First Synthesis of the Inherently Chiral Trans-4' Bisadduct of C59 N Azafullerene by Using Cyclo-[2]-dodecylmalonate as a Tether.

The multiaddition chemistry of azafullerene C59 N has been scarcely explored, and the isolation of pure bisadducts is in its infancy. Encouraged by the recent regioselective synthesis of the inherently chiral equatorialface bisadduct of C59 N, we focused on the isolation of the first trans-4 bisadduct in a simple two-step approach. The first regioselective synthesis of the trans-4 bisadduct of C59 N by using cyclo-[2]-dodecylmalonate as a tether is now reported. The newly synthesized bisadduct has C1 symmetry, as evidenced by 13 C NMR, while X-ray crystallography validated the trans-4' addition pattern. Furthermore, the inherently chiral trans-4' C59 N bisadduct was enantiomerically resolved, and the mirror-image relation of the two enantiomers was probed by circular dichroism spectroscopy. Finally, UV-Vis and redox assays suggested that the addition pattern has a reflection in the light-harvesting and redox properties of the bisadduct.

Complete Dynamic Reconstruction of C60, C70, and (C59N)2 Encapsulation into an Adaptable Supramolecular Nanocapsule.

The dynamic adaptability of tetragonal prismatic nanocapsule 18+ in the selective separation of fullerenes and endohedral metallofullerenes (EMFs) remains unexplored. Therefore, the essential molecular details of the fullerene recognition and binding process into the coordination capsule and the origins of fullerene selectivity remain elusive. In this work, the key steps of fullerene recognition and binding processes have been deciphered by designing a protocol which combines 1H-1H exchange spectroscopy (2D-EXSY) NMR experiments, long time-scale Molecular Dynamics (MD) and accelerated Molecular Dynamics (aMD) simulations, which are combined to completely reconstruct the spontaneous binding and unbinding pathways from nanosecond to second time-range. On one hand, binding (k'on) and unbinding (koff) rate constants were extracted from 1H-1H exchange spectroscopy (EXSY) NMR experiments for both C60 and C70. On the other hand, MD and aMD allowed monitoring the molecular basis of the encapsulation and guest competition processes at a very early stage under nonequilibrium conditions. The receptor capsule displays dynamical adaptability features similar to those observed in the process of biomolecular recognition in proteins. In addition, the encapsulation of bis-aza[60]fullerene (C59N)2 within a supramolecular coordination capsule has been studied for the first time, showcasing the pros and cons of the dumbbell-shaped guest in the dynamics of the encapsulation process and in the stability of the final bound adduct. The powerful combination of NMR, MD, and aMD methodologies allows to obtain a precise picture of the subtle events directing the encapsulation and is thus a predictive tool for understanding host-guest encapsulation and interactions in numerous supramolecular systems.

Tether-Directed Regioselective Synthesis of an Equatorialface Bisadduct of Azafullerene Using Cyclo-[2]-octylmalonate.

Bisazafullerene (C59 N)2 has been functionalized under aerobic conditions with cyclo-[2]-octylmalonate through a Mannich-type reaction, furnishing the corresponding monoadduct. A regioselective tether-directed Bingel cyclopropanation reaction was then carried out on the azafullerene core to yield a single bisadduct. Spectroscopic analysis of the formed bisadduct showed it to have a C1 symmetrical structure, making it inherently chiral. Single-crystal X-ray analysis revealed the addition pattern of the azafullerene bisadduct to be equatorialface . Examination of the optical properties showed the evolution of new absorption bands, which can be used as signatures for the characterization of equatorialface bisadducts of C59 N. Finally, redox assays showed that the LUMO level of the equatorialface bisadduct was increased compared to that of the parent (C59 N)2 .

The journey of L-tartaric acid in the world of enantiomerically pure bis- and trisadducts of C60 with the inherently chiral trans-3 and all-trans-3 addition patterns.

Inherently chiral multi-adducts of [60]fullerene represent unique chiral molecular tectons featuring fascinating optoelectronic properties. Herein we discuss the most recent progress in the synthesis of enantiomerically pure bis- and trisadducts of C60 with the inherently chiral trans-3 and all-trans-3 addition patterns utilizing cyclo-[n]-malonate tethers derived from (-)-dimethyl-2,3-O-isopropylidene-L-tartrate. Some future perspectives regarding the investigation of these chiral building blocks in modern areas of research are discussed.

Remote functionalization of C60 with enantiomerically pure cyclo-[2]-malonate tethers bearing C12 and C14 spacers: synthetic access to bisadducts of C60 with the inherently chiral trans-3 addition pattern.

