Unveiling the nature of supramolecular crown ether–C60 interactions

A series of exTTF-(crown ether)₂ receptors, designed to host C₆₀, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)₂·C₆₀ stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor–acceptor, π–π, n–π and CH···π interactions, which is the basis for the affinity of our novel receptors towards C₆₀.     

What causes extended layering of ionic liquids on the mica surface?

Extended layering of ionic liquids (ILs) on the mica surface has been reported by several groups previously and it is generally accepted that the electrostatic interaction at the IL/mica interface is critical to the observed extended layering. Here we report that, indeed, water adsorption on the mica surface is the key to the extended layering of ionic liquids. The atomic force microscopy (AFM), attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR) and contact angle (CA) results show that ionic liquids form extended layering on a mica surface under ambient conditions when water is adsorbed on the mica surface under such conditions. However, when airborne hydrocarbon contaminants replace the water on the mica surface at the elevated temperatures, instead of layering, ionic liquids exhibit droplet structure, i.e., dewetting. Based on the experimental results, we propose that water enables ion exchange between K+ and the cations of ILs on the mica surface and thus triggers the ordered packing of cations/anions in ILs, resulting in extended layering.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Copper-catalyzed intermolecular C(sp3)–H bond functionalization towards the synthesis of tertiary carbamates

We describe the development of an intermolecular unactivated C(sp³)–H bond functionalization towards the direct synthesis of tertiary carbamates. The transformation proceeded using a readily available, abundant first-row transition metal catalyst (copper), and isocyanates as the source of the amide moiety. This is a novel strategy for direct transformation of a variety of unactivated hydrocarbon feedstocks to N-alkyl-N-aryl and N,N-dialkyl carbamates without pre-functionalization or installation of a directing group. The reaction had a broad substrate scope with 3° > 2° > 1° site selectivity. The reaction proceeded even on a gram scale, and a corresponding free amine was directly obtained when the reaction was performed at high temperature. Kinetic studies suggested that radical-mediated C(sp³)–H bond cleavage was the rate-determining step.     

A carbon–carbon hybrid – immobilizing carbon nanodots onto carbon nanotubes

The thrust of this work is to integrate small and uniformly sized carbon nanodots (CNDs) with single-walled carbon nanotubes (SWCNT) of different diameters as electron donors and electron acceptors, respectively, and to test their synergetic interactions in terms of optoelectronic devices. CNDs (denoted pCNDs, where p indicates pressure) were prepared by pressure-controlled microwave decomposition of citric acid and urea. pCNDs were immobilized on single-walled carbon nanotubes by wrapping the latter with poly(4-vinylbenzyl trimethylamine) (PVBTA), which features positively charged ammonium groups in the backbone. Negatively charged surface groups on the CNDs lead to attractive electrostatic interactions. Ground state interactions between the CNDs and SWCNTs were confirmed by a full-fledged photophysical investigation based on steady-state and time-resolved techniques. As a complement, charge injection into the SWCNTs upon photoexcitation was investigated by ultra-short time-resolved spectroscopy.     

Acid/base-regulated reversible electron transfer disproportionation of N–N linked bicarbazole and biacridine derivatives

Regulation of electron transfer on organic substances by external stimuli is a fundamental issue in science and technology, which affects organic materials, chemical synthesis, and biological metabolism. Nevertheless, acid/base-responsive organic materials that exhibit reversible electron transfer have not been well studied and developed, owing to the difficulty in inventing a mechanism to associate acid/base stimuli and electron transfer. We discovered a new phenomenon in which N–N linked bicarbazole (BC) and tetramethylbiacridine (TBA) derivatives undergo electron transfer disproportionation by acid stimulus, forming their stable radical cations and reduced species. The reaction occurs through a biradical intermediate generated by the acid-triggered N–N bond cleavage reaction of BC or TBA, which acts as a two electron acceptor to undergo electron transfer reactions with two equivalents of BC or TBA. In addition, in the case of TBA the disproportionation reaction is highly reversible through neutralization with NEt₃, which recovers TBA through back electron transfer and N–N bond formation reactions. This highly reversible electron transfer reaction is possible due to the association between the acid stimulus and electron transfer via the acid-regulated N–N bond cleavage/formation reactions which provide an efficient switching mechanism, the ability of the organic molecules to act as multi-electron donors and acceptors, the extraordinary stability of the radical species, the highly selective reactivity, and the balance of the redox potentials. This discovery provides new design concepts for acid/base-regulated organic electron transfer systems, chemical reagents, or organic materials.     

