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.     

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.     

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.     

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.     

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.     

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.     

Designing logical codon reassignment – Expanding the chemistry in biology

Over the last decade, the ability to genetically encode unnatural amino acids (UAAs) has evolved rapidly. The programmed incorporation of UAAs into recombinant proteins relies on the reassignment or suppression of canonical codons with an amino-acyl tRNA synthetase/tRNA (aaRS/tRNA) pair, selective for the UAA of choice. In order to achieve selective incorporation, the aaRS should be selective for the designed tRNA and UAA over the endogenous amino acids and tRNAs. Enhanced selectivity has been achieved by transferring an aaRS/tRNA pair from another kingdom to the organism of interest, and subsequent aaRS evolution to acquire enhanced selectivity for the desired UAA. Today, over 150 non-canonical amino acids have been incorporated using such methods. This enables the introduction of a large variety of structures into proteins, in organisms ranging from prokaryote, yeast and mammalian cells lines to whole animals, enabling the study of protein function at a level that could not previously be achieved. While most research to date has focused on the suppression of ‘non-sense’ codons, recent developments are beginning to open up the possibility of quadruplet codon decoding and the more selective reassignment of sense codons, offering a potentially powerful tool for incorporating multiple amino acids. Here, we aim to provide a focused review of methods for UAA incorporation with an emphasis in particular on the different tRNA synthetase/tRNA pairs exploited or developed, focusing upon the different UAA structures that have been incorporated and the logic behind the design and future creation of such systems. Our hope is that this will help rationalize the design of systems for incorporation of unexplored unnatural amino acids, as well as novel applications for those already known.     

In vitro reconstitution of α-pyrone ring formation in myxopyronin biosynthesis

Myxopyronins are α-pyrone antibiotics produced by the terrestrial bacterium Myxococcus fulvus Mx f50 and possess antibacterial activity against Gram-positive and Gram-negative pathogens. They target the bacterial RNA polymerase (RNAP) “switch region” as non-competitive inhibitors and display no cross-resistance to the established RNAP inhibitor rifampicin. Recent analysis of the myxopyronin biosynthetic pathway led to the hypothesis that this secondary metabolite is produced from two separate polyketide parts, which are condensed by the stand-alone ketosynthase MxnB. Using in vitro assays we show that MxnB catalyzes a unique condensation reaction forming the α-pyrone ring of myxopyronins from two activated acyl chains in form of their β-keto intermediates. MxnB is able to accept thioester substrates coupled to either N-acetylcysteamine (NAC) or a specific carrier protein (CP). The turnover rate of MxnB for substrates bound to CP was 12-fold higher than for NAC substrates, demonstrating the importance of protein–protein interactions in polyketide synthase (PKS) systems. The crystal structure of MxnB reveals the enzyme to be an unusual member of the ketosynthase group capable of binding and condensing two long alkyl chains bound to carrier proteins. The geometry of the two binding tunnels supports the biochemical data and allows us to propose an order of reaction, which is supported by the identification of novel myxopyronin congeners in the extract of the producer strain. Insights into the mechanism of this unique condensation reaction do not only expand our knowledge regarding the thiolase enzyme family but also opens up opportunities for PKS bioengineering to achieve directed structural modifications.     

Counterion influence on the N–I–N halogen bond

A detailed investigation of the influence of counterions on the [N–I–N]⁺ halogen bond in solution, in the solid state and in silico is presented. Translational diffusion coefficients indicate close attachment of counterions to the cationic, three-center halogen bond in dichloromethane solution. Isotopic perturbation of equilibrium NMR studies performed on isotopologue mixtures of regioselectively deuterated and nondeuterated analogues of the model system showed that the counterion is incapable of altering the symmetry of the [N–I–N]⁺ halogen bond. This symmetry remains even in the presence of an unfavorable geometric restraint. A high preference for the symmetric geometry was found also in the solid state by single crystal X-ray crystallography. Molecular systems encompassing weakly coordinating counterions behave similarly to the corresponding silver(i) centered coordination complexes. In contrast, systems possessing moderately or strongly coordinating anions show a distinctly different behavior. Such silver(i) complexes are converted into multi-coordinate geometries with strong Ag–O bonds, whereas the iodine centered systems remain linear and lack direct charge transfer interaction with the counterion, as verified by ¹⁵N NMR and DFT computation. This suggests that the [N–I–N]⁺ halogen bond may not be satisfactorily described in terms of a pure coordination bond typical of transition metal complexes, but as a secondary bond with a substantial charge-transfer character.     

Well-defined silica supported aluminum hydride: another step towards the utopian single site dream?

Reaction of triisobutylaluminum with SBA15₇₀₀ at room temperature occurs by two parallel pathways involving either silanol or siloxane bridges. It leads to the formation of a well-defined bipodal [(SiO)₂Al–CH₂CH(CH₃)₂] 1a, silicon isobutyl [Si–CH₂CH(CH₃)₂] 1b and a silicon hydride [Si–H] 1c. Their structural identity was characterized by FT-IR and advanced solid-state NMR spectroscopies (¹H, ¹³C, ²⁹Si, ²⁷Al and 2D multiple quantum), elemental and gas phase analysis, and DFT calculations. The reaction involves the formation of a highly reactive monopodal intermediate: [SiO–Al–[CH₂CH(CH₃)₂]₂], with evolution of isobutane. This intermediate undergoes two parallel routes: transfer of either one isobutyl fragment or of one hydride to an adjacent silicon atom. Both processes occur by opening of a strained siloxane bridge, Si–O–Si but with two different mechanisms, showing that the reality of “single site” catalyst may be an utopia: DFT calculations indicate that isobutyl transfer occurs via a simple metathesis between the Al-isobutyl and O–Si bonds, while hydride transfer occurs via a two steps mechanism, the first one is a β-H elimination to Al with elimination of isobutene, whereas the second is a metathesis step between the formed Al–H bond and a O–Si bond. Thermal treatment of 1a (at 250 °C) under high vacuum (10^–5 mbar) generates Al–H through a β-H elimination of isobutyl fragment. These supported well-defined Al–H which are highly stable with time, are tetra, penta and octa coordinated as demonstrated by IR and ²⁷Al–¹H J-HMQC NMR spectroscopy. All these observations indicate that surfaces atoms around the site of grafting play a considerable role in the reactivity of a single site system.     

Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli

New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance. Pathogen-specific antibiotics have several advantages over broad-spectrum drugs, which include minimal perturbation to the commensal microbiota. We present a strategy for targeting antibiotics to bacterial pathogens that utilises the salmochelin-mediated iron uptake machinery of Gram-negative Escherichia coli. Salmochelins are C-glucosylated derivatives of the siderophore enterobactin. The biosynthesis and utilisation of salmochelins are important for virulence because these siderophores allow pathogens to acquire iron and evade the enterobactin-scavenging host-defense protein lipocalin-2. Inspired by the salmochelins, we report the design and chemoenzymatic preparation of glucosylated enterobactin–β-lactam conjugates that harbour the antibiotics ampicillin (Amp) and amoxicillin (Amx), hereafter GlcEnt–Amp/Amx. The GlcEnt scaffolds are based on mono- and diglucosylated Ent where one catechol moiety is functionalized at the C5 position for antibiotic attachment. We demonstrate that GlcEnt–Amp/Amx provide up to 1000-fold enhanced antimicrobial activity against uropathogenic E. coli relative to the parent β-lactams. Moreover, GlcEnt–Amp/Amx based on a diglucosylated Ent (DGE) platform selectively kill uropathogenic E. coli that express the salmochelin receptor IroN in the presence of non-pathogenic E. coli and other bacterial strains that include the commensal microbe Lactobacillus rhamnosus GG. Moreover, GlcEnt–Amp/Amx evade the host-defense protein lipocalin-2, and exhibit low toxicity to mammalian cells. Our work establishes that siderophore–antibiotic conjugates provide a strategy for targeting virulence, narrowing the activity spectrum of antibiotics in clinical use, and achieving selective delivery of antibacterial cargos to pathogenic bacteria on the basis of siderophore receptor expression.     

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%.     

Mutual stabilisation between MII 4L6 tetrahedra and MIIX4 2– metallate guests

A complex host–guest equilibrium employing metal ions incorporated into both the host and guest is discussed. M^IIX₄ ^2– metallate guests are shown to provide a good size and shape match for encapsulation within the M₄L₆ tetrahedral capsules, facilitating the generation of previously unreported Zn₄L₆ complexes. Displacement of the initial, primary template anion (ZnBr₄ ^2–) by a secondary template anion (ClO₄ ^–) is shown to result in the formation of a pentagonal-prismatic Zn₁₀L₁₅ structure that incorporates both Br^– and ClO₄ ^–. Furthermore, the formation of heterometallic complexes provides direct evidence for metal exchange between the guest and host complex.     

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.     

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.     

Linear scaling relationships and volcano plots in homogeneous catalysis – revisiting the Suzuki reaction

Linear free energy scaling relationships and volcano plots are common tools used to identify potential heterogeneous catalysts for myriad applications. Despite the striking simplicity and predictive power of volcano plots, they remain unknown in homogeneous catalysis. Here, we construct volcano plots to analyze a prototypical reaction from homogeneous catalysis, the Suzuki cross-coupling of olefins. Volcano plots succeed both in discriminating amongst different catalysts and reproducing experimentally known trends, which serves as validation of the model for this proof-of-principle example. These findings indicate that the combination of linear scaling relationships and volcano plots could serve as a valuable methodology for identifying homogeneous catalysts possessing a desired activity through a priori computational screening.     

Rh-catalyzed desymmetrization of α-quaternary centers by isomerization-hydroacylation

We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from α,α-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C–H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of α-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation.     

Pd-η 3-C6H9 complexes of the Trost modular ligand: high nuclearity columnar aggregation controlled by concentration,solvent and counterion

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η ³-C₆H₉ intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η ³-C₆H₉ species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η ³-C₆H₉ cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D₄₇) isotopologues of the resulting complexes ([1]⁺), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.     

Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

Developing approaches to discover protein–protein interactions (PPIs) remains a fundamental challenge. A chemical biology platform is applied here to identify novel PPIs for the AAA+ superfamily oncoprotein reptin. An in silico screen coupled with chemical optimization provided Liddean, a nucleotide-mimetic which modulates reptin''s oligomerization status, protein-binding activity and global conformation. Combinatorial peptide phage library screening of Liddean-bound reptin with next generation sequencing identified interaction motifs including a novel reptin docking site on the p53 tumor suppressor protein. Proximity ligation assays demonstrated that endogenous reptin forms a predominantly cytoplasmic complex with its paralog pontin in cancer cells and Liddean promotes a shift of this complex to the nucleus. An emerging view of PPIs in higher eukaryotes is that they occur through a striking diversity of linear peptide motifs. The discovery of a compound that alters reptin''s protein interaction landscape potentially leads to novel avenues for therapeutic development.