A photocaged, pH-sensitive anion transporter with AND logic dual-stimuli activation.

A pH-switchable anion transporter 1 was photocaged with two photolabile groups to enhance spatiotemporal control over its chloride transport activity. Simultaneous application of light irradiation and acidic pH restores the activity of 1, while either stimulus alone results in no or very low activity. The double activation strategy described herein has potential to yield more selectively cytotoxic anionophores for future medical applications.

Dissecting transmembrane bicarbonate transport by 1,8-di(thio)amidocarbazoles.

Synthetic ionophores able to transport bicarbonate and chloride anions across lipid bilayers are appealing for their wide range of potential biological applications. We have studied the bicarbonate and chloride transport by carbazoles with two amido/thioamido groups using a bicarbonate-sensitive europium(III) probe in liposomes and found a highly remarkable transporter concentration dependence. This can be explained by a combination of two distinct transport mechanisms: HCO3-/Cl- exchange and a combination of unassisted CO2 diffusion and HCl transport, of which the respective contributions were quantified. The compounds studied were found to be highly potent HCl transporters. Based on the mechanistic insights on anion transport, we have tested the antimicrobial activity of these compounds and found a good correlation with their ion transport properties and a high activity against Gram-positive bacteria.

Carbazole-Based Colorimetric Anion Sensors.

Owing to their strong carbazole chromophore and fluorophore, as well as to their powerful and convergent hydrogen bond donors, 1,8-diaminocarbazoles are amongst the most attractive and synthetically versatile building blocks for the construction of anion receptors, sensors, and transporters. Aiming to develop carbazole-based colorimetric anion sensors, herein we describe the synthesis of 1,8-diaminocarbazoles substituted with strongly electron-withdrawing substituents, i.e., 3,6-dicyano and 3,6-dinitro. Both of these precursors were subsequently converted into model diamide receptors. Anion binding studies revealed that the new receptors exhibited significantly enhanced anion affinities, but also significantly increased acidities. We also found that rear substitution of 1,8-diamidocarbazole with two nitro groups shifted its absorption spectrum into the visible region and converted the receptor into a colorimetric anion sensor. The new sensor displayed vivid color and fluorescence changes upon addition of basic anions in wet dimethyl sulfoxide, but it was poorly selective; because of its enhanced acidity, the dominant receptor-anion interaction for most anions was proton transfer and, accordingly, similar changes in color were observed for all basic anions. The highly acidic and strongly binding receptors developed in this study may be applicable in organocatalysis or in pH-switchable anion transport through lipophilic membranes.

Isoreticular Linker Substitution in Conductive Metal-Organic Frameworks with Through-Space Transport Pathways.

The extension of reticular chemistry concepts to electrically conductive three-dimensional metal-organic frameworks (MOFs) has been challenging, particularly for cases in which strong interactions between electroactive linkers create the charge transport pathways. Here, we report the successful replacement of tetrathiafulvalene (TTF) with a nickel glyoximate core in a family of isostructural conductive MOFs with Mn2+ , Zn2+ , and Cd2+ . Different coordination environments of the framework metals lead to variations in the linker stacking geometries and optical properties. Single-crystal conductivity data are consistent with charge transport along the linker stacking direction, with conductivity values only slightly lower than those reported for the analogous TTF materials. These results serve as a case study demonstrating how reticular chemistry design principles can be extended to conductive frameworks with significant intermolecular contacts.

A Photoswitchable Heteroditopic Ion-Pair Receptor.

Designing light-switchable heteroditopic receptors is challenging because it necessitates simultaneous (de)activation of two separate binding sites. Herein, we present the first photoswitchable heteroditopic ion-pair receptor in which both cation and anion binding sites are simultaneously and reversibly switched OFF and ON by a single photoswitch. Our receptor is simple, low molecular weight, and readily synthesized from commercially available precursors. Single-crystal X-ray structures and NMR spectroscopic titrations support ion-pair binding to the receptor both in the solid state and in solution, with strong positive cooperativity between the cation and anion binding. The receptor can be completely switched OFF by UV light-triggered photoisomerization of an acylhydrazone C═N double bond and remains kinetically stable in the deactivated form due to an intramolecular hydrogen bond. Its re-activation could be achieved by light irradiation or, more effectively, by fast acid-catalyzed back-isomerization. Our simple photoswitchable ion-pair receptor may serve as a blueprint for the design of new generations of switchable receptors, transporters, soft materials, and self-assembled systems, where incorporation of a functional heteroditopic ON/OFF photoswitch has been challenging up to now.

