Synthesis and In Vitro Biological Evaluation of Psoralen‐Linked Fullerenes

Photodynamic therapy (PDT) is a widely used medicinal treatment for the cancer therapy that utilizes the combination of a photosensitizer (PS) and light irradiation. In this study, we synthesized two novel C₆₀ fullerene derivatives, compounds 1 and 2 , with a psoralen moiety that can covalently bind to DNA molecules via cross‐linking to pyrimidine under photoirradiation. Along with several fullerene derivatives, the biological properties of several novel compounds have been evaluated. Compounds 1 and 2 , which have been shown to induce the production of hydroxyl radicals using several ROS detecting reagents, induced DNA strand breaks with relatively weak activities in the in vitro detection system using a supercoiled plasmid. However, the psoralen‐bound fullerene with carboxyl groups ( 2 ) only showed genotoxicity in the genotoxicity assay system of the umu test. Compound 2 was also seen to have cytotoxic activities in several cancer cell lines at higher doses compared to water‐soluble fullerenes.     

Functional Carbazole-Fullerene Complexes: A New Perspective of Carbazoles Acting as Nano-Octopus to Capture Globular Fullerenes

Fullerene host-guest constructs have attracted increasing attention owing to their molecular-level hybrid arrangements. However, the usage of simple carbazolic derivatives to bind with fullerenes is rare. In this research, three novel carbazolic derivatives, containing a tunable bridging linker and carbazole units for the capturing of fullerenes, are rationally designed. Unlike the general concave-convex interactions, fullerenes could interact with the planar carbazole subunits to form 2-dimensional hexagonal/quadrilateral cocrystals with alternating stacking patterns of 1 : 1 or 1 : 2 stoichiometry, as well as the controllable fullerene packing modes. At the meanwhile, good electron-transporting performances and significant photovoltaic effects were realized when a continuous C_60⋅⋅⋅C₆₀ interaction channel existed. The results indicate that the introduction of such carbazolic system into fullerene receptor would provide new insights into novel fullerene host-guest architectures for versatile applications.     

Low-Cost Synthesis of Fullerene Derivatives

Refined mixed fullerenes were used as a reagent in known organic reactions instead of the pure fullerene C₆₀ with aim to find an alternative, low-cost method for the synthesis of fullerene derivatives potentially exhibiting photoconductive properties. The isolation of C₆₀ or C₇₀ in clean form without admixtures requires the use of large quantities of toluene or other nonpolar solvents, polluting the environment and multiplying the production cost. 1,3-Dipolar cycloaddition of azomethine ylide to fullerite was chosen because this reaction is one of the most widely used for fullerene functionalization, producing material possibly presenting photoinducing behavior. The data showed that the use of the cheaper mixed fullerenes instead of pure C₆₀ leads to the isolation of the same expected products with similar yields. The photoelectric properties of mixed fullerenes and their organic derivatives were also examined. A slightly semiconductive behavior was confirmed as well as a noticeable photoresponse.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Investigations in the field of higher fullerenes

Halogenation of higher fullerene mixtures or their perfluoroalkylation with R^FI followed by HPLC separation of R^F derivatives and subsequent synchrotron X-ray crystallographic study made it possible to confirm cage connectivities of higher fullerenes and, in addition, to receive information concerning their reactivity in radical addition reactions. The data obtained are compared with theoretical predictions for higher fullerenes. Addition patterns of higher fullerene derivatives are discussed. Skeletal rearrangement of the D ₂-C₇₆ cage during chlorination has been observed for the first time.     

Photodynamic Activity of Fullerene Derivatives Solubilized in Water by Natural-Product-Based Solubilizing Agents

Water-soluble fullerenes prepared by using solubilizing agents based on natural products are promising photosensitizers for photodynamic therapy. Cyclodextrin, β-1,3-glucan, lysozyme, and liposomes can stably solubilize not only C₆₀ and C₇₀, but also some C₆₀ derivatives in water. To improve the solubilities of fullerenes, specific methods have been developed for each solubilizing agent. Water-soluble C₆₀ and C₇₀ exhibit photoinduced cytotoxicity under near-ultraviolet irradiation, but not at wavelengths over 600 nm, which are the appropriate wavelengths for photodynamic therapy. However, dyad complexes of solubilized C₆₀ derivatives combined with light-harvesting antenna molecules improve the photoinduced cytotoxicities at wavelengths over 600 nm. Furthermore, controlling the fullerene and antenna molecule positions within the solubilizing agents affects the performance of the photosensitizer.     

