Synthesis of Twisted [n]Cycloparaphenylene by Alkene Insertion.

Mono-alkene-inserted [n]cycloparaphenylenes 1 [(ene)-[n]CPP] with n=6, 8, and 10, mono-ortho-phenylene-inserted [6]CPP 2, and di-alkene-insertved [n]CPP 3 [(ene)2 -[n]CPP] with n=4, 6, and 8 were synthesized by fusing CPP precursors and alkene or ortho- phenylene groups through coupling reactions. Single-crystal X-ray diffraction analyses reveal that the strips formed by the π-surfaces of 1 and 2 exhibited a Möbius topology in the solid state. While the Möbius topology in the parent 1 and 2 in solution was lost due to the free rotation of the paraphenylene unit even at low temperatures, ene-[6]CPP 4 with eight 1-pyrrolyl groups preserved the Möbius topology even in solution. Despite a twist, 1 has in-plane conjugation and possesses a unique size dependence of the electronic properties: namely, the opposite size dependency of the HOMO-LUMO energy relative to conventional π-conjugated molecules.

Significant Effect of the Flexibility of Bridging Alkyl Chains on the Proximity of Stacked Porphyrin and Phthalocyanine Conjugated with a Fourfold Rotaxane Linkage.

Invited for the cover of this issue are Kentaro Tanaka at Nagoya University and co-workers. The image depicts the importance of the flexibility of bridging alkyl chains in a molecular conjugate to pack the components closely to generate efficient molecular communication. Read the full text of the article at 10.1002/chem.202200819.

Significant Effect of the Flexibility of Bridging Alkyl Chains on the Proximity of Stacked Porphyrin and Phthalocyanine Conjugated with a Fourfold Rotaxane Linkage.

Spatial distance is an important factor in controlling the functional interactions between molecular units in a conjugate; therefore, the bridging unit has been closely examined. Here, we examined the effect of the flexibility of bridging alkyl chains on the proximity of stacked porphyrin and phthalocyanine conjugated with a fourfold rotaxane linkage. We found that closely stacking two π systems requires bridging alkyl chains above a certain length, and the shorter bridges hinder stacking because of their lower flexibility. The stacking distance between porphyrin and phthalocyanine in the conjugate with decyl (C10 ) chains was estimated to be 4.03 Šand showed a unique physical character arising from short-distance interactions. The longer alkyl chains minimized steric restriction inside the fourfold rotaxane and allowed efficient communication between the porphyrin and phthalocyanine units. This is due to the flexibility of the side chains.

Conformational changes of α-helical peptides with different hydrophobic residues induced by metal-ion binding.

We designed peptides that formed helix bundle structures upon binding of the metal-ions to His residues to form a stable hydrophobic core, in order to analyze the effects of Ala, Val, Ile, and Leu residues, located in the hydrophobic core, together with His, on the conformational changes in respective peptides designated as HA, HV, HI, and HL, respectively. Circular dichroism measurements showed that HV and HI changed from random coil to helix bundle structures upon Zn2+ binding, similar to that observed for HA, while HL existed in the helix bundle structure even in the absence of Zn2+. Electron spin resonance measurements showed that Cu2+ coordination of HI and HL was quite different from that of HA and HV, indicating that HA and HV fluctuated to a greater extent in the solution, despite that their apparent α-helical contents being similar to those of HI and HL. This was also supported by the results obtained from the analyses of thermal stabilities. The change in the structural fluctuation for each peptide upon Zn2+ binding was evaluated based on binding thermodynamics using isothermal titration calorimetry. The structural flexibility in the metal-ion-bound state was found to be in the order HA > HV > HI, and that in the metal-ion-unbound state was found to be greater for HI than that for HL.

EPR study of NO radicals encased in modified open C60 fullerenes.

Using pulsed electron paramagnetic resonance (EPR) techniques, the low-temperature magnetic properties of the NO radical being confined in two different modified open C60-derived cages are determined. It is found that the smallest principal g value g3, being assigned to the axis of the radical, deviates strongly from the free electron value. This behaviour results from partial compensation of the spin and orbital contributions to the g3 value. The measured g3 values in the range of 0.7 yield information about the deviation of the locking potential for the encaged NO from axial symmetry. The estimated 17 meV asymmetry is quite small compared to the situation found for the same radical in polycrystalline or amorphous matrices ranging from 300 to 500 meV. The analysis of the temperature dependence of spin relaxation times resulted in an activation temperature of about 3 K, assigned to temperature-activated motion of the NO within the modified open C60-derived cages with coupled rotational and translational degrees of freedom in a complicated three-dimensional locking potential.

