Florian Beuerle

Shape‐Controlled Synthesis and Self‐Sorting of Covalent Organic Cage Compounds

The directional bonding approach is a powerful tool to rationally control both shape and stoichiometry of three-dimensional objects built from rigid building blocks under dynamic covalent conditions. Co-condensation of catechol-functionalized tribenzotriquinacene derivatives which have 90° angles between the reactive sites and diboronic acids with bite angles of 60°, 120°, and 180°, led to the efficient formation of, respectively, bipyramidal, tetrahedral, or cubic covalent organic cage compounds in a predictable manner. Investigations on the self-sorting of ternary mixtures containing two competitive boronic acids revealed either narcissistic or social self-sorting depending on the stability of the segregated cages relative to feasible three-component assemblies.

Water solubility, antioxidant activity and cytochrome C binding of four families of exohedral adducts of C60 and C70

Over the past decade, surface-modified, water soluble fullerenes have been shown by many different investigators to exhibit strong antioxidant activity against reactive oxygen species (ROS) in vitro and to protect cells and tissues from oxidative injury and cell death in vivo. Nevertheless, progress in developing fullerenes as bona fide drug candidates has been hampered by three development issues: 1) lack of methods for scalable synthesis; 2) inability to produce highly purified, single-species regioisomers compatible with pharmaceutical applications; and 3) inadequate understanding of structure-function relationships with respect to various surface modifications (e.g., anionic versus cationic versus charge-neutral polarity). To address these challenges, we have designed and synthesized more than a dozen novel water soluble fullerenes that can be purified as single isomers and which we believe can be manufactured to scale at reasonable cost. These compounds differ in addition pattern, lipophilicity and number and type of charge and were examined for their water solubility, antioxidant activity against superoxide anions and binding of cytochrome C. Our results indicate that dendritic water soluble fullerene[60] monoadducts exhibit the highest degree of antioxidant activity against superoxide anions in vitro as compared with trismalonate-derived anionic fullerenes as well as cationic fullerenes of similar overall structure. Among the higher adducts, anionic derivatives have a higher antioxidant activity than comparable cationic compounds. To achieve sufficient water solubility without the aid of a surfactant or co-solvent at least three charges on the addends are required. Significantly, anionic in contrast to cationic fullerene adducts bind with high affinity to cytochrome C.

High catalytic activity of dendritic C60 monoadducts in metal-free superoxide dismutation.

Water-soluble fullerenes, in particular the tris-malonyl-C60 derivative 1 (so-called C3), [1] have been shown to exhibit strong antioxidant activity against reactive oxygen species in vitro and to protect cells and tissue from oxidative injury and cell death in vivo. The ability to destroy the toxic superoxide O2C was suggested to be responsible for fullerene antioxidant activity, although its mechanism is still not clear. Dugan and co-workers offered evidence in support of a catalytic superoxide dismutation mechanism instead of direct radical attack on the C60 moiety of 1, thus showing that it could act as a metal-free mitochondrial manganese superoxide dismutase (MnSOD) mimetic. They proposed the formation of a complex between C3 and O2C . Herein, we present for the first time clear and unambiguous evidence for a catalytic dismutation process, the key steps of which are successive O2C oxidation, within an outersphere electron-transfer process, and fullerene-derivativemediated O2C reduction. At the same time we are able to rationalize structure–property relationships by the systematic investigation of a series of stable, readily accessible, and nontoxic monoand trisadducts 2–7 of C60. [2c,4] This led to the identification of new lead compounds for neuroprotective applications with significantly improved superoxide dismutation activity. To describe the structure–reactivity relationship with respect to superoxide dismutase (SOD) activity, we first present the redox properties of 2–7. Cyclic voltammetry measurements in DMSO have shown that in the potential range from 0 to 1 V (vs. a saturated calomel electrode, SCE) 2–6 undergo two reversible reductions, whereas 7 exhibits one reversible redox couple (Table 1, Figure 1, Figure S1 in the Supporting Information). The corresponding reduction potentials of the monoadducts 2–4 are significantly higher than those of trisadducts 5–7 and show a prominent charge

Covalent Organic Frameworks and Cage Compounds: Design and Applications of Polymeric and Discrete Organic Scaffolds

Porous organic materials are an emerging class of functional nanostructures with unprecedented properties. Dynamic covalent assembly of small organic building blocks under thermodynamic control is utilized for the intriguingly simple formation of complex molecular architectures in one-pot procedures. In this Review, we aim to analyze the basic design principles that govern the formation of either covalent organic frameworks as crystalline porous polymers or covalent organic cage compounds as shape-persistent molecular objects. Common synthetic procedures and characterization techniques will be discussed as well as more advanced strategies such as postsynthetic modification or self-sorting. When appropriate, comparisons are drawn between polymeric frameworks and discrete organic cages in terms of their underlying properties. Furthermore, we highlight the potential of these materials for applications ranging from gas storage to catalysis and organic electronics.

Reversible Assembly of a Supramolecular Cage Linked by Boron-Nitrogen Dative Bonds.

Boron-nitrogen dative bonds provide a suitable motif for reversible, yet strong and directed interactions, leading to the highly efficient self-assembly of small organic building blocks into supramolecular cage structures. A bipyramidal [2+3] assembly, as the first example of a supramolecular cage mediated by BN dative bonds that exists as a discrete species in solution, is quantitatively obtained from a tribenzotriquinacene-based trisboronate ester and 1,4-diazabicyclo[2.2.2]octane. Thermodynamic equilibria of cage formation are investigated by isothermal titration calorimetry and fully reversible cage opening can be observed at elevated temperatures.