Geometrical and Electronic Rules in Fullerene‐Based Compounds

The discovery of buckminsterfullerene C₆₀ opened up a new scientific area and stimulated the development of nanoscience and nanotechnology directly. Fullerene science has since emerged to include fullerenes, endohedral fullerenes (mainly metallofullerenes), exofullerenes, and carbon nanotubes as well. Herein, we look back at the development of fullerene science from the perspective of epistemology by highlighting the proposed main rules or criteria for understanding and predicting the structures and stability of fullerene‐based compounds. We also point out that a rule or criterion may contribute significantly to the corresponding discipline and suggest that two unsolved issues in fullerene science are the addition patterns of fullerene derivatives and the structures and stability of nonclassical fullerenes.     

Catalyst free,visible-light promoted photoaddition reactions between C60 and N-trimethylsilylmethyl-substituted tertiary amines for synthesis of aminomethyl-1,2-dihydrofullerenes

An efficient and benign method for the preparation of aminomethyl-substituted fullerenes has been developed. The process, involving catalyst free, visible-light irradiation of 10% EtOH-toluene solutions containing fullerene C₆₀ and N-trimethylsilylmethyl-substituted amines by using a 20 W compact fluorescent lamp, leads to formation of aminomethyl-substituted fullerene adducts in a highly efficient manner. The photoaddition reaction takes place via a pathway initiated by visible light absorption by C₆₀, followed by SET from the amine to the triplet excited state of C₆₀. Ethanol-promoted desilylation of the resulting a minimum radical then generates the corresponding α-amino radical which couples with the C₆₀ radical anion to form the anion precursor of the fullerene adducts. The new approach using visible-light takes place under mild conditions and it does not require the use of photocatalysts. Thus, the method developed in this effort could broadens the range of functionalized fullerene derivatives that can be readily prepared.     

Regioselective synthesis of tetra(aryl)-mono(silylmethyl)[60]fullerenes and derivatization to methanofullerene compound

A method for the facile synthesis of tetraaryl-trimethylsilylmethyl-hydro[60]fullerenes, C₆₀Ar₄(CH₂SiMeR)H, has been developed in which readily prepared anionic mono(silylmethyl) fullerene is subjected to reaction conditions for organocopper-mediated multiple addition. Penta(organo)fullerene derivatives bearing different substituents and diverse functionality were synthesized in moderate to good yield under simple and mild reaction conditions. Further organic and organometallic transformations of these fullerenes allowed us to synthesize transition-metal complexes and a new methanofullerene derivative, 1,9-methano-6,12,15,18-tetraphenyl[60]fullerene, C₆₀Ph₄(CH₂).     

Spectroscopic and electrochemical studies on the interaction of an inclusion complex of β-cyclodextrin/fullerene with bovine serum albumin in aqueous solution

The potential effect of human exposure to carbonaceous nanomaterials (e.g., fullerenes or their derivatives) in the environment has become a concern. In the current study, we report the interaction of one water-soluble fullerene with bovine serum albumin using spectroscopic and electrochemical methods under aqueous solutions. The novel supramolecular inclusion complex of the water-soluble fullerene (β-CD)₂/C₆₀ was synthesized and characterized. In the mechanism discussed, the spectroscopic methods such as fluorescence quenching and ultraviolet-visible absorption, proved that the fluorescence quenching of BSA by (β-CD)₂/C₆₀ was the result of the formation of (β-CD)₂/C₆₀-BSA complex and that the mechanism of quenching might be a static quenching procedure. The binding constants K_a, the number of binding sites n, and the corresponding thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures were calculated through fluorescence spectroscopy, then as an auxiliary method, the electrochemical impedance spectroscopy (EIS) experiments confirmed this conclusion. The results indicated that the electrostatic interactions play a major role in (β-CD)₂/C₆₀-BSA association. The circular dichroism spectra show the conformation change of the effect of (β-CD)₂/C₆₀ on the conformation of BSA, which was confirmed by the results of the three-dimensional fluorescence spectra. Site marker competitive experiments indicate that the binding of (β-CD)₂/C₆₀ to BSA primarily took place in site I. The distance r between donor (BSA) and acceptor ((β-CD)₂/C₆₀) was obtained according to fluorescence resonance energy transfer (FRET). This work aims to demonstrate the mechanisms of the formation of the complex between water-soluble fullerene and protein under physiological conditions, as well as the remediation for the possible unwarranted biological effects of water-soluble fullerene.     