Spying on the boron–boron triple bond using spin–spin coupling measured from 11B solid-state NMR spectroscopy

There is currently tremendous interest in the previously documented example of a stable species exhibiting a boron–boron triple bond (Science, 2012, 336, 1420). Notably, it has recently been stated using arguments based on force constants that this diboryne may not, in reality, feature a boron–boron triple bond. Here, we use advanced solid-state NMR and computational methodology in order to directly probe the orbitals involved in multiple boron–boron bonds experimentally via analysis of ¹¹B–¹¹B spin–spin (J) coupling constants. Computationally, the mechanism responsible for the boron–boron spin–spin coupling in these species is found to be analogous to that for the case of multiply-bonded carbon atoms. The trend in reduced J coupling constants for diborenes and a diboryne, measured experimentally, is in agreement with that known for alkenes and alkynes. This experimental probe of the electronic structure of the boron–boron multiple bond provides strong evidence supporting the originally proposed nature of the bonds in the diboryne and diborenes, and demonstrates that the orbitals involved in boron–boron bonding are equivalent to those well known to construct the multiple bonds between other second-row elements such as carbon and nitrogen.     

Bypassing the lack of reactivity of endo-substituted norbornenes with the catalytic rectification–insertion mechanism

The catalytic 1,2-insertion polymerization of polar norbornenes (NBEs) leads to the formation of functional rigid macromolecules with exceptional thermal, optical and mechanical properties. However, this remarkable reaction is plagued by the low reactivity of the polar monomers, and most notably of those bearing a functional group in endo position. We have examined the polymerization mechanism of NBEs bearing one or two CO₂Me groups either in exo or endo position catalyzed by the so-called naked allyl Pd⁺ SbF₆^– catalyst (1). Although endo dimethyl ester of 5-norbornene-2,3-dicarboxylic acid (NBE(CO₂Me)₂) is polymerized by 1, two endo units are never inserted consecutively along the polymer chain. Indeed, 1 is a tandem catalyst which not only catalyzes the insertion of the monomer but also the isomerization of endo and exo isomers. Thus, the polymerization of endo monomers proceeds via a novel mechanism, coined rectification–insertion mechanism, whereby half of the endo monomers are rectified into exo ones prior insertion, leading to the formation of an alternating endo–exo copolymer using an endo only feedstock. With this mechanism, the lack of reactivity of endo norbornenes is bypassed, and the polymerization of predominantly endo polar NBEs bearing a variety of functionalities such as esters, imides, acids, aldehydes, alcohols, anhydrides, or alkyl bromides proceeds with catalyst loadings as low as 0.002 mol%.     

Consecutive C–F bond activation and C–F bond formation of heteroaromatics at rhodium: the peculiar role of FSi(OEt)3

C–F activation of 2,3,5,6-tetrafluoropyridine at [Rh{Si(OEt)₃}(PEt₃)₃] (1) yields [Rh{2-(3,5,6-C₅F₃HN)}(PEt₃)₃] (2) and FSi(OEt)₃, but in an unprecedented consecutive reaction FSi(OEt)₃ acts as a fluoride source to give [Rh(4-C₅F₄N)(PEt₃)₃] (4) by regeneration of the C–F bond and C–H activation. Analogous refluorination steps were observed for other 2-pyridyl rhodium complexes. NMR spectroscopic studies revealed a delicate balance between the feasibility for C–F bond formation accompanied by a C–H activation and the occurrence of competing reactions such as hydrodefluorinations induced by the intermediary presence of H₂.     

Cytocompatible in situ cross-linking of degradable LbL films based on thiol–exchange reaction

Formation of both mechanically durable and programmably degradable layer-by-layer (LbL) films in a biocompatible fashion has potential applications in cell therapy, tissue engineering, and drug-delivery systems, where the films are interfaced with living cells. In this work, we developed a simple but versatile method for generating in situ cross-linked and responsively degradable LbL films, based on the thiol–exchange reaction, under highly cytocompatible conditions (aqueous solution at pH 7.4 and room temperature). The cytocompatibility of the processes was confirmed by coating individual yeast cells with the cross-linked LbL films and breaking the films on demand, while maintaining the cell viability. In addition, the processes were applied to the controlled release of an anticancer drug in the HeLa cells.     

