Stochastic Sensing of Chloride Anions Using an α-Hemolysin Pore with semiaza-Bambusuril Adapter.

Pores containing molecular adapters provide internal selective binding sites, thereby allowing the stochastic sensing of analytes. Herein, we demonstrate that semiaza-bambusuril (BU) acts as a non-covalent molecular adapter when lodged within the lumen of the wild-type α-hemolysin (WT-αHL) protein pore. Because the bambusurils are recognized as anion receptors, the anion binding site within the adapter-nanopore complex allows the detection of chloride anions, thus converting a non-selective pore into an anion sensor.

Selective Perchlorate Sensing Using Electrochemical Impedance Spectroscopy with Self-Assembled Monolayers of semiaza-Bambusurils.

In the last two decades, perchlorate salts have been identified as environmental pollutants and recognized as potential substances affecting human health. We describe self-assembled monolayers (SAMs) of novel semiaza-bambus[6]urils (semiaza-BUs) equipped with thioethers or disulfide (dithiolane) functionalities as surface-anchoring groups on gold electrodes. Cyclic voltammetry (CV) with Fe(CN)6 3-/4- as a redox probe, together with X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM) and ellipsometry, were employed to characterize the interactions at the interface between the anchoring groups and the metal substrate. Data showed that the anion receptors' packing on the gold strongly depends on the anchoring group. As a result, SAMs of BUs with lipoic amide side chains show a concentration-dependent layer thickness. The BU SAMs are extremely stable on repeated electrochemical potential scans and can selectively recognize perchlorate anions. Our electrochemical impedance spectroscopy (EIS) studies indicated that semiaza-BU equipped with the lipoic amide side chains binds perchlorate (2-100 mM) preferentially over other anions such as F- , Cl- , I- , AcO- , H2 PO4 - , HPO4 2- , SO4 2- , NO2 - , NO3 - , or CO3 2- . The resistance performance is 10 to 100 times more efficient than SAMs containing all other tested anions.

semiaza-Bambusurils are anion-specific transmembrane transporters.

semiaza-Bambus[6]urils efficiently transport anions across lipid membranes. A systematic modification of their lipophilic side chains to include various alkyl groups and thioethers reveals that the most efficient chloride transporters are those that agree with Lipinski's rule-of-lipophilicity, exhibiting clog Po/w values close to 5. Furthermore, vesicle anion-transport assays show that the new anion-transporters are independent of the cation identity but exhibit high anion selectivity, NO3- > Br- > Cl- > SO42-, in agreement with the Hofmeister series. These findings will allow for the design of highly specific anion transporters for biomedical applications, particularly for managing anion channelopathies.

Thiourea-Mediated Halogenation of Alcohols.

The halogenation of alcohols under mild conditions expedited by the presence of substoichiometric amounts of thiourea additives is presented. The amount of thiourea added dictates the pathway of the reaction, which may diverge from the desired halogenation reaction toward oxidation of the alcohol, in the absence of thiourea, or toward starting material recovery when excess thiourea is used. Both bromination and chlorination were highly efficient for primary, secondary, tertiary, and benzyl alcohols and tolerate a broad range of functional groups. Detailed electron paramagnetic resonance (EPR) studies, isotopic labeling, and other control experiments suggest a radical-based mechanism. The fact that the reaction is carried out at ambient conditions, uses ubiquitous and inexpensive reagents, boasts a wide scope, and can be made highly atom economic, makes this new methodology a very appealing option for this archetypical organic reaction.

Inherently Chiral Bambus[4]urils.

A new class of bambus[4]urils (BU[4]s) composed of asymmetric N,N'-disubstituted glycoluril subunits with different alkyl groups were designed, synthesized, and fully characterized by NMR techniques and X-ray crystallography. Structural studies showed that four macrocyclic diastereoisomers are possible: two Sn symmetric achiral macrocycles and two macrocycles that are "inherently" chiral. The relative "head-to-tail" arrangement of the N-substituents in Bn4Me4BU[4], 5a, clearly observed by X-ray spectroscopy analysis, determines the overall symmetry of the bambusuril structure. Chiral Pr4Me4BU[4], 4b, was resolved by chiral high-performance liquid chromatography (HPLC) into its enantiomers, and all four inherently chiral bambusuril pairs (two Pr4Me4BU[4] and two Bn4Me4BU[4] stereoisomers, 4b, 4d, 5b, and 5d) were clearly observed by 1H NMR spectroscopy with the aid of (R)-BINOL as a chiral solvating agent. This latter methodology provides a rapid and powerful approach for investigating the enantiopurity of inherently chiral cavitands, which complements and augments the conventional chromatographic approaches.