In this Article, we describe the synthesis of two optically pure diols bearing a 1,2-diol moiety masked as an isopropylidene acetal group and long alkyl chains comprised of 12 and 14 carbon atoms, respectively. The synthetic methodology that was developed offers a general way for the synthesis of optically pure diols with long alkyl chains. Diols (-)-4 and (-)-9 were subjected to a condensation reaction with malonyl dichloride to afford two cyclo-[2]-malonate tethers that were separated by column chromatography in optically pure form. The bismalonates (-)-4b and (-)-9b proved to be excellent tethers for the regioselective Bingel functionalization of C60, furnishing in a regioselective manner the corresponding (f,s)C and (f,s)A trans-3 bisadducts with low diastereoselectivity but in very good to excellent total yields. In both cases, the formed trans-3 bisadducts were isolated in pure form by simple column chromatography and were fully characterized. The successful acetal deprotection of the synthesized trans-3 bisadducts afforded quantitatively the corresponding polyalcohols, which represent novel chiral fullerene compounds equipped with glycol moieties.

A highly porous interpenetrated metal-organic framework from the use of a novel nanosized organic linker.

The initial use of a novel elongated tricarboxylic acid H(3)hmpib in metal-organic framework (MOF) chemistry resulted in a [Zn(4)O(hmpib)(2)] MOF (UCY-1) with pyrite topology. The compound displays a remarkably high internal surface area despite its double-interpenetrated structure as well as high CO(2) uptake and selective adsorption for it over CH(4).

Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations.

A series of experimentally reported as well as computationally designed monoadducts and bisadducts of [60]fullerene analogues have been used in order to analyze the binding interactions between fullerene based inhibitors and HIV-1 PR employing docking studies. MD simulations of ligand-free and the inhibitor bound HIV-1 PR systems complemented the above studies and provided proper input structure of HIV-1 PR in docking simulations. The obtained results revealed a different orientation of the beta-hairpin flaps at these two systems. In inhibitor bound system, the flaps of the enzyme are pulled in toward the bottom of the active site (the closed form) while, in ligand-free system flaps shifted away from the dual Asp25 catalytic site and this system adopts a semi-open form. The structural analysis of these systems at catalytic and flexible flap regions of the HIV-1 PR through the simulation, assisted in understanding the structural preferences of these regions, as well as, the adopted orientations of fullerene derivatives within the active site of the enzyme. Five different combinations of steroelectronic fields of 3D QSAR/CoMSIA models were obtained from the set of biologically evaluated and computationally designed fullerene derivatives (training set=43, test set=6) in order to predict novel compounds with improved inhibition effect. The best 3D QSAR/CoMSIA model yielded a cross validated r(2) value of 0.739 and a non-cross validated r(2) value of 0.993. The derived model indicated the importance of steric (42.6%), electrostatic (12.7%), H-bond donor (16.7%) and H-bond acceptor (28.0%) contributions. The derived contour plots together with de novo drug design were then used as pilot models for proposing the novel analogues with enhanced binding affinities. Such structures may trigger the interest of medicinal chemists for novel HIV-1 PR inhibitors possessing higher bioactivity.

A chiral dumbbell shaped bis(fullerene) oligoelectrolyte.

The first icosacationic bis(fullerene) whose water solubility is provided by twenty peripheral ammonium groups has a rigid, almost cylindrical shape and was synthesized by connecting two fullerene cores with a chiral cyclo-bis(malonate), followed by the regioselective addition of ten amino-terminated malonates into the octahedral positions of the fullerene moieties and subsequent cleavage of the Boc-protecting groups.

Application and evaluation of solvent-free matrix-assisted laser desorption/ionization mass spectrometry for the analysis of derivatized fullerenes.

A variety of derivatized fullerenes have been studied by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. Of particular emphasis has been the evaluation of a recently introduced solvent-free sample/target preparation method. Solvent-free MALDI is particularly valuable in overcoming adverse solvent-related effects, such as insolubility and/or degradation of the sample. The method was applied to fullerene derivatives susceptible to decomposition under insufficiently "soft" MALDI conditions. Analytes included the hydrofullerene: C(60)H(36), fluorofullerenes: C(60)F(x) where x = 18, 36, 46, 48 and C(70)F(x) where x = 54, 56, methano-bridged amphiphilic ligand adducts to C(60) and the [4 + 2] cycloadduct of tetracene to C(60). The new solvent-free sample preparation is established as an exceedingly valuable addition to the repertoire of preparation protocols within MALDI. The MALDI mass spectra were of very high quality throughout, providing a testimony that "soft" MALDI conditions could be achieved. Using the [4 + 2] cycloadduct of tetracene to C(60) as the model analyte for direct comparison with solvent-based MALDI, the solvent-free approach led to less fragmentation and more abundant analyte ions. Applying solvent-free sample preparation, different matrix compounds have been examined for use in the MALDI of derivatized fullerenes, including sulfur, tetracyanoquinodimethane (TCNQ), 9-nitroanthracene (9-NA) and trans-2-[3-(4-tert-butylphenyl)-2-methyl-2- propenylidene]malononitrile (DCTB). DCTB was confirmed as the best performing matrix, reducing unwanted decomposition and suppression effects.

