a molecular switch. Similar systems a very fast polymerization occurs and polymers with ultrahigh can be accomplished when ion-pairs[55b] ionic liquids[53a,b] or molar mass are obtained in several minutes (Figure 15).[56] even dendrimers[53c] are attached at the apex of the self- When the monomer self-assemble in a globular shape, above a assembling dendron. certain degree of polymerization, the quasi-equivalent dendron changes its conformation from conical to tapered and the resulting polymer changes its shape from globular of spherical 11. Self-Interrupted Radical Polymerization in to columnar (Figure 15). The resulting polymers can display multimillion molar mass that is obtained in several minutes Dilute Solution and Accelerated Radical reaction time. Multimillion molar masses were defined by Polymerization in the Self-Assembled State of Elias as Mega[2g] and therefore these polymers as well as Dendronized Monomers similar supramolecular assemblies are Mega assemblies.[41,56b,c] Alternatively, as predicted by deGennes, both divergent and Dendronized monomers provide a pathway to perform the convergent synthesis of dendrimers can self-interrupt.[56d] polymerization of the monomer in dilute solution or in self- assembled state. Polymerization in dilute solution generates an oligomer with reactivity that decreases as its size increases and eventually at high degree of polymerization can generate a 12. Deracemization in the Crystal State. From self-interruption process. In conventional polymerization re- Racemic or Atactic Supramolecular Polymers to actions the reactivity of the growing species is independent on Homochiral Isotactic Supramolecular Polymers chain length.[2h] I recommend the young generation of scientists to consult Deracemization in solution was pioneered by Pasteur.[57a] Until reference 2h, written by Paul Flory as a basic textbook several years ago it has been considered that there is no motion (Figure 14), in addition to more recent textbooks. However, in in the crystal state and therefore no deracemization in the dendronized monomers that self-organize into spherical crystal state is possible. Recently, a supramolecular polymer assemblies the reactivity decreases and at a certain oligomer assembled from a dendronized CTV crown has been shown to size the polymerization reaction can self-interrupt. Under these undergo deracemization in the columnar crystal state and

Figure 12. Self-assembly of constitutional and conformational isomeric dendritic dipeptides into homochiral helical Aquaporin-like channels and hollow supramolecular spheres. This Figure was designed by combining Figure 2 of ref. [54i], Figure 2e of ref. [54a], and Figure 10a of ref. [49a]. Reproduced with permission from ref. [54a]. Copyright 2004 Springer Nature. Reproduced with permission from ref. [54i]. Copyright 2011, Wiley-VCH Verlag GmbH &Co. KGaA. Reproduces with permission from ref. [49a]. American Chemical Society.

provide a transition from a semi-crystalline racemic assembly 13. A Cogwheel Supramolecular Double Helix or nearly atactic dynamic supramolecular polymer to a that Disregards Chirality crystalline homochiral assembly or stereoregular isotactic polymer. Deracemization in the crystal state was also encountered in a The driving force for this process is provided by the cogwheel supramolecular double helical assembly. Again, the hexagonal crystal lattice of the homochiral assembly (Fig- hexagonal crystallization facilitates both the deracemization ure 16) Since there is a single column in the unit cell of the and the formation of a highly ordered hexagonal crystal of the hexagonal crystal crystallization in a hexagonal array requires perfection that was not encountered even in biology. Most all columns forming it to be homochiral and this provides the unusual is that the cogwheel supramolecular assembly is driving force for deracemization in the crystal state where generated by a benzyl amine dendron attached in a cis- rather solid state NMR demonstrated sufficient motion.[57b] This than trans-conformation. The trans-conformers were usually concept can have tremendous impact on the application of exploited to generate main-chain and side-chain LPCs based supramolecular polymers in recycling. on conformational isomerism,[34] while in the cogwheel assembly process the cis-conformer of the benzyl amine facilitates this new mechanism of self-assembly. Most unusual and unexpected is that the very slow transition to the cogwheel helical assembly can be dramatically accelerated by a

Figure 13. Addressing the question of why sergeants and soldiers and majority rules are no employed by biology by investigating the structure of the supramolecular assemblies and the mechanism of supramolecular polymerization with dendritic dipeptides exhibiting the highest degree of stereochemical purity, enantiopure homochiral, to heterochiral and to partially and fully racemic dendritic dipeptides.[54g,h] Reproduced with permission from ref. [54i]. Copyright 2011, Wiley-VCH Verlag GmbH &Co. KGaA. sequence-defined arrangement of the side groups of the self- assembling dendron (Figure 17).[58]