Flat corannulene: when a transition state becomes a stable molecule.

Flat corannulene has been considered so far only as a transition state of the bowl-to-bowl inversion process. This study was driven by the prediction that substituents with strong steric repulsion could destabilize the bowl-shaped conformation of this molecule to such an extent that the highly unstable planar geometry would become an isolable molecule. To examine the substituents' effect on the corannulene bowl depth, optimized structures for the highly-congested decakis(t-butylsulfido)corannulene were calculated. The computations, performed with both the M06-2X/def2-TZVP and the B3LYP/def2-TZVP methods (the latter with and without Grimme's D3 dispersion correction), predict that this molecule can achieve two minimum structures: a flat carbon framework and a bowl-shaped structure, which are very close in energy. This rather unusual compound was easily synthesized from decachlorocorannulene under mild reaction conditions, and X-ray crystallographic studies gave similar results to the theoretical predictions. This compound crystallized in two different polymorphs, one exhibiting a completely flat corannulene core and the other having a bowl-shaped conformation.

Equatorial Sulfur Atoms in Bambusurils Spawn Cavity Collapse.

This study confirms the hypothesis that bambusurils (BUs) with equatorial sulfur atoms cannot assume an anion-binding jigger conformation due to strong intramolecular van der Waals attractive interactions. NMR, X-ray crystallography, and computation with newly synthesized eq-semithio-BU[4] and ax-semiaza-eq-semithio-BU[4]s indicate that they all assume compact conformations. Intramolecular distances and a torsional angle serve as reliable indicators of the conformation of any BU. Chemoselective alkylation at the peripheral (equatorial) thiourea functions provides a convenient entry to novel hetero-BUs.

Intramolecular van der Waals Interactions Challenge Anion Binding in perthio-Bambusurils.

Bambusurils (BUs) are known to be rigid cavitands that feature an extended, jigger-like conformation, and the BU[6]s strongly bind anions within their hydrophobic cavity. These features are not necessarily shared by the family of perthio-BUs. This study reveals that perthio-BUs assume a compact conformation and perthio-BU[6]s are poor anion binders, crystallizing as anion-free species from solutions containing halide salts. Computational studies show that the equatorial sulfur atoms compete against guest anions for binding with the glycoluril methine groups via strong van der Waals (vdW) attractive interactions. These competitive contacts not only account for the diminished anion-binding of perthio-BUs, but also explain their compact conformation. The semithio- and perthio-BU[4]s form linear coordination polymers with HgII in the solid-state regardless of their intrinsic molecular conformation. The strong involvement of sulfur atoms in intramolecular interactions differentiates the equatorial from the axial (peripheral) heteroatoms, thus offering chemoselective and regioselective transformations.

Synthetic Evolution of the Multifarene Cavity from Planar Predecessors.

The stepwise evolution of curved multifarene structures from planar precursors is demonstrated, highlighting three architectural design elements: 1) employment of various aromatic units, 2) changing the hybridization of the linking atoms from sp2 to sp3 , and 3) rigidification of the system by the introduction of five-membered rings. Similar design elements have been employed to transform graphene sheets into curved carbon structures. Specifically, the stepwise synthetic evolution of multifarene[2+2], which has a curved, quite rigid structure, begins with a planar, tetraimine precursor, conversion to pairs of vicinal diamines, and the transformation of these pairs to cyclic thiourea groups. This process was probed by NMR spectroscopy and X-ray crystallography. Since varying the carbonylation conditions resulted in carbamates or thiocarbamates rather than the urea or thiourea isomers, the isomeric interconversion was studied both experimentally and by DFT computations. The carbamate versus urea preference was found to reflect either kinetic or thermodynamic control, respectively.

Guiding a divergent reaction by photochemical control: bichromatic selective access to levulinates and butenolides.

Allylic and acrylic substrates may be efficiently transformed by a sequential bichromatic photochemical process into derivatives of levulinates or butenolides with high selectivity when phenanthrene is used as a regulator. Thus, UV-A photoinduced cross-metathesis (CM) couples the acrylic and allylic counterparts and subsequent UV-C irradiation initiates E-Z isomerization of the carbon-carbon double bond, followed by one of two competing processes; namely, cyclization by transesterification or a 1,5-H shift and tautomerization. Quantum chemical calculations demonstrate that intermediates are strongly blue-shifted for the cyclization while red-shifted for the 1,5-H shift reaction. Hence, delaying the double bond migration by employing UV-C absorbing phenanthrene, results in a selective novel divergent all-photochemical pathway for the synthesis of fundamental structural motifs of ubiquitous natural products.