Size-tunable MRI-visible nitroxide-based magnetic mixed micelles: preparation, stability, and theranostic application.

Metal-free magnetic mixed micelles (mean diameter: 16 nm) composed of biocompatible surfactant Tween 80 and hydrophobic pyrrolidine-N-oxyl radical were prepared by mixing them in phosphate-buffered saline. The magnetic mixed micelles were characterized by dynamic light scattering and small angle neutron scattering measurements. The stability of the micelles is found to depend on the length of alkyl side chain in the nitroxide compounds and degree of unsaturation in the hydrophobic chain in the surfactant. The size of the mixed micelle can be tuned by changing the molar ratio of Tween 80 and nitroxyl radical. In view of theranostic application of the micelle, the cytotoxicity and stability in a physiological environment was investigated; the mixed micelle exhibited no cytotoxicity, high colloidal stability and high resistance towards reduction by large excess ascorbic acid. The in vitro and in vivo magnetic resonance imaging (MRI) revealed sufficient contrast enhancement in the proton longitudinal relaxation time (T 1) weighted images. In addition, hydrophobic fluorophores and an anticancer drug are stably encapsulated in the mixed micelles and showed fluorescence (FL) upon reduction by ascorbic acid and cytotoxicity to cancer cells, respectively. For example, the paclitaxel-loaded mixed micelles efficiently suppressed cancer cell growth. Furthermore, they were found to give higher MRI contrast (higher r 1 value) in vitro than the micelles without paclitaxel. The magnetic mixed micelles presented here are promising theranostic agents in nanomedicine due to their high biocompatibility and high resistivity towards reduction as well as functioning as a drug carrier in therapy and MR or FL imaging probe in diagnosis.

Magnetic Mixed Micelles Composed of a Non-Ionic Surfactant and Nitroxide Radicals Containing a D-Glucosamine Unit: Preparation, Stability, and Biomedical Application.

Metal-free magnetic mixed micelles (mean diameter: < 20 nm) were prepared by mixing the biocompatible non-ionic surfactant Tween 80 and the non-toxic, hydrophobic pyrrolidine-N-oxyl radicals bearing a D-glucosamine unit in pH 7.4 phosphate-buffered saline (PBS). The time-course stability and in vitro magnetic resonance imaging (MRI) contrast ability of the mixed micelles was found to depend on the length of the alkyl chain in the nitroxide radicals. It was also confirmed that the mixed micelles exhibited no toxicity in vivo and in vitro and high stability in the presence of a large excess of ascorbic acid. The in vivo MRI experiment revealed that one of these mixed micelles showed much higher contrast enhancement in the proton longitudinal relaxation time (T1) weighted images than other magnetic mixed micelles that we have reported previously. Thus, the magnetic mixed micelles presented here are expected to serve as a promising contrast agent for theranostic nanomedicines, such as MRI-visible targeted drug delivery carriers.

Platinum(II) Terpyridine Complex That Switches Its Photochemical Reactivity in Response to Its Chromic Behavior in the Crystalline State.

A platinum(II) terpyridine complex having an enantiopure lactate anion afforded hydrated crystals l- or d-1hyd containing infinite chains of interacting Pt centers, while their dehydration induced crystal-to-crystal transformation into l- or d-1dehyd, respectively, exhibiting less significant Pt-Pt and/or ligand-ligand interactions. That transformation was accompanied by changes in the color as well as the photochemical reactivity of the crystals, where l-1dehyd showed higher reactivity than l-1hyd in the presence of amines under visible-light irradiation.

Construction of a Metal-Free Electron Spin System by Encapsulation of an NO Molecule Inside an Open-Cage Fullerene C60 Derivative.

A reactive radical species, nitric oxide (NO), was encapsulated in a unimolecular form inside an open-cage fullerene derivative under high-pressure conditions in the solid state. Surprisingly, the molecular complex showed sharp 1 H NMR signals despite the existence of the paramagnetic species inside the carbon cage. Owing to the paramagnetic shifts, the escape rate of the NO was determined experimentally. After constructing a stopper on the rim of the opening, the NO was found to stay inside the cage even at 50 °C. The ESR measurements of the powdery sample showed paramagnetic properties at low temperature. The single-crystal X-ray structure analysis clearly demonstrated the existence of the encapsulated NO molecule, suggesting rapid rotation inside the cage. The 1 H NMR chemical shifts displayed a large temperature dependence owing to the paramagnetic effects.

