Virgil Percec

Constitutional isomerism has been previously demonstrated by one of our laboratories to represent a powerful design strategy for the elaboration of complex functional self-organizations. Here we report the design, synthesis, and characterization of 14 positional, skeletal, and functional constitutional isomeric one-component, multifunctional, sequence-defined, amphiphilic ionizable Janus dendrimers (IAJDs). Their coassembly by simple injection with luciferase mRNA (Luc-mRNA) to form dendrimersome nanoparticles (DNPs) was studied. Subsequently, the resulting DNPs were employed to investigate, with screening experiments, the delivery of Luc-mRNA in vivo. Constitutional isomerism was shown to produce changes of up to two orders of magnitude of the total-body luciferase activity and targeted luciferase activity to the spleen and liver, of up to three orders of magnitude difference in targeted luciferase activity …

This Perspective is dedicated to the 25th Anniversary of Biomacromolecules. It provides a personal view on the developing field of the polymer and biology interface over the 25 years since the journal was launched by the American Chemical Society (ACS). This Perspective is meant to bridge an article published in the first issue of the journal and recent bioinspired developments in the laboratory of the corresponding author. The discovery of supramolecular spherical helices self-organizing into Frank–Kasper and quasicrystals as models of icosahedral viruses, as well as of columnar helical assemblies that mimic rodlike viruses by supramolecular dendrimers, is briefly presented. The transplant of these assemblies from supramolecular dendrimers to block copolymers, giant surfactants, and other self-organized soft matter follows. Amphiphilic self-assembling Janus dendrimers and glycodendrimers as mimics of …

Amphiphilic Janus dendrimers (JDs) are constructed from hydrophobic and hydrophilic dendrons, providing a synthetic alternative to lipids in drug delivery applications. These JDs self-assemble into vesicles called dendrimersomes (DSs) with tunable structural characteristics and can encapsulate both hydrophobic cargo as well as nucleic acids. Compared to liposomes, DSs demonstrate enhanced stability due to increased intermolecular interactions between aromatic branching centers and due to an increase in the number of hydrophobic chains per molecule. Despite these attractive characteristics, drug delivery functionality is limited because decorating the periphery of DSs with biomacromolecules such as proteins and nucleic acids remains a challenge. Here, we report the successful conjugation of azide-modified JDs to alkyne-modified DNAs using copper-catalyzed click chemistry. These 16-nucleotide DNA …

Amphiphilic Janus dendrimers (JDs), synthetic alternatives to lipids, have the potential to expand the scope of nanocarrier delivery systems. JDs self-assemble into vesicles called dendrimersomes, encapsulate both hydrophobic cargo and nucleic acids, and demonstrate enhanced stability in comparison to lipid nanoparticles (LNPs). Here, we report the ability to enhance the cellular uptake of Janus dendrimersomes using DNA aptamers. Azido-modified JDs were synthesized and conjugated to alkyne-modified DNAs using copper-catalyzed azide alkyne cycloaddition. DNA-functionalized JDs form nanometer-sized dendrimersomes in aqueous solution via thin film hydration. These vesicles, now displaying short DNAs, are then hybridized to transferrin receptor binding DNA aptamers. Aptamer-targeted dendrimersomes show improved cellular uptake as compared to control vesicles via fluorescence microscopy and …

After a brief introduction highlighting the challenges of fluorine chemistry and the latest developments in the field, this Perspective will discuss how a combination of fluorine and fluorous chemistry together with fluorinated reagents helped to bridge between organic, molecular, macromolecular, supramolecular and biological sciences to create functions in the laboratory of the corresponding author. The reactivity of fluoride as a leaving group is best illustrated by SNAr reactions when it helped to demonstrate single electron transfer-mediated side reactions and through molecular design replaced activated aryl fluorides with aryl chlorides in the synthesis of poly(etherketone)s. Subsequently it was demonstrated how Ni(II) sigma complexes provided an orthogonal approach to the Suzuki-type cross-coupling of arylfluorides, other halides and all aryl C–O based electrophiles. Fluorinated reagents facilitated …

In 2022, the Nobel Prize in Chemistry was awarded to Bertozzi, Meldal, and Sharpless “for the development of click chemistry and biorthogonal chemistry”. Since 2001, when the concept of click chemistry was advanced by Sharpless laboratory, synthetic chemists started to envision click reactions as the preferred choice of synthetic methodology employed to create new functions. This brief perspective will summarize research performed in our laboratories with the classic Cu(I)-catalyzed azide-alkyne click (CuAAC) reaction elaborated by Meldal and Sharpless, with the thio-bromo click (TBC) and with the less-used, irreversible TERminator Multifunctional INItiator (TERMINI) dual click (TBC) reactions, the last two elaborated in our laboratory. These click reactions will be used to assemble, by accelerated modular-orthogonal methodologies, complex macromolecules and self-organizations of biological relevance. Self-assembling amphiphilic Janus dendrimers and Janus glycodendrimers together with their biological membrane mimics known as dendrimersomes and glycodendrimersomes as well as simple methodologies to assemble macromolecules with perfect and complex architecture such as dendrimers from commercial monomers and building blocks will be discussed. This perspective is dedicated to the 75th anniversary of Professor Bogdan C. Simionescu, the son of my (VP) Ph.D. mentor, Professor Cristofor I. Simionescu, who as his father, took both science and science administration in his hands, and dedicated his life to handling them in a tandem way, to their best.

Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics.

Helical self‐organizations are, most probably, the broadest class of complex systems encountered for billions of years in natural phenomena, for several thousands of years in art and architecture, for few thousand years in early examples of machines, and since about only 1950 in covalent and supramolecular biological and synthetic assemblies and macromolecules. They occur at all length scales, from mega to nano, and emerge in functions that are responsible for life and affect, sometimes in a dramatic and irreversible way by self‐control and adaptation, our way of life. This chapter will first introduce the reader to complex systems and derived functions. It will subsequently present examples of complex helical self‐organizations in art, architecture, early examples of machines, and natural phenomena. The discovery of helical self‐organizations in biology provided the pioneers of the …

The principles for the selection of the stereochemistry of phospholipids of biological membranes remain unclear and continue to be debated. Therefore, any new experiments on this topic may help progress in this field. To address this question, three libraries of constitutional isomeric glycerol-amphiphilic Janus dendrimers (JDs) with nonsymmetric homochiral, racemic, and symmetric achiral branching points were synthesized by an orthogonal–modular–convergent methodology. These JDs amplify self-assembly, and therefore, monodisperse vesicles known as dendrimersomes (DSs) with predictable dimensions programmed by JD concentration were assembled by rapid injection of their ethanol solution into water. DSs of homochiral JD enantiomers, racemic, including mixtures of different enantiomers, and achiral exhibited similar DS size-concentration dependence. However, the number of bilayers of DSs …

DMSO, an interesting solvent for copper‐catalyzed living radical polymerization (LRP) mediated by disproportionation, does not exhibit the greatest disproportionation of Cu(I)X into Cu(0) and Cu(II)X2. Under suitable conditions, DMSO provides 100% conversion and absence of termination, facilitating the development of complex‐architecture methodologies by living and immortal polymerizations. The mechanism yielding this level of precision is being investigated. Here we compare Cu(0)‐wire‐catalyzed LRP of methyl acrylate mediated by disproportionating ligands tris(2‐dimethylaminoethyl)amine, Me6‐TREN, tris(2‐aminoethyl)amine, TREN, and Me6‐TREN/TREN = 1/1 in presence of eight disproportionating solvents, some more efficient than DMSO in disproportionation. Unexpectedly, we observed that all solvents increased the rate of polymerization when monomer concentration decreased. This reversed …

All activities of our daily life, of the nature surrounding us and of the entire society and its complex economic and political systems are affected by stimuli. Therefore, understanding stimuli-responsive principles in nature, biology, society, and in complex synthetic systems is fundamental to natural and life sciences. This invited Perspective attempts to organize, to the best of our knowledge, for the first time the stimuli-responsive principles of supramolecular organizations emerging from self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers. Definitions of stimulus and stimuli from different fields of science are first discussed. Subsequently, we decided that supramolecular organizations of self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers may fit best in the definition of stimuli from biology. After a brief historical introduction to the discovery and development of conventional and self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers, a classification of stimuli-responsible principles as internal- and external-stimuli was made. Due to the enormous amount of literature on conventional dendrons, dendrimers, and dendronized polymers as well as on their self-assembling and self-organizable systems we decided to discuss stimuli-responsive principles only with examples from our laboratory. We apologize to all contributors to dendrimers and to the readers of this Perspective for this space-limited decision. Even after this decision, restrictions to a limited number of examples were required. In spite of this, we expect that this Perspective will provide a new …

Herman Francis Mark produced brilliant contributions to the fields of organic chemistry, structural chemistry, molecular biology, and polymer science in academia and in industry in four different countries from two continents. This Legacy article outlines the author's view on how Mark, who was universally known as the father of polymer science, also pioneered the science, education, publishing, and lecturing styles for the fields of structural chemistry and molecular biology with his disciplined and elegant leadership.

Delivery of nucleic acids with viral and synthetic vectors has pioneered genetic nanomedicine. Four-component lipid nanoparticles (LNPs) consisting of ionizable lipids, phospholipids, cholesterol, and PEG-conjugated lipids, assembled by microfluidic or T-tube, are the benchmark synthetic vector for delivery of mRNA. One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery systems for mRNA were developed by us to complement LNPs. IAJDs consist of multifunctional hydrophilic low-generation dendrons or minidendrons conjugated to hydrophobic dendrons. They were inspired by amphiphilic Janus dendrimers and glycodendrimers. IAJDs coassemble with mRNA into predictable-size vesicles, named dendrimersome nanoparticles (DNPs), by simple injection in acetate buffer, rather than by the complex technology required by LNPs. Assembly of DNPs by simple …

2,3,6,7,10,11-Hexakis(alkyloxy)triphenylene (HATn) containing n = 4 to 12 carbons in its alkyl groups, are a classic group of discotic molecules self-organizing columnar liquid crystals. The structure of the crystalline assemblies of these discotic molecules were neglected since they were invented 45 years ago. Recently, we discovered that the crystal state of HAT4 consists of a highly ordered 8/1 helical chiral pyramidal 3D self-organization. In this publication we report the structural analysis of all 3D self-organizations of HATn containing n = 4 to 12 carbons in their achiral alkyls. Unexpectedly, the highly ordered 8/1 helical chiral pyramidal crystalline columns assembled from the crown-conformation of HAT4 is encountered also in the crystalline periodic array of HAT5. HAT6 self-organizes a 5/1 helical chiral pyramidal 3D column. HAT7 to HAT10 maintain their crown conformation in their 3D supramolecular pyramidal …

