Gas Phase Cucurbit[n]uril Chemistry

The chemistry of cucurbit[n]urils is commanding increasing interest because of potential applications of these molecules in supramolecular structures; in drug encapsulation, protection, and delivery; and in sensitive new analytical assays. It is widely recognized that the binding properties of cucurbit[n]urils are sensitively dependent on solvents and counterions. Hence, gas phase studies, where neither solvent nor counterion species are present, are vital to gain fundamental understanding of cucuribituril complexes and to facilitate future applications. We use Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and ion mobility techniques to investigate the gas phase chemistry of cucurbit[n]urils and related species, addressing problems such as how trapping molecules inside the cucurbit[n]uril cavity affects the binding of cations on the rims, the mechanism of exchange of bound/trapped species, and the origin of the large pK_a shifts that occur for trapped guests. This paper is a review of our work.     

Cucurbit[n]uril Host-Guest Complexes of Acids,Photoacids, and Super Photoacids

The supramolecular chemistry of host-guest complexes of cucurbit[n]urils (CB[n]) with acidic guests in the ground (HG⁺) and excited states (HG⁺*) are reviewed. The effects of CB[n] complexation on the guests’ pK_a and/or pK_a* values are related to relative binding constants and host-guest structures of the acid form of the guest and its conjugate base. Included are carbon acids, guests of biological and medicinal interest, dyes and related polyaromatic guests, and other organic and organometallic guests. The applications of the pK_a shifts to the solubility, stability, and bioavailabilty of drug molecules, the stability and enhanced spectral properties of dyes, and in pH-induced self-sorting, micelle formation, host-guest shuttling, and controlled guest release, are discussed.     

The Potential of Cucurbit[n]urils in Drug Delivery

In this paper we review cucurbit[n]urils (CB[n]), a relatively new family of macrocycles that has shown potential in improving drug delivery. Encapsulation of drugs within the homologues CB[6], CB[7], or CB[8] can impart enhanced chemical and physical stability, improve drug solubility, and control drug release. The formulation of CB[n] into a dosage form suitable for clinical use is a non-trivial task, because the free macrocycle and its host-drug complex generally exhibit pseudo-polymorphism in the solid state. Despite this, cucurbiturils have been included in tablets for oral delivery and inserts for nasal delivery. Here we examine the potential use of cucurbiturils in drug delivery in the context of getting a new drug into clinical trials and discuss what further research is needed in this area.     

Ultrastable Host–Guest Complexes and Their Applications

This review describes monovalent synthetic receptor–ligand (or host–guest) pairs with extremely high binding affinity, comparable to that of the biotin–avidin pair, and their applications. Cucurbit[7]uril (CB[7]), a member of the host family cucurbit[n]uril (CB[n], n=5–8, 10), forms ultrastable host–guest complexes with ferrocene-, adamantane- or bicyclo[2.2.2]octane-based molecules having ammonium groups properly positioned to interact with the carbonyl oxygens at the portals of CB[7]. The extremely high affinity is achieved by a large enthalpic gain arising from the near perfect size/shape complementarity between the rigid CB cavity and the rigid core of the guest molecules, with the critical assistance of the positive entropy change due to the extensive dehydration of the host and guest. The high stability of the complexes allowed us and others to explore several biological applications such as immobilization of biomolecules on a solid surface, protein isolation, triggering intracellular events, and regulating enzymatic activities. These complexes with their exceptional affinity, chemical robustness, simple preparation, biocompatibility, and easy handling may replace the biotin–(strept)avidin system in diverse areas of research, including affinity chromatography, high throughput biochemical assays, imaging, and sensor technologies.     

Acyclic Cucurbit[n]uril‐Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents

Two acyclic cucurbit[n]uril (CB[n])‐type molecular containers that differ in the length of the (CH₂)_n linker ( M2C2 : n=2, M2C4 : n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm ) and M2C4 (196 mm ) are higher than the analogue with a (CH₂)₃ linker ( M2 , 14 mm ) studied previously. ¹H NMR dilution experiments show that M2C2 and M2C4 do not self‐associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2 , M2C2 , M2C4 , hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD), and sulfobutylether‐β‐cyclodextrin (SBE‐β‐CD) toward 15 insoluble drugs. We found that M2C2 and M2C4 —as gauged by the slope of their PSDs—are less potent solubilizing agents than M2 . However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE‐β‐CD were similar in many cases, with K_rel values averaging 23 and 12, respectively, relative to HP‐β‐CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2 .     

Nitroxide Radicals with Cucurbit[n]urils and Other Cavitands

The interface of nitroxide radicals with cucurbit[n]urils (CB[n]) is covered in this review. Either used as spin probes, spin labels, or stoppers for paramagnetic rotaxanes, nitroxides offer new opportunities to investigate CB[n] and their inclusion complexes, especially thanks to EPR spectroscopy. On the other hand, CB[n] also offer interesting opportunities to modulate nitroxide properties such as protection or structuring. The multiple back and forth between the two well-established areas where nitroxides bring information about CB[n], and CB[n] modulate nitroxide properties, have enabled to shed some light at this new interesting interface.     