Crystalline functionalized endohedral C60 metallofullerides.

Endohedral metallofullerenes have been extensively studied since the first experimental observation of La@C60 in a laser-vaporized supersonic beam in 1985. However, most of these studies have focused on metallofullerenes larger than C60 such as (metal)@C82, and there are no reported purified C60-based monomeric metallofullerenes, except for [Li@C60]+(SbCl6)- salt. Pure (metal)@C60 compounds have not been obtained because of their extremely high chemical reactivity. One route to their stabilization is through chemical functionalization. Here we report the isolation, structural determination and electromagnetic properties of functionalized crystalline C60-based metallofullerenes Gd@C60(CF3)5 and La@C60(CF3)5. Synchrotron X-ray single-crystal diffraction reveals that La and Gd atoms are indeed encapsulated in the Ih-C60 fullerene. The HOMO-LUMO gaps of Gd@C60 and La@C60 are significantly widened by an order of magnitude with addition of CF3 groups. Magnetic measurements show the presence of a weak antiferromagnetic coupling in Gd@C60(CF3)3 crystals at low temperatures.

Programmable arrangement of metal ions in a cofacially stacked assembly of porphyrinoids toward molecular tags.

Cofacial assemblies of metalloporphyrinoids represent a fascinating platform for the fabrication of novel functional molecular assemblies based on π-π, d-d, and d-π interactions between components. In this paper, we present a novel synthetic strategy for the programmable arrangement of different metal ions inside a cofacially stacked trimer of porphyrinoids. A combination of two different assemblies was utilized for our purpose: a tetracationic fourfold rotaxane heterodimer between a porphyrin with four alkylammonium chains and a phthalocyanine bearing four peripheral crown ethers, and a stacked assembly between the fourfold rotaxane heterodimer and an additional tetraanionic porphyrin. Three metal ions, namely Cu(ii), Ag(ii), and Au(iii), were arranged inside the cofacially stacked assembly of three porphyrinoids. Moreover, paramagnetic Cu(ii) ions were arranged inside a cofacially stacked heterotrimer of porphyrinoids and were precisely programmed, affording the desired spin-spin communications as readable information. These results indicated that the developed strategy is effective for arranging various metal ions in cofacially stacked assemblies of porphyrinoids toward the creation of molecular tags or bar codes.

Dynamic Molecular Invasion into a Multiply Interlocked Catenane.

A multiply interlocked catenane with a novel molecular topology was synthesized; a phthalocyanine bearing four peripheral crown ethers was quadruply interlocked with a cofacial porphyrin dimer bridged with four alkylammonium chains. The supramolecular conjugate has two nanospaces surrounded by a porphyrin, a phthalocyanine, and four alkyl chains to accommodate guest molecules. Because the phthalocyanine can move along the alkyl chains, it acts as an adjustable wall, thus permitting the invasion of large molecules into the nanospaces without spoiling the affinity of the association. The dynamic molecular invasion allowed the intercalation of dianionic porphyrins into both nanospaces with high affinity. A photometric titration experiment revealed the two-step inclusion phenomenon. The multiply interlocked catenane complexed with three Cu2+ ions, and the spin-spin interaction was switched off by the intercalation of dianionic porphyrins.

Bis-Copper(II)/π-Radical Multi-Heterospin System with Non-innocent Doubly N-Confused Dioxohexaphyrin(1.1.1.1.1.0) Ligand.

A contracted doubly N-confused dioxohexaphyrin(1.1.1.1.1.0) complex consisting of two paramagnetic copper metals and open-shell π-radical ligand was synthesized as a new multi-heterospin motif. X-ray spectroscopy supported the divalent character of the inner copper centers, and electron paramagnetic resonance and magnetometric studies suggested the presence of unpaired d electrons strongly antiferromagnetically coupled with π-radicals delocalized on the macrocycle. The 25 π non-innocent dioxohexaphyrin ligand allowed the facile interconversion between antiaromatic 24 π and aromatic 26 π species, respectively, upon redox reactions.

Preparation of Robust Metal-Free Magnetic Nanoemulsions Encapsulating Low-Molecular-Weight Nitroxide Radicals and Hydrophobic Drugs Directed Toward MRI-Visible Targeted Delivery.