The evolution and development of several examples of functionality-tolerant living polymerizations to the level of perfection that they could be employed to solve fundamental concepts in supramolecular science by living polymerization of self-assembling monomers and self-organizable dendronized monomers is briefly reviewed. The review focuses on the development of the living polymerization methodology with brief examples on how they impacted the field of self-assembly and self-organization. The first polymerization reaction discussed is the stereoselective polymerization of phenylacetylene and of other arylacetylenes to generate helical poly(arylacetylene) stereoisomers. The transition from functionality non-tolerant to functionality-tolerant stereoselective polymerizations and the evolution to functionality-tolerant living stereoselective polymerization of phenylacetylene is used as the main example of this brief …

This Backstory outlines the author's view on why it took over 2,000 years between the discoveries of the first helical machine, known as the Archimedes screw, used even today as an irrigation pump and energy generator, and the molecular helix. Between 1950 and 1953, the α-helix of proteins and the double helix of DNA were discovered. Scientific failures leading to success via competition between worldwide laboratories and the minds of significant contributors involved in these failures and discoveries are briefly discussed.

The accurate spatial segregation into distinct phases within cell membranes coordinates vital biochemical processes and functionalities in living organisms. One of nature’s strategies to localize reactivity is the formation of dynamic raft domains. Most raft models rely on liquid-ordered L0 phases in a liquid-disordered Ld phase lacking correlation and remaining static, often necessitating external agents for phase separation. Here, we introduce a synthetic system of bicomponent glycodendrimersomes coassembled from Janus dendrimers and Janus glycodendrimers (JGDs), where lactose–lactose interactions exclusively drive lateral organization. This mechanism results in modulated phases across two length scales, yielding raft-like microdomains featuring nanoarrays at the nanoscale. By varying the density of lactose and molecular architecture of JGDs, the nanoarray type and size, shape, and spacing of the …

Liquid crystals of disc-like molecules are known for 45 years. 2,3,6,7,10,11-Hexakis(alkyloxy)triphenylene (HATn) containing n = 4 to 11 carbons in its achiral alkyl groups, represents one of the classic families of disc-like molecules. X-ray analysis suggested that disc-like molecules stack on top of each other at irregular spacing in columns distributed in the melt of their alkyl groups forming discotic or columnar or discotic nematic liquid crystals. Interest in discotic liquid crystals comes mostly from their conducting and photoconducting properties. While writing a recent perspective on the 45th anniversary of discotic liquid crystals we realized that the molecular structures of the 3D crystal and 2D liquid crystal phases of discotic molecules were never determined at the molecular level, in spite of the great interest in their physical properties. Since structure determines function, we decided to perform a detailed investigation …

Cu(0)-catalyzed single-electron transfer-living radical polymerization (SET-LRP) has shown great potential for applications in which well-defined chain end-functionalized polymers are demanded as final products or as intermediates. However, the use of polar reaction media favoring the disproportionation of Cu(I)X species into Cu(0) and Cu(II)X2 was considered a limiting factor specially in the synthesis of complex hydrophobic polymers with functional chain ends. “Self-generated” biphasic systems, in which the polymer phase-separates from the homogeneous reaction mixture above a certain molecular weight, together with fundamental studies on the role of solvent, including catalytic solvent effect, and methodological developments such us the “mixed-ligand” concept served as inspiration, although sometimes in an unknown way, to solve this problem. Today, SET-LRP of both acrylic and methacrylic vinyl …

Building functional mimics of cell membranes is an important task toward the development of synthetic cells. So far, lipid and amphiphilic block copolymers are the most widely used amphiphiles with the bilayers by the former lacking stability while membranes by the latter are typically characterized by very slow dynamics. Herein, a new type of Janus dendrimer containing a zwitterionic phosphocholine hydrophilic headgroup (JDPC) and a 3,5‐substituted dihydrobenzoate‐based hydrophobic dendron is introduced. JDPC self‐assembles in water into zwitterionic dendrimersomes (z‐DSs) that faithfully recapitulate the cell membrane in thickness, flexibility, and fluidity, while being resilient to harsh conditions and displaying faster pore closing dynamics in the event of membrane rupture. This enables the fabrication of hybrid DSs with components of natural membranes, including pore‐forming peptides, structure …

Metal-chelating ligands such as nitrilotriacetic acid (NTA) bind to polyhistidine-tagged (His-tagged) proteins. Lipids conjugated to NTA are widely used to decorate the surface of liposomes with proteins in cell biology applications. Multivalent NTA ligands such as tris-nitrilotriacetic acid (TrisNTA) display higher affinities than the monovalent NTA when co-assembled with phospholipids and cholesterol in liposomes. However, there is a limited number of available lipids conjugated to NTA and only few are commercially available. Additionally, their activity diminishes during storage or upon exposure to air. Here we report a library of five amphiphilic Janus dendrimers conjugated to NTA (JD-NTA) and three to TrisNTA (JD-TrisNTA). Both JD-NTA and JD-TrisNTA are indefinitely stable at room temperature in air and preliminary results demonstrate that they co-assemble with phospholipids and cholesterol into liposomes …