14. Constructing Unprecedentedly Complex Figure 14. My preferred textbook of Polymer Chemistry. This book Supramolecular Architectures by the was bought from the honorarium I received by giving my first lecture Orientational Memory Effect in US at the Midland Molecular Institute on November 24, 1981, at the invitation of H.-G. Elias (see ref. [2g]). Complete information on the book is in Reference [2h]. The Nobel Laureate Paul Flory signed Recently an orientational memory effect was discovered at the the book in 1982 while visiting my office at CWRU. transition from A15 and BCC assemblies generated from spherical supramolecular dendrimers or polymers upon cooling into a columnar hexagonal assembly.[59a–b] phospholipid membrane components as well as by other Orthogonal (Figure 18a) or tetrahedral (Figure 18b) archi- synthetic building blocks.[60] Polymersomes assembled from tectures of supramolecular columns or supramolecular colum- amphiphilic block copolymers are the most recent entry to this nar polymers that cannot be generated by any other mechanism field. Stability, polydispersity and dimensions together with are self-organized so far only from dendritic crowns. It is not bilayer thickness and method of their preparation are the major yet certain if conical self-assembling dendrons would not be obstacles to be overcomed in order to make progress in this able to generate this orientationl memory effect. We expect field. Recently self-assembling amphiphilic Janus dendrimers that this extremely complex memory effect could be used as a and Janus glycodendrimers have been discovered to self- model to understand diseases created from misfolded assemble by simple injection from an organic solvent such as proteins.[59c] ethanol into water or buffer into monodisperse vesicles with predictable dimensions named dendrimersomes and glycoden- drimersomes exhibiting similar bilayer thickness with that of 15. Synthetic and Hybrid Cells natural cell membranes.[61a–d] They can be co-assembled with bacterial and mammalian cell membranes and their engineered Mimics of biological membranes represent an old topic of surface can generate rafts that are accessible for structural research that is aiming to complement research based on analysis by diffraction and diffraction-like methods.[61e–h]

biological membranes and facilitate rapid progress in the newly developing area named synthetic cell biology.

16. Summary and Outlook

This brief personal historical review that summarizes the merger of macromolecular and supramolecular chemistry into bioinspired synthesis of complex systems based on work mostly from our laboratory did not discuss, due to limited space, related research from other laboratories and unrelated but complementary research from our laboratory. The early events of living condensation polymerization,[26a,62,63] single electron transfer mediated condensation polymerization by radical anion[64] and radical cation[65] processes, metal catalyzed living radical polymerizations initiated with aryl halides and SET-LRP,[66] the replacement of Pd with Ni in Suzuki and Stille cross-coupling based mostly on CÀO electrophiles, borylation reaction, mixed-ligand effect and sigma Ni- complexes[67] that were extensively used to facilitate the research summarized here were not discussed at all. However, we expect that this very condensed, brief and personalized review will be inspirational since it bridges between macro- Figure 15. Conventional radical polymerizations of conical dendron- molecular chemistry some of it accomplished during the days ized monomers and the structure and shape of the resulting of Staudinger. Carothers and Flory work performed at the polymers. Adapted from Figure 2 of ref. [56b]. Copyright 1998 Experimental Station of DuPont[2f,h,24] paved the way to the Springer Nature. current state of the art in the field. Additional historical events of the field are well documented.[2a–f,h] Reviews from our laboratory and other laboratories discuss the definition of They also have been shown to exhibit the proper complex systems and their implications to different complex combination of properties that facilitates the endocytosis of systems including society.[25,42,43,68,69] Frank-Kasper living bacteria in the absence of the machinery of natural cells supramolecular assemblies discovered in supramolecular den- (Figure 19).[61i] This evolving field of research is expected to drimers by our laboratory in 1997,[47] 2003 and 2004[52] started complement all previous methodologies elaborated to mimic to be discovered in block copolymers, surfactants, DNA nanoparticles and in many other assemblies.[52d,69] They were

Figure 16. Isotactic (homochiral) supramolecular polymers by stereo-sequence rearrangement of dynamic atactic (racemic) polymers in crystal state. Reproduced with permission from ref. [57b]. Copyright 2014, American Chemical Society.

Figure 17. The cogwheel mechanism of self-organization of dendronized perylene bisimides. Adapted from Figure 1 of Ref. [58b]. Reproduced with permission from ref. [58b]. Copyright 2019, American Chemical Society.

Figure 18. The orientational memory effect forming orthogonal columnar (a) and tetrahedral assemblies (b) of supramolecular columns upon cooling from the A15 and BCC cubic phases to the columnar hexagonal phase. Adapted from Figure 2 of Reference 59c. Reproduced with permission from ref. [59c]. Copyright 2018, Royal Society of Chemistry.

not discussed here. The beautiful story of one week of lectures different place. If bioinspired synthesis will ever be able to given in front of Sir Charles Frank at the university of Bristol, design and predict complex systems the biggest beneficiary the Frank from Frank-Kasper phases, in UK will be told in a will not be only science but also society since society is

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V. Percec* 1 – 20 Merging Macromolecular and Supramolecular Chemistry into Bi- oinspired Synthesis of Complex Systems