Fullerene C60 derivatives as antimicrobial photodynamic agents

Functionalized fullerenes have shown interesting biomedical applications as potential phototherapeutic agents. The hydrophobic carbon sphere of fullerene C₆₀ can be substituted by cationic groups to obtain amphiphilic structures. These compounds absorb mainly UV light, but absorption in the visible region can be enhanced by anchoring light-harvesting antennas to the C₆₀ core. Upon photoexcitation, fullerenes act as spin converters by effective intersystem crossing. From this excited state, they can react with ground state molecular oxygen and other substrates to form reactive oxygen species. This process leads to the formation of singlet molecular oxygen by energy transfer or superoxide anion radical by electron transfer. Photodynamic inactivation experiments indicate that cationic fullerenes are highly effective photosensitizers with applications as broad-spectrum antimicrobial agents. In these structures, the hydrophobic character of C₆₀ improves membrane penetration, while the presence of positive charges increases the binding of the fullerene derivatives with microbial cells. Herein, we summarize the progress of antimicrobial photodynamic inactivation based on substituted fullerenes specially designed to improve the photodynamic activity.     

Surface-induced enantiomorphic crystallization of achiral fullerene derivatives in thin films

The chirality of organic semiconductors is important for various applications in optoelectronics and spintronics. Here, we propose a new strategy to induce structural chirality in achiral organic semiconductors in thin films. Enantiomeric fullerene derivatives (S)-pSi and (R)-pSi, which have oligo(dimethylsiloxane) as a low-surface-energy moiety, were synthesized and used as surface-segregated monolayers (SSMs) in spin-coated films of several achiral fullerene derivatives. Upon thermal annealing, the presence of the chiral SSMs led to the crystallization of the fullerenes in the films as an SSM-induced crystal phase at lower temperatures. The crystallized films showed circular dichroism ascribed to the fullerene absorption, the sign and the intensity of which depended on the handedness of the SSM molecules and the film thickness, respectively. These results indicate that the achiral fullerene derivatives in the films were induced by the SSMs to crystallize into enantiomorphic crystals. Our approach to inducing chirality in organic thin films is compatible with many device applications.

Chiral induction: surface-segregated monolayers of chiral molecules induce the enantiomorphic crystallization of achiral fullerene derivatives in thin films.     