The first generation self-assembling dendron (4Bp-3,4)nG1CO2CH3 where Bp is biphenyl, n is an achiral linear, n-dodecyl, or branched chiral alkyl group, (S)-3,7-dimethyl-octyl (dm8*) undergoes helical self-organization in bulk state and in solution. The supramolecular columns assembled from this dendron are helical, regardless, if the alkyl groups on its periphery are achiral or chiral. This demonstrates self-organization of helical columns both from achiral and chiral dendrons and reveals that the role of the stereocenter is to select the helical sense of an already helical column. This very simple self-assembling dendron can be subjected to a large diversity of chemical modifications and functionalization, all expecting to maintain the helical function in bulk and in solution in the range of temperature of interest to investigate helical self-organization and supramolecular polymerization.

Programming living and soft complex matter via primary structure and self-organization represents the key methodology employed to design functions in biological and synthetic nanoscience. Memory effects have been used to create commercial technologies including liquid crystal displays and biomedical applications based on shape memory polymers. Supramolecular orientational memory (SOM), induced by an epitaxial nucleation mediated by the close contact spheres of cubic phases, emerged as a pathway to engineer complex nanoscale soft matter of helical columnar hexagonal arrays. SOM preserves the crystallographic directions of close contact supramolecular spheres from the 3D phase upon cooling to the columnar hexagonal periodic array. Despite the diversity of 3D periodic and quasiperiodic nanoarrays of supramolecular dendrimers, including Frank-Kasper and quasicrystal, all examples of SOM to …

Primary structure endows tertiary structure while tertiary structure determines function. This fundamental principle is responsible for the generation of high order and precise functions in both biological assemblies including giant and mega proteins and nucleic acids as well as in metals generated from only few atoms. However, this size-independent ability to generate high order and very precise functions is not yet accessible in non-biological assemblies that use the same principles for their hierarchical self-organization. Here we report a study investigating the role of the molecular parameters on the hierarchical self-organizations of helical columnar assemblies produced from the column-forming self-assembling dendron (4-3,4-3,5)-X with a linear or branched hydrogenated or linear semifluorinated alkyl groups while apex is -CO2CH3 or -CH2OH. A combination of differential scanning calorimetry, small and wide …

The shape, breadth, and average molecular weight of the overall molecular weight distribution (MWD) largely define polymer properties. In conventional free-radical polymerization, control over this distribution is through the many competing kinetic pathways dominated by radical termination events. “Living” radical polymerization mechanistically minimizes these termination events, providing a facile route to a desired Gaussian distribution with the distribution breadth dependent upon the activity of the catalyst or modulating agent. However, producing unusually shaped distributions can only be achieved through modeling of the complex polymerization kinetics and invoking feeding and other methods. Here, we construct square, slanted, and chair-like MWDs by blending two to four polymers made using a low-reactive RAFT agent with dispersities close to 2. The synthesis of these polymers, unlike that of polymers …

We report a green solvent-to-polymer upgrading transformation of chemicals of the lactic acid portfolio into water-soluble lower critical solution temperature (LCST)-type acrylic polymers. Aqueous Cu(0)-mediated living radical polymerization (SET-LRP) was utilized for the rapid synthesis of N-substituted lactamide-type homo and random acrylic copolymers under mild conditions. A particularly unique aspect of this work is that the water-soluble monomers and the SET-LRP initiator used to produce the corresponding polymers were synthesized from biorenewable and non-toxic solvents, namely natural ethyl lactate and BASF's Agnique® AMD 3L (N,N-dimethyl lactamide, DML). The pre-disproportionation of Cu(I)Br in the presence of tris[2-(dimethylamino)ethyl]amine (Me6TREN) in water generated nascent Cu(0) and Cu(II) complexes that facilitated the fast polymerization of N-tetrahydrofurfuryl lactamide and N,N …

A library of triphenylene (Tp) dendronized with self-assembling dendrons via a diethylene glycol linker was synthesized and the corresponding self-organizations were analyzed. They self-organize via a crown conformation in helical columns and spherical helices that produce hexagonal columnar, Frank-Kasper and soft quasicrystal assemblies. The same self-organizations are produced in the absence of the diethylene glycol linker except that the phase transitions and isotropization temperatures occur at lower temperatures in the presence of the linker. The incorporation of the flexible diethylene glycol linker induces also strong π-π stacking in helical columns. Spherical helices are spherical distorted short fragments of helical columns and therefore the same principles determine the thermal stability of the hexagonal columnar and of Frank-Kasper and quasicrystal assemblies except that the length of the …

Viral and synthetic vectors for the delivery of nucleic acids were key to the rapid development of the extraordinarily efficient Covid-19 vaccines and of genetic nanomedicine. The four-component lipid nanoparticles, statistically distributed in nanoparticles, are the leading delivery non-viral vector used by BioNTech/Pfizer and Moderna to access their Covid-19 mRNA vaccines. Here we report the molecular design principles to target mRNA delivery and activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer system derived from plant phenolic acids. The precise location of the functional groups in the one-component system demonstrates target being induced by the hydrophilic region and activity by the hydrophobic domain of the Janus. These principles, and a hypothetic mechanism explaining them, simplify preparation, handling and storage of vaccines, reduce price, while employing renewable starting materials. Therefore, an increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics may become available by simple molecular design principles.