1,8-Diamidocarbazoles: an easily tuneable family of fluorescent anion sensors and transporters.

The synthesis, structure and anion recognition properties of an extensive, rationally designed series of bisamide derivatives of 1,8-diaminocarbazole and 1,8-diamino-3,6-dichlorocarbazole are described. Despite simple structures and the presence of only three hydrogen bond donors, such compounds are remarkably strong and selective receptors for oxyanions in DMSO + 0.5%H2O. Owing to their carbazole fluorophore, they are also sensitive turn-on fluorescent sensors for H2PO4- and AcO-, with a more than 15-fold increase in fluorescence intensity upon binding. Despite relatively weak chloride affinity, some of the diamidocarbazoles have also been shown, for the first time, to be very active chloride transporters through lipid bilayers. The binding, sensing and transport properties of these receptors can be easily modulated by the usually overlooked variations in the length and degree of branching of their alkyl side arms. Overall, this study demonstrates that the 1,8-diamidocarbazole binding unit is a very promising and synthetically versatile platform for the development of fluorescent sensors and transporters for anions.

Selective turn-on fluorescence sensing of sulfate in aqueous-organic mixtures by an uncharged bis(diamidocarbazole) receptor.

A linear, uncharged, hydrogen bonding receptor A with two carbazole-based binding domains was synthesised and evaluated for its anion binding properties in DMSO/H2O mixtures. 1H NMR titrations revealed that, in DMSO/H2O 0.5%, A forms both 1 : 1 and 1 : 2 complexes with SO42-, H2PO4-, PhCOO- and Cl-. In 1 : 1 complexes the receptor encloses the tetrahedral anions tightly, forming a helical structure, while Cl- binds with a single carbazole unit only. In the presence of 10% of water the 1 : 2 complexes with SO42- and PhCOO- disappear, and the respective 1 : 1 binding constants decrease sufficiently to be quantified by UV-Vis titration. In this highly competitive medium, A binds sulfate with K1:1 = 105.47 M-1, i.e., it binds approx. 30, 360 and >1000 times more strongly than H2PO4-, PhCOO- and Cl-, respectively. Furthermore, the association with sulfate is over 50 times stronger than that for a model diamidocarbazole 1 under identical conditions, suggesting a very strong chelating effect due to the diglycoyl linker. Increasing the amount of water to 25% (the solubility limit of A) lowers the 1 : 1 binding constant with SO42- to 103.73 M-1. Receptor A was shown to act as a selective turn-on fluorescent sensor for sulfate, able to sense sulfate in sulfate-rich mineral water.

Multivalency by self-assembly: binding of concanavalin†A to metallosupramolecular architectures decorated with multiple carbohydrate groups.

Multiplication of functional units through self-assembly is a powerful way to new properties and functions. In particular, self-organization of components decorated with recognition groups leads to multivalent entities, amenable to strong and selective binding with multivalent targets, such as protein receptors. Here we describe an efficient, supramolecular, one-pot valency multiplication process proceeding through self-organization of monovalent components into well-defined, grid-shaped [2×2] tetranuclear complexes bearing eight sugar residues for multivalent interaction with the tetrameric lectin, concanavalin A (Con A). The grids are stable in water under physiological pH at a relatively high concentration, but dissociate readily at slightly more acidic pH or upon dilution below a certain threshold, in a type of on-off behavior. The carbohydrate-decorated grids interact strongly and selectively with Con A forming triply supramolecular bio-hybrid polymeric networks, which lead to a highly specific phase-separation and quasi-quantitative precipitation of Con A out of solution. Dramatic effects of valency number on agglutination properties were demonstrated by comparison of grids with divalent carbohydrates of covalent and non-covalent (L-shaped, mononuclear zinc complex) scaffolds. The results presented here provide prototypical illustration of the power of multivalency generation by self-assembly leading to defined arrays of functional groups and binding patterns.

Anion-templated synthesis of a switchable fluorescent [2]catenane with sulfate sensing capability.

Anion templation strategies have facilitated the synthesis of various catenane and rotaxane hosts capable of strong and selective binding of anions in competitive solvents. However, this approach has primarily relied on positively charged precursors, limiting the structural diversity and the range of potential applications of the anion-templated mechanically interlocked molecules. Here we demonstrate the synthesis of a rare electroneutral [2]catenane using a powerful, doubly charged sulfate template and a complementary diamidocarbazole-based hydrogen bonding precursor. Owing to the unique three-dimensional hydrogen bonding cavity and the embedded carbazole fluorophores, the resulting catenane receptor functions as a sensitive fluorescent turn-ON sensor for the highly hydrophilic sulfate, even in the presence of a large excess of water. Importantly, the [2]catenane exhibits enhanced binding affinity and selectivity for sulfate over its parent macrocycle and other acyclic diamidocarbazole-based receptors. We demonstrate also, for the first time, that the co-conformation of the catenane may be controlled by reversible acid/base induced protonation and deprotonation of the anionic template, SO42-. This approach pioneers a new strategy to induce molecular motion of interlocked components using switchable anionic templates.