A single crystalline porphyrinic titanium metal–organic framework

We successfully assembled the photocatalytic titanium-oxo cluster and photosensitizing porphyrinic linker into a metal–organic framework (MOF), namely PCN-22. A preformed titanium-oxo carboxylate cluster is adopted as the starting material to judiciously control the MOF growth process to afford single crystals. This synthetic method is useful to obtain highly crystalline titanium MOFs, which has been a daunting challenge in this field. Moreover, PCN-22 demonstrated permanent porosity and photocatalytic activities toward alcohol oxidation.     

Insights into the structure–photoreactivity relationships in well-defined perovskite ferroelectric KNbO3 nanowires

Structure–function correlations are a central theme in heterogeneous (photo)catalysis. In this study, the geometric and electronic structure of perovskite ferroelectric KNbO₃ nanowires with respective orthorhombic and monoclinic polymorphs have been systematically addressed. By virtue of aberration-corrected scanning transmission electron microscopy, we directly visualize surface photocatalytic active sites, measure local atomic displacements at an accuracy of several picometers, and quantify ferroelectric polarization combined with first-principles calculations. The photoreactivity of the as-prepared KNbO₃ nanowires is assessed toward aqueous rhodamine B degradation under UV light. A synergy between the ferroelectric polarization and electronic structure in photoreactivity enhancement is uncovered, which accounts for the prominent reactivity order: orthorhombic > monoclinic. Additionally, by identifying new photocatalytic products, rhodamine B degradation pathways involving N-deethylation and conjugated structure cleavage are proposed. Our findings not only provide new insights into the structure–photoreactivity relationships in perovskite ferroelectric photocatalysts, but also have broad implications in perovskite-based water splitting and photovoltaics, among others.     

Studying the active-site loop movement of the S?o Paolo metallo-β-lactamase-1

Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibiotics. We report biophysical and kinetic studies on the São Paulo MBL (SPM-1), which reveal its Zn(ii) ion usage and mechanism as characteristic of the clinically important di-Zn(ii) dependent B1 MBL subfamily. Biophysical analyses employing crystallography, dynamic ¹⁹F NMR and ion mobility mass spectrometry, however, reveal that SPM-1 possesses loop and mobile element regions characteristic of the B2 MBLs. These include a mobile α3 region which is important in catalysis and determining inhibitor selectivity. SPM-1 thus appears to be a hybrid B1/B2 MBL. The results have implications for MBL evolution and inhibitor design.     

Clˉ as the halogen bond acceptor: studies on strong halogen bonds

The Clˉ anion as the halogen bond acceptor, the diiodotetrafluoroethane I(CF₂)₂I and its derivatives I(MF₂)_nI (M = C, Si, Ge, Sn) as the halogen bond donor, and the strong halogen bonds could be formed. The halogen bonds between I(MF₂)_nI and Clˉ have been designed and investigated by Moller–Plesset perturbation/aug-cc-pVDZ calculations together with the aug-cc-pVDZ-pp basis set for iodine and stannum. The halogen bonds in the I(MF₂)_nI???Clˉ complexes are strong, which are apparently related to the group IV elements, becoming stronger along the sequence of M = Si, C, Ge, Sn. Accompanied with increasing number (n) of MF₂ unit, the halogen bonds (M = Si, Ge, Sn) also become stronger. The energy decomposition analyses reveal that the exchange energy contributes most in forming these halogen-bonded interactions. In the meantime, the electrostatic energy is also a significant factor for the I???Clˉ interactions. The halogen bonds of I(MF₂)nI???Clˉ(M = C, Ge, Sn) belong to partial-covalent interactions, while they are noncovalent interactions when M = Si.     

A catalytic asymmetric total synthesis of (–)-perophoramidine

We report a catalytic asymmetric total synthesis of the ascidian natural product perophoramidine. The synthesis employs a molybdenum-catalyzed asymmetric allylic alkylation of an oxindole nucleophile and a monosubstituted allylic electrophile as a key asymmetric step. The enantioenriched oxindole product from this transformation contains vicinal quaternary and tertiary stereocenters, and is obtained in high yield along with high levels of regio-, diastereo-, and enantioselectivity. To install the second quaternary stereocenter in the target, the route utilizes a novel regio- and diastereoselective allylation of a cyclic imino ether to deliver an allylated imino ether product in near quantitative yield and with complete regio- and diastereocontrol. Oxidative cleavage and reductive amination are used as final steps to access the natural product.     