With a view to developing a theranostic nanomedicine for targeted drug delivery systems visible by magnetic resonance (MR) imaging, robust metal-free magnetic nanoemulsions (mean particle size less than 20 nm) consisting of a biocompatible surfactant and hydrophobic, low molecular weight 2,2,5-trimethyl-5-(4-alkoxy)phenylpyrrolidine-N-oxyl radicals were prepared in pH 7.4 phosphate-buffered saline (PBS). The structure of the nanoemulsions was characterized by electron paramagnetic resonance spectroscopy, and dynamic light scattering and small-angle neutron-scattering measurements. The nanoemulsions showed high colloidal stability, low cytotoxicity, enough reduction resistance to excess ascorbic acid, and sufficient contrast enhancement in the proton longitudinal relaxation time (T1 ) weighted MR images in PBS in vitro (and preliminarily in vivo). Furthermore, the hydrophobic anticancer drug paclitaxel could be encapsulated inside the nanoparticles, and the resulting paclitaxel-loaded nanoemulsions were efficiently incorporated into HeLa cells to suppress cell growth.

Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex.

The Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2) complex is essential for LPS recognition and induces innate immune responses against Gram-negative bacteria. As activation of TLR4/MD-2 is also critical for the induction of adaptive immune responses, TLR4/MD-2 agonists have been developed as vaccine adjuvants, but their efficacy has not yet been ascertained. Here, we demonstrate that a funiculosin (FNC) variant, FNC-RED, and FNC-RED and FNC derivatives are agonists for both murine and human TLR4/MD-2. FNC-RED induced nuclear factor-κB (NF-κB) activation via murine TLR4/MD-2, whereas FNC had no TLR4/MD-2 stimulatory activity. Biacore analysis revealed that FNC-RED binds to murine TLR4/MD-2 but not murine radioprotective 105 (RP105)/myeloid differentiation factor-1 (MD-1), another LPS sensor. FNC-RED induced CD14-independent expressions of pro-inflammatory cytokines and co-stimulatory molecules in murine macrophages and dendritic cells. In contrast, FNC-RED stimulation was reduced in CD14-dependent LPS responses, including dimerization and internalization of TLR4/MD-2 and IFN-ß expression. FNC-RED-induced IL-12p40 production from murine dendritic cells was dependent on NF-κB but not MAPK pathway. In addition, fetal bovine serum augmented lipid A-induced NF-κB activation but blocked FNC-RED-mediated responses. Two synthetic phosphate group-containing FNC-RED and FNC derivatives, FNC-RED-P01 and FNC-P01, respectively, activated human TLR4/MD-2, unlike FNC-RED. Finally, computational analysis revealed that this species-specific activation by FNC-RED and FNC-RED-P01 resulted from differences in electrostatic surface potentials between murine and human TLR4/MD-2. We conclude that FNC-RED and its synthetic derivative represent a novel category of murine and human TLR4/MD-2 agonist.

Fullerene C70 as a Nanoflask that Reveals the Chemical Reactivity of Atomic Nitrogen.

To investigate the intrinsic reactivity of atomic nitrogen, which had previously been accomplished only by examining its decay in the gas phase using special equipment, a nitrogen atom was inserted into a series of molecule-encapsulating C60 and C70 fullerenes. Among the studied endofullerenes, H2 @C70 was able to encapsulate an additional nitrogen atom within the fullerene cage under radiofrequency plasma conditions. The product was analyzed by ESR spectroscopy and mass spectrometry in solution, which revealed that the nitrogen atom with a quartet ground state does not react but weakly interact with the H2 molecule, thus demonstrating the utility of such fullerenes as "nanoflasks".

A Stable, Soluble, and Crystalline Supramolecular System with a Triplet Ground State.

A supramolecular complex was constructed by encapsulation of a 3 O2 molecule inside an open-cage C60 derivative. Its single-crystal X-ray diffraction analysis revealed the presence of the 3 O2 at the center of the fullerene cage. The CV measurements suggested that unprecedented dehydrogenation was promoted by the encapsulated 3 O2 after two-electron reduction. The ESR measurements displayed the triplet character as well as the anisotropy of the 3 O2 . Additionally, the SQUID measurements also demonstrated the paramagnetic behavior above 3 K without an antiferromagnetic transition. Upon photoirradiation with visible light, three phosphorescent bands at the NIR region were observed, arising from the exited 1 O2 generated by self-sensitization with the outer cage, whose lifetimes were not affected by the environments. These studies confirmed that the complex is a crystalline triplet system with incompatible "high spin density" but "small interspin interaction" properties.