Vitamin B12 and a metal-organic framework enable the photocatalytic generation of alkyl radicals.

A versatile Co-catalyst-vitamin B12 (cobalamin)-can be photochemically reduced to its catalytically active Co(I) form under visible light irradiation, in the presence of MIL-125-NH2(Ti) as a photocatalyst and utilized for the generation of alkyl radicals. The prior reduction of cobalamin to the Co(II) form is not required in this method.

pH-Dependent transport of amino acids across lipid bilayers by simple monotopic anion carriers.

The transport of amino acids across lipid membranes is vital for the proper functioning of every living cell. In spite of that, examples of synthetic transporters that can facilitate amino acid transport are rare. This is mainly because at physiological conditions amino acids predominantly exist as highly polar zwitterions and proper shielding of their charged termini, which is necessary for fast diffusion across lipophilic membranes, requires complex and synthetically challenging heteroditopic receptors. Here we report the first simple monotopic anion receptor, dithioamide 1, that efficiently transports a variety of natural amino acids across lipid bilayers at physiological pH. Mechanistic studies revealed that the receptor rapidly transports deprotonated amino acids, even though at pH 7.4 these forms account for less than 3% of the total amino acid concentration. We also describe a new fluorescent assay for the selective measurement of the transport of deprotonated amino acids into liposomes. The new assay allowed us to study the pH-dependence of amino acid transport and elucidate the mechanism of transport by 1, as well as to explain its exceptionally high activity. With the newly developed assay we screened also four other representative examples of monotopic anion transporters, of which two showed promising activity. Our results imply that heteroditopic receptors are not necessary for achieving high amino acid transport activities and that many of the previously reported anionophores might be active amino acid transporters. Based on these findings, we propose a new strategy for the development of artificial amino acid transporters with improved properties.

Boosting Anion Transport Activity of Diamidocarbazoles by Electron Withdrawing Substituents.

Artificial chloride transporters have been intensely investigated in view of their potential medicinal applications. Recently, we have established 1,8-diamidocarbazoles as a versatile platform for the development of active chloride carriers. In the present contribution, we investigate the influence of various electron-withdrawing substituents in positions 3 and 6 of the carbazole core on the chloride transport activity of these anionophores. Using lucigenin assay and large unilamellar vesicles as models, the 3,6-dicyano- and 3,6-dinitro- substituted receptors were found to be highly active and perfectly deliverable chloride transporters, with EC50,270s value as low as 22 nM for the Cl-/NO3 - exchange. Mechanistic studies revealed that diamidocarbazoles form 1:1 complexes with chloride in lipid bilayers and facilitate chloride/nitrate exchange by carrier mechanism. Furthermore, owing to its increased acidity, the 3,6-dinitro- substituted receptor acts as a pH-switchable transporter, with physiologically relevant apparent pKa of 6.4.

Transmembrane anion transport promoted by thioamides.

Thioamide groups represent useful hydrogen-bonding motifs for the development of active transmembrane anion transporters. Using a 1,8-di(thioamido)carbazole scaffold the superior performance of thioamides compared with the parent amides has been demonstrated.

Oxyanion transport across lipid bilayers: direct measurements in large and giant unilamellar vesicles.

A simple di(thioamido)carbazole 1 serves as a potent multispecific transporter for various biologically relevant oxyanions, such as drugs, metabolites and model organic phosphate. The transport kinetics of a wide range of oxyanions can be easily quantified by a modified lucigenin assay in both large and giant unilamellar vesicles.

Interlocked host anion recognition by an indolocarbazole-containing [2]rotaxane.