Primary structure endows the tertiary structure while the tertiary structure determines the function of hierarchical self-organizations. This is a well-established fundamental principle both for biological and non-biological synthetic assemblies. The role of the conformational flexibility-rigidity in this process is less understood. Here we select the conformationally flexible monodisperse tetramer of veratrole, 2, 3, 7, 8, 12, 13, 17, 18-octamethoxy-5, 10, 15, 20-tetrahydrotetrabenzo [a, d, g, j]-cyclododecatetraene, known as cyclotetraveratrylene (CTTV) and use it as an apex model to compare with the less flexible corresponding trimer known as cyclotriveratrylenes (CTV) and with the rigid triphenylene (Tp) and 1, 3, 5-trihydroxybenzene (THB) when dendronized with libraries of self-assembling dendrons and with n-alkyl groups. Unexpectedly, a large diversity of chiral helical assemblies including supramolecular columns …

In 1977 Chandrasekhar laboratory reported the first examples of a new class of thermotropic liquid crystals self-organized from planar disc-like molecules substituted with alkyl groups. X-ray analysis demonstrated that these disc-like molecules stack on top of each other at irregular spacing in columns located in the paraffin melt of their alkyl groups. These supramolecular columns self-organize in a hexagonal array defined as the new thermotropic discotic or columnar hexagonal liquid crystal phase. This new thermotropic liquid crystal phase has translational periodicity in two dimensions and liquid-like disorder in the third one, along the column axis. In 2002 Bushby and Lozman dedicated a brief review article to the 25 anniversary of discotic liquid crystals. This review also included a brief discussion of supramolecular discs and columns self-organized from self-assembling dendrons and dendrimers. The current …

Viral and synthetic vectors for delivery of nucleic acids impacted genetic nanomedicine by aiding the rapid development of the extraordinarily efficient Covid-19 vaccines. Access to targeted delivery of nucleic acids is expected to expand the field of nanomedicine beyond most expectations. Both viral and synthetic vectors have advantages and disadvantages. The major advantage of the synthetic vectors is their unlimited synthetic capability. The four-component lipid nanoparticles (LNPs) are the leading nonviral vector for mRNA used by Pfizer and Moderna in Covid-19 vaccines. Their synthetic capacity inspired us to develop a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA. The first experiments on IAJDs provided, through a rational-library design combined with orthogonal-modular accelerated synthesis and sequence control in their …

Rosalind Franklin's short scientific carrier produced brilliant contributions to the structure of carbon, DNA, and helical and spherical viruses. At 30, she was a recognized authority who switched from carbon to DNA research and, a few years later, to nucleic-acid-protein complexes known as viruses. She made landmark contributions that led to two Nobel Prizes. She did not receive or witness either of them. 100 years after her birthday, Franklin's scientific contributions are even more important now than during her lifetime.

Five libraries of natural and synthetic phenolic acids containing five AB3, ten constitutional isomeric AB2, one AB4, and one AB5 were previously synthesized and reported by our laboratory in 5 to 11 steps. They were employed to construct seven libraries of self-assembling dendrons, by divergent generational, deconstruction, and combined approaches, enabling the discovery of a diversity of supramolecular assemblies including Frank–Kasper phases, soft quasicrystals, and complex helical organizations, some undergoing deracemization in the crystal state. However, higher substitution patterns within a single dendron were not accessible. Here we report three libraries consisting of 30 symmetric and nonsymmetric constitutional isomeric phenolic acids with unprecedented sequenced patterns, including two AB2, three AB3, eight AB4, five AB5, six AB6, three AB7, two AB8, and one AB9 synthesized by accelerated …

Helical architectures including artwork and monuments, such us the Trajan’s column from Rome, were constructed as early as in the year 113 while the assemblies and the self-organizations of biological and synthetic macromolecules, only started to be discovered, elucidated and respectively designed during the early 1950s. This personalized account will first provide a historical journey starting from the Trajan’s column, that represents a classic mesoscopic helical architecture, to nanoscale biological macromolecules such as proteins, nucleic acids, carbohydrates and to supramolecular helical co-assemblies of proteins with nucleic acids, such as tobacco mosaic virus (TMV). It will continue with examples of synthetic helical covalent and supramolecular macromolecules. Their emerging functions ranging from mesoscopic scale to nanoscale and the current limitations of synthetic helical self-organizations will …

Homochiral helical self‐organizations provide some of the most fundamental architectures of biological macromolecules and of their co‐assemblies although they were first discovered and elucidated only during the early 1950. Helical synthetic covalent macromolecules started to be discovered soon after and were followed by supramolecular macromolecules and their co‐assemblies few decades later. This perspective will provide a brief historical development of chiral helical self‐organizations in biology and in supramolecular chemistry. Helical covalent and supramolecular macromolecules self‐organize and co‐organize helical supramolecular columns and spherical helices that can generate complex liquid crystals, crystals including Frank‐Kasper phases, and quasicrystals. The design of new functions based on synthetic helical assemblies will also be discussed. Personal events from the life of scientists …