Synthesis of Enantiopure T-Symmetrical [6:0]-Hexakis Adducts of C60 Equipped with 1,2-Glycol Substituted cyclo-Monomalonate Addends.

The synthesis of T-symmetrical [6:0]-hexakis adducts of C60 bearing enantiopure cyclo-monomalonate addends equipped with 1,2-glycol groups masked as isopropylidene acetals is presented. The deprotection of the acetals afforded functional fullerene building blocks bearing six 1,2-glycol moieties in an octahedral geometry as connection sites with appropriate linear organic spacers targeting 3D chiral extended networks with cubic building units. Evaluation of the experimental results revealed the advantageous synthetic accessibility to hexakis adduct (-)-9 which carries six homochiral C12 cyclo-monomalonate addends.

Construction of 2D nanoporous networks by coupling on-surface dynamic imine chemistry and dipole-stabilized self-assembly.

Double-walled nanoporous networks based on the Schiff base reaction of nonplanar tripodic building blocks and subsequent dipole-directed self-assembly were fabricated on highly oriented pyrolytic graphite (HOPG) at the gas-solid interface. This is the first example of nonplanar molecules exploited as precursors for a surface reaction.

Regio- and stereoselective synthesis of enantiomerically pure [60]fullerene tris-adducts with an inherently chiral e,e,e addition pattern.

The synthesis and flash column chromatographic separation of enantiomerically pure tris-adducts of C60 with an e,e,e-addition pattern is achieved via cyclopropanation with chiral D3-symmetrical cyclo-tris(malonate) tethers.

Regioselective synthesis and zone selective deprotection of [60]fullerene tris-adducts with an e,e,e addition pattern.

D(3h)-symmetrical tripodal tris(malonate) tethers have been used for the synthesis of [60]fullerene tris-adducts with an e,e,e addition pattern bearing topologically distinct polar and equatorial addend zones that can selectively be deprotected.

Synthesis and self-photooxygenation of alkenyl-linked [60]fullerene derivatives. A regioselective ene reaction.

[reaction: see text] Alkenyl-linked C(60) derivatives undergo self-photooxygenation regioselectively, by the preferential abstraction of allylic hydrogens on the fullerene side of the double bond.

Addition of electron-rich aromatics to azafullerenium carbocation. A stepwise electrophilic substitution mechanism.

[reaction: see text] The reaction between the C(59)N(+) carbocation and the electron-rich aromatic compounds toluene and anisole has been mechanistically studied. The measured intermolecular kinetic isotope effects are consistent with an electrophilic aromatic substitution mechanism in which the arenium cation is formed by electrophilic attack of C(59)N(+) on the aromatic ring in the first step of the reaction, followed by hydrogen abstraction in a rate-determining second step.

An unexpected stereoisomerism in enantiomerically pure trisadducts of C60 with an inherently chiral trans-3,trans-3,trans-3 addition pattern.

We have synthesized and isolated two C2-symmetric enantiomerically pure trisadducts of C60 with an inherently chiral trans-3,trans-3,trans-3 addition pattern with the aid of an enantiopure cyclo-tris-malonate tether. An unexpected stereoisomerism was observed which was attributed to the spatial arrangement of spacers in the tether.

The first one-pot synthesis of a chiral pentakis-adduct of C60 utilising an opened-structure malonate tether.

A pentakis-adduct of C60 with an incomplete octahedral addition pattern was synthesised via a one-pot procedure using a tether equipped with five malonate moieties. The five-fold Bingel cyclopropanation of C60 was completely regioselective and afforded a chiral, C2-symmetric pentakis-adduct which was easily separated by column chromatography on SiO2.

A facile access to enantiomerically pure [60]fullerene bisadducts with the inherently chiral trans-3 addition pattern.

The Bingel reaction between C(60) and an enantiopure bismalonate tether equipped with two acetonide moieties led to the synthesis and successful column chromatographic isolation of the enantiomerically pure (f,s)C and (f,s)A bisadducts with the inherently chiral trans-3 addition pattern. Acidic deprotection of the acetonide groups gave access to novel chiral fullerene compounds which combine the inherent chirality of the fullerene core with the functional glycol groups located on the tether.

One-pot regioselective synthesis and X-ray crystal structure of a stable [60]fullerene trisadduct with the e(edge),e(face),trans-1 addition pattern.

The Bingel functionalisation of C(60) with a structurally novel tether equipped with three reactive malonate groups afforded a C(2v)-symmetrical e(edge),e(face),trans-1 trisadduct in a complete regioselective manner and in an excellent yield of 65%. The [60]fullerene trisadduct showed pronounced ability to crystallise and gave X-ray quality single crystals for analysis.

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.