The design, synthesis, structure, and anion-binding properties of the first indolocarbazole-containing interlocked structure are described. The novel [2]rotaxane molecular structure incorporates a neutral indolocarbazole-containing axle component which is encircled by a tetracationic macrocycle functionalized with an isophthalamide anion recognition motif. (1)H NMR and UV-visible spectroscopies and X-ray crystallography demonstrated the importance of pi-donor-acceptor, CH...pi, and electrostatic interactions in the assembly of pseudorotaxanes between the electron-deficient tetracationic macrocycle and a series of pi-electron-rich indolocarbazole derivatives. Subsequent urethane stoppering of one of these complexes afforded a [2]rotaxane, which was shown by (1)H NMR spectroscopic titration experiments to exhibit enhanced chloride and bromide anion recognition compared to its non-interlocked components. Computational molecular dynamics simulations provide further insight into the mechanism and structural nature of the anion recognition process, confirming it to involve cooperative hydrogen-bond donation from both macrocycle and indolocarbazole components of the rotaxane. The observed selectivity of the [2]rotaxane for chloride is interpreted in terms of its unique interlocked binding cavity, defined by the macrocycle isophthalamide and indolocarbazole N-H protons, which is complementary in size and shape to this halide guest.

Interlocked host rotaxane and catenane structures for sensing charged guest species via optical and electrochemical methodologies.

The potential of interlocked host rotaxane and catenane structures as innovative optical and electrochemical sensors is highlighted. Interlocked structures can be engineered to bind specific guests within the topologically constrained three dimensional cavities created during their template-driven syntheses. This binding ability, when coupled to the signal transduction capabilities associated with appended reporter groups and their dynamic structures, make catenanes and rotaxanes highly promising candidates for the development of molecular sensors. With the ultimate challenge of fabricating highly selective anion sensing configurations, a three-staged strategy has been followed. First, we developed a general anion templation methodology for the construction of a variety of interpenetrated and interlocked molecular structures. [2]Rotaxanes and [2]catenanes synthesised using this novel protocol show, after template removal, favourable selective anion binding characteristics distinct from their separate components. At the second stage, the incorporation of redox- and photo-active groups into these interlocked frameworks converts them into electrochemical/optical molecular sensors. In the final third stage, the confinement of interlocked anion receptors at surfaces results in the fabrication of devices exhibiting highly selective binding and electrochemical and/or optical sensing behaviour.

Sulfate anion templation of a neutral pseudorotaxane assembly using an indolocarbazole threading component.

The first example of anion templated pseudorotaxane formation between two neutral components in solution and in surface assembled monolayers is described.

Anion templated surface assembly of a redox-active sensory rotaxane.

Anion templation is used to assemble novel redox-active bis-ferrocene functionalised rotaxane self-assembled monolayers (SAMs) on to gold electrode surfaces; after template removal, the unique SAM rotaxane binding domain is capable of selectively sensing chloride ions electrochemically.

TEMPO-Appended Metal-Organic Frameworks as Highly Active, Selective, and Reusable Catalysts for Mild Aerobic Oxidation of Alcohols.

Metal-organic frameworks (MOFs) decorated with stable organic radicals are highly promising materials for redox catalysis. Unfortunately however, the synthesis of chemically robust MOFs typically requires harsh solvothermal conditions, which are not compatible with organic radicals. Here, we describe the synthesis of two isoreticular families of stable, mixed component, zirconium MOFs with UiO-66 and UiO-67 structures and controlled amounts of covalently attached TEMPO radicals. The materials were obtained using a relatively low-temperature, HCl-modulated de novo method developed by Hupp and Farha and shown to contain large amounts of missing cluster defects, forming nanodomains of the reo phase with 8-connected clusters. In the extreme case of homoleptic UiO-67-TEMPO(100%), the material exists as an almost pure reo phase. Large voids due to missing clusters and linkers allowed these materials to accommodate up to 2 times more of bulky TEMPO substituents than theoretically predicted for the idealized structures and proved to be beneficial for catalytic activity. The TEMPO-appended MOFs were shown to be highly active and recyclable catalysts for selective aerobic oxidation of a broad range of primary and secondary alcohols under exceptionally mild conditions (room temperature, atmospheric pressure of air). The influence of various parameters, including the pore size and TEMPO content, on the catalytic activity was also comprehensively investigated.

Facile post-synthetic deamination of MOFs and the synthesis of the missing parent compound of the MIL-101 family.

A versatile method for the post-synthetic removal of primary amino groups from metal-organic frameworks (MOFs) has been developed. The method allowed the first successful synthesis of the missing parent compound of an important family of MOFs - the unsubstituted (Al)MIL-101. The material was shown to be a useful reference compound for the elucidation of the role of amino groups in the adsorption and deactivation of olefin metathesis catalysts. The chemoselectivity of the deamination is sufficient for the selective removal of NH2 substituents from mixed-linker MOFs bearing both NH2 and RCONH groups.