The small 3-O-sulfated galactose head group of sulfatides, an abundant glycosphingolipid class, poses the (sphinx-like) riddle on involvement of glycan bridging by tissue lectins (sugar code). First, synthesis of head group derivatives for functionalization of amphiphilic dendrimers is performed. Aggregation of resulting (biomimetic) vesicles, alone or in combination with lactose, demonstrates bridging by a tissue lectin (galectin-4). Physiologically, this can stabilize glycolipid-rich microdomains (rafts) and associate sulfatide-rich regions with specific glycoproteins. Further testing documents importance of heterobivalency and linker length. Structurally, sulfatide recognition by galectin-8 is shown to involve sphingosine's OH group as substitute for the 3′-hydroxyl of glucose of lactose. These discoveries underscore functionality of this small determinant on biomembranes intracellularly and on the cell surface. Moreover …

Efficient viral or nonviral delivery of nucleic acids is the key step of genetic nanomedicine. Both viral and synthetic vectors have been successfully employed for genetic delivery with recent examples being DNA, adenoviral, and mRNA-based Covid-19 vaccines. Viral vectors can be target specific and very efficient but can also mediate severe immune response, cell toxicity, and mutations. Four-component lipid nanoparticles (LNPs) containing ionizable lipids, phospholipids, cholesterol for mechanical properties, and PEG-conjugated lipid for stability represent the current leading nonviral vectors for mRNA. However, the segregation of the neutral ionizable lipid as droplets in the core of the LNP, the “PEG dilemma”, and the stability at only very low temperatures limit their efficiency. Here, we report the development of a one-component multifunctional ionizable amphiphilic Janus dendrimer (IAJD) delivery system for …

The vital functions of cell membranes require their ability to quickly change shape to perform complex tasks such as motion, division, endocytosis, and apoptosis. Membrane curvature in cells is modulated by very complex processes such as changes in lipid composition, the oligomerization of curvature-scaffolding proteins, and the reversible insertion of protein regions that act like wedges in the membrane. But, could much simpler mechanisms support membrane shape transformation? In this work, we demonstrate how the change of amphiphile topology in the bilayer can drive shape transformations of cell membrane models. To tackle this, we have designed and synthesized new types of amphiphiles—Janus dendrimers—that self-assemble into uni-, multilamellar, or smectic-ordered vesicles, named dendrimersomes. We synthesized Janus dendrimers containing a photo-labile bond that upon UV-Vis irradiation …

The effect of the two‐dimensional glycan display on glycan‐lectin recognition remains poorly understood despite the importance of these interactions in a plethora of cellular processes, in (patho)physiology, as well as its potential for advanced therapeutics. Faced with this challenge we utilized glycodendrimersomes, a type of synthetic vesicles whose membrane mimics the surface of a cell and offers a means to probe the carbohydrate biological activity. These single‐component vesicles were formed by the self‐assembly of sequence‐defined mannose‐Janus dendrimers, which serve as surrogates for glycolipids. Using atomic force microscopy and molecular modeling we demonstrated that even mannose, a monosaccharide, was capable of organizing the sugar moieties into periodic nanoarrays without the need of the formation of liquid‐ordered phases as assumed necessary for rafts. Kinetics studies of …

Targeted and efficient delivery of nucleic acids with viral and synthetic vectors is the key step of genetic nanomedicine. The four-component lipid nanoparticle synthetic delivery systems consisting of ionizable lipids, phospholipids, cholesterol, and a PEG-conjugated lipid, assembled by microfluidic or T-tube technology, have been extraordinarily successful for delivery of mRNA to provide Covid-19 vaccines. Recently, we reported a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) synthetic delivery system for mRNA relying on amphiphilic Janus dendrimers and glycodendrimers developed in our laboratory. Amphiphilic Janus dendrimers consist of functional hydrophilic dendrons conjugated to hydrophobic dendrons. Co-assembly of IAJDs with mRNA into dendrimersome nanoparticles (DNPs) occurs by simple injection in acetate buffer, rather than by microfluidic …

Glycan-lectin recognition is vital to processes that impact human health, including viral infections. Proceeding from crystallographical evidence of case studies on adeno-, corona-, and rotaviral spike proteins, the relationship of these adhesins to mammalian galectins was examined by computational similarity assessments. Intrafamily diversity among human galectins was in the range of that to these viral surface proteins. Our findings are offered to inspire the consideration of lectin-based approaches to thwart infection by present and future viral threats, also mentioning possible implications for vaccine development.