Radical scavenging efficiency of different fullerenes C60-C70 and fullerene soot

This investigation was undertaken to determine the antioxidant activity of a range of fullerenes C₆₀ and C₇₀ in order to rank them according to their comparative efficiency. The model reaction of initiated (2,2′- azobisisobutyronitrile, AIBN) cumene oxidation was used to determine rate constants for addition of radicals to fullerenes. Measurements of oxidation rates in the presence of different fullerenes showed that the antioxidant activity as well as the mechanism and mode of inhibition were different for fullerenes C₆₀ and C₇₀ and fullerene soot. All fullerenes - C₆₀ of gold grade, C₆₀/C₇₀ (93/7, mix 1), C₆₀/C₇₀ (80 ± 5/20 ± 5, mix 2) and C₇₀ operated as alkyl radical acceptora, whereas fullerene soot surprisingly retarded the model reaction by a dual mode similar to that for the fullerenes and with an induction period like many of the sterically hindered phenolic and amine antioxidants. For the C₆₀ and C₇₀ the oxidation rates were found to depend linearly on the reciprocal square root of the concentration over a sufficiently wide range thereby fitting the mechanism for the addition of cumylalkyl radicals to the fullerene core. This is consistent with literature data on the more ready and rapid addition of alkyl and alkoxy radicals to the fullerenes compared with peroxy radicals. Rate constants for the addition of cumyl radicals to the fullerenes were determined to be k_(333K) = (1.9 ± 0.2) × 10⁸ (C₆₀); (2.3 ± 0.2) × 10⁸ (C₆₀/C₇₀, mix 1); (2.7 ± 0.2) × 10⁸ (C₆₀/C₇₀, mix 2); (3.0 ± 0.3) × 10⁸ (C₇₀), M⁻¹ s⁻¹. The increasing C₇₀ constituent in the fullerenes leads to a corresponding increase in the rate constant.The fullerene soot inhibits the model reaction according to the mechanism of trapping of peroxy radicals; the oxidation proceeds with a pronounced induction period and kinetic curves are linear in semi-logarithmic coordinates.For the first time the effective concentration of inhibiting centres and inhibition rate constants for the fullerene soot have been determined to be fn[C₆₀−soot] = (2.0 ± 0.1) × 10⁻⁴ mol g⁻¹ and k_inh = (6.5 ± 1.5) × 10³ M⁻¹ s⁻¹ respectively.The kinetic data obtained specify the level of antioxidant activity for the commercial fullerenes and scope for their rational use in different composites. The results may be helpful for designing an optimal profile of composites containing fullerenes.     

Water-soluble fullerenes using solubilizing agents, and their applications

Host–guest and supramolecular chemistry can produce water-solubilization of fullerenes such as C₆₀, C₇₀, and C_60/70 derivatives by hydrophobic interactions, CH–π interactions, and/or π–π interactions. For materials and biomedical applications, these water-soluble host–fullerene complexes must have the following important properties: (i) high solubility, (ii) high stability, and (iii) functionalization of the host–fullerene complex. These objectives can be achieved by selection of appropriate host molecules, development of novel solubilizing methods, and synthesis of functionalized host molecules. This review describes the introduction of a variety of host molecules that can solubilize fullerenes in water. In addition, we describe applications of host–fullerene complexes, in particular using photoinduced energy- and electron-transfer processes in water.     

Photosynthetic reactions in fullerene based donor-acceptor complexes

Donor-acceptor interaction changes essentially the terms of the ground state of binary complexes imparting them a multi-well, in particular, two-well form. A quantum chemical analysis of formation conditions for the amine derivatives of fullerenes depending on the type of the term has been performed by the example of binary complexes, including fullerenes C₆₀ and C₇₀ as acceptors of electrons and amines as donors,. It is found that the addition reaction of amines to fullerene hampered between neutral molecules can occur when the latter are ionized by light.     

Trifluoromethyl Derivatives of Elusive Fullerene C98

Data concerning the isomeric composition of C₉₈ and the chemistry of C₉₈ derivatives are scarce due to very low abundance of C₉₈ in the fullerene soot. Trifluoromethylation of C₉₈-containing mixtures followed by HPLC separation of CF₃ derivatives and single crystal X-ray diffraction study resulted in structural characterization of four compounds C₉₈(248)(CF₃)_18/20, C₉₈(116)(CF₃)₁₈, and C₉₈(120)(CF₃)₂₀. To date, these compounds represent the largest fullerenes isolated as CF₃ derivatives with experimentally determined molecular structures. The addition patterns of C₉₈(CF₃)_18/20 are discussed in detail revealing the stabilizing factors, such as isolated double C=C bonds and benzenoid rings on C₉₈ fullerene cages. A detailed comparison with the addition patterns of the known C₉₈Cl_n allowed us to contribute to the better understanding the chemistry of elusive C₉₈ fullerene.     

Ring-opening reaction of tetrahydrofuran on the penta(organo)[60]fullerenes: synthesis of hydroxybutyl, methacrylate, and norbornene derivatives

Ring-opening reaction of tetrahydrofuran takes place on penta(methyl)- and penta(n-butylphenyl)[60]fullerenes in the presence of chlorotrimethylsilane giving penta(organo)fullerene hydroxybutyl derivatives, C₆₀R₅(C₄H₈OH) (R = Me, ⁿBuC₆H₄). The hydroxyl groups were further transformed into methacrylate and norbornylcarbonyloxy groups via esterification with the corresponding acid chlorides. The methacrylate derivative, penta(methyl)[60]fullerenylbutyl methacrylates was crystallographically characterized.     