Three-phase junction for modulating electron–hole migration in anatase–rutile photocatalysts

The heterophase solid–solid junction as an important type of structure unit has wide applications for its special mechanics and electronic properties. Here we present a first three-phase atomic model for the anatase–rutile TiO₂ heterophase junction and determine its optical and electronic properties, which leads to resolution of the long-standing puzzles on the enhanced photocatalytic activity of anatase–rutile photocatalysts. By using a set of novel theoretical methods, including crystal phase transition pathway sampling, interfacial strain analysis and first principles thermodynamics evaluation of holes and electrons, we identify an unusual structurally ordered three-phase junction, a layer-by-layer “T-shaped” anatase/TiO₂-II/rutile junction, for linking anatase with rutile. The intermediate TiO₂-II phase, although predicted to be only a few atomic layers thick in contact with anatase, is critical to alleviate the interfacial strain and to modulate photoactivity. We demonstrate that the three-phase junction acts as a single-way valve allowing the photogenerated hole transfer from anatase to rutile but frustrating the photoelectron flow in the opposite direction, which otherwise cannot be achieved by an anatase–rutile direct junction. This new model clarifies the roles of anatase, rutile and the phase junction in achieving high photoactivity synergistically and provides the theoretical basis for the design of better photocatalysts by exploiting multi-phase junctions.     

NHC-catalysed benzoin condensation – is it all down to the Breslow intermediate?

The Breslow catalytic cycle describing the benzoin condensation promoted by N-heterocyclic carbenes (NHC) as proposed in the late 1950s has since then been tried by generations of physical organic chemists. Emphasis has been laid on proofing the existence of an enaminol like structure (Breslow intermediate) that explains the observed umpolung of an otherwise electrophilic aldehyde. The present study is not focusing on spectroscopic elucidation of a thiazolydene based Breslow intermediate but rather tries to clarify if this key-intermediate is indeed directly linked with the product side of the overall reaction. The here presented EPR-spectroscopic and computational data provide a fundamentally different view on how the benzoin condensation may proceed: a radical pair could be identified as a second key-intermediate that is derived from the Breslow-intermediate via an SET process. These results highlight the close relationship to the Cannizarro reaction and oxidative transformations of aldehydes under NHC catalysis.     

NKT cell-dependent glycolipid–peptide vaccines with potent anti-tumour activity

It is known that T cells can eliminate tumour cells through recognition of unique or aberrantly expressed antigens presented as peptide epitopes by major histocompatibility complex (MHC) molecules on the tumour cell surface. With recent advances in defining tumour-associated antigens, it should now be possible to devise therapeutic vaccines that expand specific populations of anti-tumour T cells. However there remains a need to develop simpler efficacious synthetic vaccines that possess clinical utility. We present here the synthesis and analysis of vaccines based on conjugation of MHC-binding peptide epitopes to α-galactosylceramide, a glycolipid presented by the nonpolymorphic antigen-presenting molecule CD1d to provoke the stimulatory activity of type I natural killer T (NKT) cells. The chemical design incorporates an enzymatically cleavable linker that effects controlled release of the active components in vivo. Chemical and biological analysis of different linkages with different enzymatic targets enabled selection of a synthetic vaccine construct with potent therapeutic anti-tumour activity in mice, and marked in vitro activity in human blood.     

Can acyclic conformational control be achieved via a sulfur–fluorine gauche effect?

The gauche conformation of the 1,2-difluoroethane motif is known to involve stabilising hyperconjugative interactions between donor (bonding, σ_C–H) and acceptor (antibonding, σ*C–F) orbitals. This model rationalises the generic conformational preference of F–C_β–C_α–X systems (φ_FCCX ≈ 60°), where X is an electron deficient substituent containing a Period 2 atom. Little is known about the corresponding Period 3 systems, such as sulfur and phosphorus, where multiple oxidation states are possible. Conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed here, thus extending the scope of the fluorine gauche effect to the 3rd Period (F–C–C–S(O)_n; φ_FCCS ≈ 60°). Synergy between experiment and computation has revealed that the gauche effect is only pronounced in structures bearing an electropositive vicinal sulfur atom (S⁺–O^–, SO₂).     

Counterion effects in the preparation of aldehyde–bisulfite adducts

The identification and development of an aldehyde–bisulfite adduct as an isolable starting material in the synthesis of the CETP inhibitor Evacetrapib are described. The physical properties of the sodium and potassium analogs are compared, and the extension of the scope of this study to include an investigation into the solid state properties of a range of sodium and potassium bisulfite adducts of commonly encountered aldehydes is discussed.