Semithiobambus[6]uril is a transmembrane anion transporter.

Semithiobambus[6]uril is shown to be an efficient transmembrane anion transporter. Although all bambusuril analogs (having either O, S or N atoms in their portals) are excellent anion binders, only the sulfur analog is also an effective anion transporter capable of polarizing lipid membranes through selective anion uniport. This notable divergence reflects significant differences in the lipophilic character of the bambusuril analogs.

Attractive Interactions between Heteroallenes and the Cucurbituril Portal.

In this paper, we report on the noteworthy attractive interaction between organic azides and the portal carbonyls of cucurbiturils. Five homologous bis-α,ω-azidoethylammonium alkanes were prepared, where the number of methylene groups between the ammonium groups ranges from 4 to 8. Their interactions with cucurbit[6]uril were studied by NMR spectroscopy, IR spectroscopy, X-ray crystallography, and computational methods. Remarkably, while the distance between the portal plane and most atoms at the guest end groups increases progressively with the molecular size, the ß-nitrogen atoms maintain a constant distance from the portal plane in all homologues, pointing at a strong attractive interaction between the azide group and the portal. Both crystallography and NMR support a specific electrostatic interaction between the carbonyl and the azide ß-nitrogen, which stabilizes the canonical resonance form with positive charge on the ß-nitrogen and negative charge on the γ-nitrogen. Quantum computational analyses strongly support electrostatics, in the form of orthogonal dipole-dipole interaction, as the main driver for this attraction. The alternative mechanism of n → π* orbital delocalization does not seem to play a significant role in this interaction. The computational studies also indicate that the interaction is not limited to azides, but generalizes to other isoelectronic heteroallene functions, such as isocyanate and isothiocyanate. This essentially unexploited attractive interaction could be more broadly utilized as a tool not only in relation to cucurbituril chemistry, but also for the design of novel supramolecular architectures.

Aza-Bambusurils En Route to Anion Transporters.

Previous calculations of anion binding with various bambusuril analogs predicted that the replacement of oxygen by nitrogen atoms to produce semiaza-bambus[6]urils would award these new cavitands with multiple anion binding properties. This study validates the hypothesis by efficient synthesis, crystallography, thermogravimetric analysis and calorimetry. These unique host molecules are easily accessible from the corresponding semithio-bambusurils in a one-pot reaction, which converts a single anion receptor into a potential anion channel. Solid-state structures exhibit simultaneous accommodation of three anions, linearly positioned within the cavity along the main symmetry axis. The ability to hold anions at a short distance of about 4 Šis reminiscent of natural chloride channels in E. coli, which exhibit similar distances between their adjacent anion binding sites. The calculated transition-state energy for double-anion movement through the channel suggests that although these host-guest complexes are thermodynamically stable they enjoy high kinetic flexibility to render them efficient anion channels.

Enhanced anion binding by heteroatom replacement in bambusurils.

This study was driven by the hypothesis that heteroatom replacement in bambusurils could significantly modify their anion binding properties. Indeed, calculations with various glycoluril and bambusuril analogs predict that such replacements significantly alter their molecular electrostatic potential and binding properties. Both polarization and electrostatic interactions contribute to anion binding, leading to a general trend of affinity among the neutral molecules: X = S > O > NH. In bambusurils the heteroatom replacement at the portal carbonyls affect the induced dipole more significantly than replacements at the equatorial carbonyls. The stronger polarization and stronger anion binding manifest the increased aptitude of the portal heteroatoms as electron sinks. Notably, this study predicts that protonated aza-bambusurils would not only bind multiple anions along their main axis, but could also function as synthetic anion channels.

A Light-Activated Olefin Metathesis Catalyst Equipped with a Chromatic Orthogonal Self-Destruct Function.

A sulfur-chelated photolatent ruthenium olefin metathesis catalyst has been equipped with supersilyl protecting groups on the N-heterocyclic carbene ligand. The silyl groups function as an irreversible chromatic kill switch, thus decomposing the catalyst when it is irradiated with 254 nm UV light. Therefore, different types of olefin metathesis reactions may be started by irradiation with 350 nm UV light and prevented by irradiation with shorter wavelengths. The possibility to induce and impede catalysis just by using light of different frequencies opens the pathway for stereolithographic applications and novel light-guided chemical sequences.

Dual-functional semithiobambusurils.