Synthesis of [60]fullerene derivatives bearing five-membered heterocyclic wings and an investigation of their photophysical kinetic properties

The preparation, characterization and photophysical properties of six new stable [6,6]-closed fullerene cycloadducts bearing five-membered heterocycles are described. The modified [60]fullerenes are obtained by a simple and rapid synthesis via a Bingel-type reaction with tetrazole and oxadiazole malonate derivatives. The photophysical kinetics of these new fullerene derivatives in toluene solution under ultraviolet illumination (375 nm, UVA) are studied by electron paramagnetic resonance and free-radical spin-trapping using α-phenyl-N-tert-butyl nitrone as a spin-trap. The results are compared with pure [60]fullerene and [6,6]-phenyl C₆₁ butyric acid methyl ester (C₆₀-PCBM). It is concluded that for all six new compounds as well as pure [60]fullerene and PCBM both superoxide and singlet oxygen are produced in the first stages of UVA illumination following the type I and II mechanisms, respectively. In all cases singlet oxygen is produced as the primary dominant species; however, the type I mechanism always occurs in parallel with type II. In the end, the superoxide is self-dismuted into hydroxyl radicals, thus yielding PBN-OH spin adducts (g = 2.007 and a_hf (¹⁴N) = 1.54 mT). The kinetic reaction constants and their efficiencies in the production of reactive oxygen species at 375 nm and per mW of absorbed power are determined. The experimental results are consistent with an autocatalytic reaction model in which the system evolutes under UVA illumination, with superoxide catalyzing the conversion of singlet oxygen into more superoxide.     

Stable Non‐IPR C60 and C70 Fullerenes Containing a Uniform Distribution of Pyrenes and Adjacent Pentagons

The most abundant fullerenes, C₆₀ and C₇₀, and all the pure carbon fullerenes larger than C₇₀, follow the isolated‐pentagon rule (IPR). Non‐IPR fullerenes containing adjacent pentagons (APs) have been stabilized experimentally in cases where, according to Euler’s theorem, it is topologically impossible to isolate all the pentagons from each other. Surprisingly, recent experiments have shown that a few endohedral fullerenes, for which IPR structures are possible, are stabilized in non‐IPR cages. We show that, apart from strain, the physical property that governs the relative stabilities of fullerenes is the charge distribution in the cage. This charge distribution is controlled by the number and location of APs and pyrene motifs. We show that, when these motifs are uniformly distributed in the cage and well‐separated from one other, stabilization of non‐IPR endohedral and exohedral derivatives, as well as pure carbon fullerene anions and cations, is the rule, rather than the exception. This suggests that non‐IPR derivatives might be even more common than IPR ones.     

Benzene Adsorption on C<Subscript>24</Subscript>, Si@C<Subscript>24</Subscript>, Si-Doped C<Subscript>24</Subscript>, and C<Subscript>20</Subscript> Fullerenes

The absorption feasibility of benzene molecule in the C₂₄, Si@C₂₄, Si-doped C₂₄, and C₂₀ fullerenes has been studied based on calculated electronic properties of these fullerenes using Density functional Theory (DFT). It is found that energy of benzene adsorption on C₂₄, Si@C₂₄, and Si-doped C₂₄ fullerenes were in range of –2.93 and –51.19 kJ/mol with little changes in their electronic structure. The results demonstrated that the C₂₄, Si@C₂₄, and Si-doped C₂₄ fullerenes cannot be employed as a chemical adsorbent or sensor for benzene. Silicon doping cannot significantly modify both the electronic properties and benzene adsorption energy of C₂₄ fullerene. On the other hand, C₂₀ fullerene exhibits a high sensitivity, so that the energy gap of the fullerene is changed almost 89.19% after the adsorption process. We concluded that the C₂₀ fullerene can be employed as a reliable material for benzene detection.