Base assisted C-C coupling between carbonyl and polypyridyl ligands in a Ru-NADH-type carbonyl complex.

A reaction of a ruthenium(ii) NAD-type complex, [Ru(tpy)(pbn)(Cl)]+ (tpy = 2,2':6',2''-terpyridine; pbn = 2-(pyridin-2-yl)benzo[b][1,5]naphthyridine), with pressurized CO (2 MPa) at 150 °C in H2O selectively produced a two-electron reduced ruthenium(ii)-NADH-type carbonyl complex, [Ru(tpy)(pbnHH)(CO)]2+ (pbnHH = 2-(pyridin-2-yl)-5,10-dihydrobenzo[b][1,5]naphthyridine), rather than the oxidized [Ru(tpy)(pbn)(CO)]2+ complex. Indeed, [Ru(tpy)(pbnHH)(CO)]2+ was quantitatively oxidized to [Ru(tpy)(pbn)(CO)]2+ upon treatment with one equiv. of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The reactivity of [Ru(tpy)(pbnHH)(CO)]2+ with various bases was studied herein. Treatment of [Ru(tpy)(pbnHH)(CO)]2+ with a suitable organic base, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), resulted in the formation of a new five-membered Ru-CO-bridge metallacycle quantitatively in acetonitrile under air at room temperature. A probable mechanism was proposed for this reaction based on UV-vis, NMR, and EPR spectral studies and other experimental data. Furthermore, a reaction of the five membered Ru-CO-bridge metallacycle with NH4PF6 in CH3CN : H2O (1 : 1) under air smoothly produced another new six-membered Ru-OCO-bridge complex. A mechanism for the formation of a Ru-OCO-bridge complex was also proposed here on the basis of H2O18 experiments, DDQ treatment and other experimental data. These newly synthesized complexes appended with NAD-type ligands may have potential use as renewable hydride sources for organic reductions.

9,10-Diaminoanthracenes Revisited: The Influence of N-Substituents on Their Electronic States.

The electronic and molecular structures of 9,10-diamino-substituted anthracenes with different N-substituents have been re-examined. In particular, different N-substituents influence both the electronic and molecular structures of the oxidized species of 9,10-diaminoanthracenes. The anthrylene moiety of 9,10-bis(N,N-di(p-anisyl)amino)anthracene retains its planarity during the course of two successive one-electron oxidations, whereas 9,10-bis(N,N-dimethylamino)anthracene and 9,10-bis(N-p-anisyl-N-methylamino)anthracene undergo a substantial structural change to a butterfly-like structure through a two-electron oxidation process. The structural changes observed for the oxidized states are ascribed to significant differences in the frontier molecular orbitals of the above-mentioned three kinds of 9,10-diaminoanthracenes due to different extents of mixing between the amine-localized and anthrylene-localized orbitals.

Assembly of Multi-Phthalocyanines on a Porphyrin Template by Fourfold Rotaxane Formation.

A stacked assembly composed of a porphyrin and two phthalocyanines was prepared through fourfold rotaxane formation. Two phthalocyanine molecules, bearing four 24-crown-8 units, were assembled onto a porphyrin template incorporating four sidechains with two dialkylammonium ions each through pseudorotaxane formation between crown ether units and ammonium ions. The Staudinger phosphite reaction, as the stoppering reaction, resulted in the formation of the stacked heterotrimer composed of a porphyrin and two phthalocyanines connected through a fourfold rotaxane structure. UV/Vis spectroscopic and electrochemical studies of the heterotrimer indicated that there is a significant electronic interaction between the two phthalocyanine units due to the close stacking. The electrochemical oxidation process of the stacked heterotrimer was studied by cyclic voltammetry and spectroelectrochemistry. Electron paramagnetic resonance (EPR) spectroscopy of a dinuclear Cu(II) complex, in which two Cu(II) phthalocyanines were assembled on a metal-free porphyrin template, revealed that two Cu(II) phthalocyanines were located within the stacking distance, which resulted in an antiferromagnetic interaction between the two S=1/2 spins in the ground state of the Cu(2+) ions in the heterotrimer.