Semithiobambusurils, which represent a new family of macrocyclic host molecules, have been prepared by a convenient, scalable synthesis. These new cavitands are double functional: they strongly bind a broad variety of anions in their interiors and metal ions at their sulfur-edged portals. The solid-state structure of semithiobambus[4]uril with HgCl2 demonstrates the ability of these compounds to form linear chains of coordination polymers with thiophillic metal ions. The crystal structure of semithiobambus[6]uril with tetraphenylphosphonium bromide exhibits the unique anion-binding properties of the host cavity and the characteristics of the binding site.

Prophylactic treatment of asthma by an ozone scavenger in a mouse model.

Our hypothesis that inflammation in asthma involves production of ozone by white blood cells and that ozone could be an inflammatory mediator suggests that scavengers of reactive oxygen species (ROS), for example, electron-rich olefins, could serve for prophylactic treatment of asthma. Olefins could provide chemical protection against either exogenous or endogenous ozone and other ROS. BALB/c mice pretreated by inhalation of d-limonene before an ovalbumin challenge exhibited significant attenuation of the allergic asthma symptoms. Diminution of the inflammatory process was evident by reduced levels of aldehydes, reduced counts of neutrophils in the BAL fluid and by histological tests. A surprising systemic effect was observed by decreased levels of aldehydes in the spleen, suggesting that the examination of tissues and organs that are remote from the inflammation foci could provide valuable information on the distribution of the oxidative stress and may serve as guide for targeted treatment.

Time-resolved, laser initiated detonation of TATP supports the previously predicted non-redox mechanism.

Our previously reported computational study of the decomposition pathways of triacetone triperoxide (TATP), 1, predicted that unlike most energetic materials, which involve self-combustion of fuel and oxidants, 1 decomposes via a thermoneutral, non-redox pathway that involves entropy burst. These predictions are now corroborated by time-resolved monitoring of deflagration or detonation of 1 using a fast video camera following initiation by a short pulse focused laser beam. While a fireball always accompanies the explosion of 1 under air, the formation of a fireball is totally prevented under a nitrogen atmosphere. These observations indicate that combustion of the gaseous primary products occurs as a secondary event only in the presence of exogenous oxygen. The composition of the product mixture was found to depend on the experimental conditions. With long pulse focused laser beam (150 µs at 1064 nm) at either 210 or 110 mJ, the small amounts of charcoal needed for initiation suggest that the energy required to initiate 1 by pulse laser is 4-10 mJ, much smaller than the energy required for initiation by either mechanical stress or electric discharge. This time-resolved study highlights the very unusual properties of the peroxide based explosives.

Lateral cis-1,3,5,7-tetraazadecalin podands and their complexes: synthesis, structure, and strong binding with Pb(II) and other heavy metal ions.

The chemistry and complexation behavior of diaminal podands based on cis-1,3,5,7-tetraazadecalin (cis-TAD) were elaborated, reassessed, and extended. The synthesis of 2,6-bis(hydroxymethylene)-cis-TAD (9) and 2,6-bis(α,α'-dimethyl-ß- hydroxyethyl)-cis-TAD (10) as well as of suitably substituted 2,6-diaryl-cis-TAD podands is laid out. For the latter, the effect of electron donating or withdrawing substituents on the benzaldehyde reagents was examined while 9 and 10 were probed and showed considerable propensity for heavy metal-ion chelation. The [Cd(II)·(9)] and [Pb(II)·(9)] complexes stood out indeed, and their structure and properties show a particularly interesting 5-amino-1,3-diazane chelation type and strong ligand-ion binding mode, with intramolecular donor exchange in solution, all strongly influenced by the anomeric effect in the ligand.

Bistable cucurbituril rotaxanes without stoppers.

Bistable rotaxanes are important design elements of molecular devices for a broad range of applications, such as controlled drug release, molecular rotary motors, and chemical sensors. The host-guest complexes of cucurbit[6]uril and 1,4-bis(alkylaminomethyl)benzene were found to exhibit two stable binding modes with an unexpectedly high barrier between them. Their structural and dynamic properties, kinetic and thermodynamic parameters, as well as different chemical reactivity towards the azide-alkyne [3+2] cycloaddition reaction (click chemistry), were discovered by NMR spectroscopy, X-ray crystallography, and isothermal titration microcalorimetry. The highly stable 2:1 complex, which is formed at room temperature, was found to be a kinetic product, which may be converted to the thermodynamic 1:1 complex upon prolonged heating to 100 °C. The latter is a very stable rotaxane despite the fact that it lacks bulky end groups.