Frank-Kasper phases are available in both hard and soft complex matter. They have been discovered in metal alloys and subsequently in self-organisations of supramolecular spheres from self-assembling dendrons, dendrimers and dendronized polymers. Recently, they were found in block copolymers, lipids, surfactants, giant surfactants, nanoparticles, DNA particles and even in condensed small molecules such as N2, O2, and CO. Here we report the discovery of an amphiphilic Janus dendrimer, that self-assembles in water into vesicles known as dendrimersomes, self-organised also in bulk state into helical columns and spheres forming columnar hexagonal and a Frank-Kasper A15 phase known as Pmn. These self-organisations display a supramolecular orientational memory (SOM) effect that is induced by an epitaxial nucleation at the transition from columns to spheres and during the reverse process. This …

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single–single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ …

Biological macromolecules such as proteins and nucleic acids are monodisperse just as low-molar-mass organic compounds are. However, synthetic macromolecules contain mixtures of different chain lengths, the most uniform being generated by living polymerizations, which exhibit a maximum of 1–3% of chains with the desired length. Monodisperse natural and synthetic oligomers can be obtained in low quantities by tedious, multistep iterative methods. Here we report a methodology to synthesize monodisperse synthetic macromolecules by self-interrupted living polymerization. This methodology relies on a concept that combines supramolecular and macromolecular chemistry and differs from the conventional reactivity principles employed in the synthesis of polymers for over 100 years.

The synthesis of alkenes (olefins) is a central subject in the synthetic community. The transition-metal-catalyzed reductive cross-coupling of vinyl electrophiles has emerged as a promising tool to produce alkenes with improved flexibility, structural complexity, and functionality tolerance. In this review, we summarized the progress in this field with respect to cross-electrophile couplings and reductive Heck reactions using vinyl electrophiles. 1 Introduction 2 Cross-Electrophile Coupling of Vinyl Electrophiles 3 Reductive Heck Reaction of Vinyl Electrophiles 4 Summary and Outlook

The mixed-ligand system consisting of tris(2-aminoethyl)amine (TREN) and tris(2-dimethylaminoethyl)amine (Me6-TREN) during the Cu(0) wire-catalyzed single electron transfer-living radical polymerization (SET-LRP) of methyl acrylate (MA) in “programmed” biphasic mixtures of the dipolar aprotic solvents NMP, DMF, and DMAc with H2O is reported. Kinetic and chain end analysis studies by NMR and MALDI-TOF before and after thio-bromo “click” reaction demonstrated that Me6-TREN complements and makes the less expensive TREN a very efficient ligand in the absence of externally added Cu(II)Br2. Statistical analysis of the kinetic data together with control experiments demonstrated that this mixed-ligand effect enhanced the apparent rate constant of propagation, monomer conversion, and molecular weight control. The most efficient effect was observed at a 1/1 molar ratio between these two ligands …

The cogwheel model of hierarchical self-organization provides a route to highly ordered crystalline helical columnar hexagonal arrays of perylene bisimides (PBIs) conjugated to (3,4,5)-dimethyloctyl (racemic dm8*, r) minidendrons. Cogwheel PBIs assemble with identical structural order irrespective of molecular chirality to generate helical columns jacketed with an alkyl coat with length equal to half the helical pitch, exhibiting helical deracemization in the crystal state. These assemblies were accessible only via annealing or cooling and reheating at 1 °C/min. Recently it was discovered that hybrid rr8 sequence-defined dendrons with r and linear n-octyl (8) chains enabled the formation of the cogwheel phase at 10 °C/min upon heating but not cooling. Here we report four libraries of hybrid PBIs with sequence-defined dendrons containing r and n-alkyl (CnH2n+1) chains with n = 6, 7, 9, and 10. Structural analysis of …

A recent communication from our laboratory demonstrated that the presence of a small hydrophobic initiator residue (core) in water-soluble telechelic dibromo homopolymers can drive their self-assembly in aqueous solution into micelle-like nano-objects in which polymer chains adopt a folded conformation. Centered on the use of site-selective cleavable difunctional initiators, we demonstrate herein that this approach offers bottom-up and facile access to multistimuli-sensitive nanostructures for effective cargo delivery. Here, we first report the synthesis of homopolymers and copolymers encoding hydrophobicity and cleavable sites in their initiator residue in a precise sequence by single-electron transfer living radical polymerization (SET-LRP) from oligo(ethylene glycol) (macro)monomers. Employing a designed acid pH/UV light dual-cleavable initiator integrating a 2-nitroresorcinol diacetal sequence enabled on …

Hermann Staudinger was born in Worms, Germany on March 23, 1881 and studied chemistry at University of Halle, Technical University, Darmstadt and Ludwig Maximillian University, Munich. In 1903 when he was only 22 years old, he obtained his PhD in Chemistry with Daniel Vorlaender in Halle. He started his habilitation with J. Thiele at the University of Strasbourg where in 1905, at age 25 he reported the discovery of ketenes. In 1907 at age 26 he discovered the [2 + 2] cycloaddition of ketenes with imines. This reaction remains even today the method of choice for the synthesis of β-lactams the main building block of antibiotics. This reaction is known as the Staudinger synthesis. In 1907 he obtained his habilitation in Strasbourg and moved as a junior faculty to the Technical University in Karslruhe. In Karslruhe he became for the first time interested in polymers. In 1912 he moved as professor of organic …

α-Aryl amines are prevalent in pharmaceutically active compounds and natural products. Herein, we describe a Ni-catalyzed protocol for their synthesis from readily available α-aryl ethers. While α-aryl ethers have been used as electrophiles in Ni-catalyzed C–C bond formations, their use in C–heteroatom bond formation is much less prevalent. Preliminary mechanistic insight suggests that oxidative addition is facilitated by an anionic ligand and that reductive elimination is a reversible process.