Synthesis of Amphiphilic [60]Fullerene [3:3]Hexakisadducts with Four Spherically Defined Addend Zones

New [3:3]hexakisadducts 3, 6, and 7 have been synthesized by a stepwise addition of two tripodal malonate tethers to pristine [60]fullerene. For the first time, [3:3]hexakisadducts of two sets of asymmetrically substituted malonate addends could be prepared as single in/out isomers by following this synthetic protocol. Thereby, four spherically defined addend zones I-IV were created with various similar degrees of latitude on the fullerene sphere. Four amphiphilic [3:3]hexakisadducts 12, 14, 18, and 19 were prepared with different relative arrangements of both the hydrophilic and lipophilic moieties in the addend zones I/II and III/IV, respectively.

Cytoprotective activities of water-soluble fullerenes in zebrafish models

Using zebrafish (Danio rerio) embryos as a model system, we compared the antioxidant and cytoprotective effects of a series of new water-soluble fullerenes 1–12. Since zebrafish embryos are transparent during the first week of life, the effects of fullerenes on multiple organ systems, including CNS, PNS, and heart, could be assessed in situ. Both positively charged and negatively charged water-soluble fullerenes were added at concentrations between 1 and 500 µM to 96 well plates containing zebrafish embryos at 24–120 hours post fertilization (hpf). Direct toxicity of each fullerene compound was assessed by LC50. In addition, we assessed the ability of each fullerene to protect against toxicity induced by known chemical toxins in this system. Four different drug/chemical toxicity models were used in our study: (i) protection of neuromast hair cells from gentamicin-induced toxicity; (ii) protection of neuromast hair cells from cisplatinum-induced toxicity; (iii) protection of tyrosine hydroxylase-containing dopaminergic CNS neurons from 6-hydroxydopamine toxicity; and (iv) protection of total CNS neurons from 6-hydroxydopamine toxicity. Our results indicate that (i) positively charged water-soluble fullerenes tend to exhibit greater toxicity than negatively charged fullerenes with similar structures; (ii) toxicity varies considerably among negatively charged fullerenes from very low to moderate, depending on structural features; (iii) dendrofullerenes 2–7 (monoadducts of C60) show stronger protection against cisplatinum toxicity in neuromast hair cells while then the e,e,e-trismalonic acid 1 (so called C3) shows stronger protection against gentamicin-induced cytotoxicity in the same cells; (iv) C3 (1) is relatively unstable in all aqueous solvents tested and breaks down mainly through decarboxylation reactions to form penta, tetra and tris carboxylated forms, which exhibit increased toxicity in vivo compared with C3 (1). Our findings indicate that water-soluble fullerenes can protect against chemical toxin-induced apoptotic cell death in a vertebrate, whole-animal model that may be useful for predicting the efficacy and toxicity of these compounds in mammals. Furthermore, the relative potential for pharmacologic use of these compounds varies considerably with respect to stability.

Synthesis and Orthogonal Functionalization of [60]Fullerene e,e,e‐Trisadducts with Two Spherically Defined Addend Zones

e,e,e-Trisadducts 13 and 15 have been prepared by a highly regioselective threefold cyclopropanation of tripodal malonates 10 and 12 with C60. The yield and regioselectivity depend on the length and structure of the tethers that connect the malonate units to the focal benzene core of 13-15. As a consequence of the template-directed synthesis, all e,e,e-trisadducts were formed as in/out isomers exclusively and contain two spherically well-defined addend zones with equatorial and polar orientation, respectively. By variation of the outer malonate termini of the tethers, selective functionalization of the equatorial addend zone could be achieved, thus leading to fine-tuning of intermolecular interactions, such as solubility or aggregation phenomena. After removal of the focal benzene moiety in 14 and 15, selective functionalization of the polar addend zone could be achieved. Strong intramolecular hydrogen-bonding networks of the polar substituents in the polar addend zone could be observed by 1H NMR spectroscopic analysis. By orthogonal functionalization of both addend zones, fullerene derivatives 44-48 could be synthesized as one single in/out isomer, thus greatly enhancing the potential of e,e,e-trisadducts as building blocks in supramolecular architectures.

Arranging pseudorotaxanes octahedrally around 60 fullerene

The formation of both [2]- and [7]pseudorotaxanes, which are obtained by mixing of a dibenzylammonium derivative with mono- and hexakis-adducts of [60]fullerene bearing malonato-benzo[25]crown-8 rings, has been monitored in dichloromethane by both 1D and 2D (1)H NMR spectroscopies.

Three-Dimensional Metal–Fullerene Frameworks

Hexakis-substituted [60]fullerene adducts with icosahedral symmetry provide an unprecedented scaffold for the spatial arrangement of twelve functional groups with high geometric precision. This unique molecular symmetry identifies such polyfunctional organic building blocks as potential highly connective linkers for coordination polymer and metal-organic framework synthesis. Hereby, the linker exhibits a higher connectivity than the metal ions and with the main connectivity based on the ligand, this can create a new type of inversely cross-linked framework. Two hexakis adducts bearing either twelve glycolic acid or 3-hydroxypropionic acid side chains attached to its malonate units were incorporated as organic connectivity centers in the first fullerene-containing three-dimensional frameworks by coordination with Zn(2+) .