• Programmed “biphasic” SET-LRP is one of the living polymerizations in which the Cu (0) acts as a catalyst to activate an alkyl halide by an outer sphere electron donation (reductive dehalogenation) to radicals in the organic phase while Cu (II) X2 acts as radical deactivator at the interphase and aqueous region to provide a LRP.• The biphasic reaction mixture are “programmed” by partitioning the Cu (I) X produced during the activation step in the water phase where it disproportionate quantitively to highly active Cu (0) and Cu (II) X2• The kinetic studies, molecular weight evolution and chain end analysis was carried out to demonstrate mixed ligand and catalytic effect of solvent.

In 1920, at age 39 and the peak of his professional carrier, one of the most distinguished organic chemists of his generation, Hermann Staudinger, claimed that natural and synthetic polymers are covalent macromolecules rather than colloidal aggregates. This idea initiated chain reactions supporting and dismissing the covalent macromolecular concept. The story of his 1953 Nobel Prize in Chemistry is reported here.

A supramolecular orientational memory (SOM) effect that provides access to complex columnar hexagonal architectures that cannot be designed by any other methodology was recently reported by our laboratory. This SOM concept is encountered upon heating and cooling a hexagonal columnar periodic array via a Frank–Kasper phase that is generated from supramolecular spheres. Here, a library of twenty-four supramolecular spheres self-organizing into Frank–Kasper phases and columnar hexagonal arrays was investigated for SOM. Twenty of these supramolecular spheres, that were self-assembled from conical shaped dendrons, did not exhibit SOM. The four supramolecular spheres assembled from covalent and supramolecular dynamic crowns displayed SOM. The supramolecular dynamic crowns forming spheres by a strong and directional H-bonding process, generated via SOM, a previously …

Increasing the rate of polymerization while decreasing the molecular weight distribution and maintaining well-defined chain ends remains one of the most challenging problems of macromolecular synthesis. In this issue of Chem, the Anastasaki laboratory demonstrates that mixed-RAFT agents provide a living radical polymerization that makes a very important step toward this goal.

Nickel-catalyzed anti-selective alkyne functionalization reactions are reviewed with an emphasis on the mechanisms that lead to their observed stereoselectivity. Since the isomerization of alkenylnickel species plays a key role in a large number of these reactions, the potential mechanisms for these processes are also described in detail. 1 Introduction 2 anti-Selective Hydroarylation 3 anti-Selective Carboborylation 4 anti-Selective Dicarbofunctionalization 4.1 Carbocyanative Cyclization 4.2 Cyclization with Aryl Donors 4.3 Cyclization with CO2 4.4 Intermolecular Dicarbofunctionalization 5 anti-Selective Carbosulfonylation 6 Alkenylnickel Isomerization 7 Conclusions

A mixed-ligand effect was observed for mixtures of tris(2-dimethylaminoethyl)amine (Me6-TREN) with tris(2-aminoethyl)amine (TREN) ligands during Cu(0) wire-catalyzed, single-electron transfer-living radical polymerization (SET-LRP) of methyl acrylate (MA) initiated with bis(2-bromopropionyl)ethane (BPE) in DMSO. The external order of reaction of SET-LRP both in the presence of Me6-TREN, TREN and of the mixed-ligand Me6-TREN/TREN, in DMSO, demonstrated a catalytic activity for DMSO similar to that reported in the presence of Cu(0) powder. The catalytic activity of DMSO, with close to 100% chain-end functionality, facilitates the much less expensive TREN to act as a very efficient ligand that is competitive with Me6-TREN and with the mixed-ligand and revitalizes TREN into an excellent ligand. The highest activity of the mixed-ligand at 1/1 ratio between ligands suggests that in addition to a fast exchange …

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus …

Well-defined hydrophilic telechelic dibromo poly(triethylene glycol monomethyl ether acrylate)s were prepared by single-electron transfer living radical polymerization employing a hydrophobic difunctional initiator containing acetal and disulfide linkages. Although the resulting homopolymers have low hydrophobic contents (<8.5 wt % of the entire structure), they are able to self-assemble in water into nanoscale micellelike particles via chain folding. Acetal and disulfide linkages were demonstrated to be “keystone” units for their dual stimuli-responsive behavior under biochemically relevant conditions. Their site-selective middle-chain cleavage under both acidic pH and reductive conditions splits the homopolymer into two equal-sized fragments and results in the breakdown of the nanoassemblies. The drug loading/delivery potential of these nanoparticles was investigated using curcumine combining in vitro drug …

Biological macromolecules such as nucleic acids and proteins are homochiral, display monodisperse chain length with mega, multimillion, molecular weight and encode functions by their precise sequence via self-organization. The functions of biological macromolecules are either independent on molecular weight or, like in the case of ribosome, are programmed by the self-organization of their mega molecular weight. In spite of the fact that Staudinger coined the name macromolecule 100 years ago, self-organizable synthetic covalent and supramolecular mega macromolecules exhibiting the symptoms of biological macromolecules started to emerge only recently. This personal perspective will discuss, with examples mostly from our laboratory, methodologies for the synthesis of self-organizable covalent and supramolecular mega macromolecules for which functions are encoded, programmed and perfected via …

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