Synthesis and properties of block polypseudorotaxanes by threading cucurbit[6]uril

A novel water-soluble block polypseudorotaxane (4) was synthesized in water from cucurbit[n]uril (n?=?6), designated as CB[6], and a block copolymer of methoxy poly(ethylene glycol)-b-poly-[N ¹-(4-vinylbenzyl)-pentane-1,5-diamine dihydrochloride]-b-methoxy poly(ethylene glycol) (P3). Driven by the hydrophobic/hydrophobic interaction and the association between the diamine and glycoluril units, CB[6] beads are localized on the pentamethylene units in the side chains of P3 as found by NMR studies. The degree of threading, i.e., the average number of CB[6] beads per repeat recognition unit of P3, can be controlled from 0.25 to 1.0 by varying the amount of CB[6] added. This molecular feature leads to interesting aggregation behavior of the polypseudorotaxanes in aqueous solutions, as revealed by dynamic light scattering measurements, transmission electron microscopy observations, ultraviolet/visible spectroscopy (UV?Cvis) and fluorescence spectrometry. The average hydrodynamic radius (R _h), the intensity of UV?Cvis absorption band and the fluorescence intensity (I _f) of the block polypseudorotaxanes in solution increase with the increasing of threaded CB[6]. With the solution temperature increasing, the size of the aggregates in water increased and the fluorescence intensity (I _f) of the solution decreased, which shows the polypseudorotaxanes can sensitively respond to temperature changes. This opens the door for the application of the block polypseudorotaxanes in various fields such as drug delivery and controlled release.     

Inclusion Complexes of Hymexazol with Three Different Cucurbit[n]uril: Preparation,and Physicochemical and Antifungal Characterization

Host-guest inclusion complexes of hymexazol with three different cucurbit[n]uril, cucurbit[7]uril (Q[7]), hemimethyl-substituted cucurbit[6]uril (HHMeQ[6]), and twisted cucurbit[14]uril (tQ[14]) have been investigated by means of ¹H NMR spectroscopy, quadrupole-time of flight mass spectrometry (Q-TOF), and isothermal titration calorimetry (ITC). ¹H NMR experimental results revealed that hymexazol resides within the respective cavities of the selected Q[n], and mass spectrometric experimental results revealed that it interacts with these three Q[n] through the formation of 1 : 1 inclusion complexes. ITC experimental results indicated moderate binding constants. In vitro assays showed that the complexation of hymexazol by the Q[n] increased its inhibitory effect on the mycelia growth of Botrytis cinerea Pers.     

Molecular Recognition of Water-soluble Pillar[n]arenes Towards Biomolecules and Drugs

The exploration of molecular recognition of synthetic macrocycles in aqueous media is significantly important since most biological functions, activities and processes take place in water. Pillar[n]arenes (n=5–10) have been recognized as a new generation of macrocyclic arenes; much attention has been devoted to their host-guest chemistry. This review summarizes the host-guest properties of water-soluble pillararenes towards biologically significant molecules and drugs. These water-soluble pillararenes are classified into three major classes according to the electric charges of hydrophilic groups at their portals: anionic pillar[n]arenes ( AP[n]s ), cationic pillar[n]arenes ( CP[n]s ), and neutral pillar[n]arenes ( NP[n]s ). The host–guest affinities, binding modes, binding selectivity, stimuli-responsiveness, as well as biomedical applications are comprehensively discussed.     

Micellization behavior of ionic liquid surfactants with two hydrophobic tail chains in aqueous solution

The drop volume method was used to determine the surface tensions of two series of polymerizable ionic liquid surfactants, namely, 1‐acryloyloxypropyl‐3‐alkylimidazolium chloride [APC_nim][Cl] (n = 8, 10, 12) containing two hydrophobic tail chains and 1‐propionyloxypropyl‐3‐alkylimidazolium chloride [PPC_nim][Cl] (n = 8, 10, 12), which showed similar structures with [APC_nim][Cl] (n = 8, 10, 12) at 25°C. The surface properties of the surfactants were also compared. Furthermore, the thermodynamic behavior of [PPC_nim][Cl] (n = 10, 12, 14) micellization in aqueous solution and the enthalpy–entropy compensation phenomenon were studied. The two kinds of surfactants had high surface activity. Double bonds had almost no effect on the surface properties of [APC_nim][Cl]. The micellization of [PPC_nim][Cl] in aqueous solution was spontaneous and entropy‐driven. For the surfactant with specific structure, micellization ability initially increased and then decreased with temperature increase. The entropic contribution to Gibbs free energy change tended to decrease, whereas the enthalpic contribution increased. In addition, the enthalpy–entropy compensation phenomenon occurred during the micellization process. For all [PPC_nim][Cl], the compensation temperature was (314 ± 1) K, which remained unaffected by the surfactant molecular structure. However, when the hydrophobic carbon chain length increased, both micelle formation ability and stability increased. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Potential Applications of Cucurbit[n]urils Inclusion Complexes in Photodynamic Therapy

Cucurbit[n]urils (CB[n]s) have emerged as potential candidates for drug delivery in several areas due to their strong binding interactions and low toxicity. More recently, their benefits for a type of cancer treatment termed Photodynamic Therapy (PDT) have been recognized. The outcomes of this therapy rely on better drug delivery strategies and improving overall photoactivity of the drugs, which is where CB[n]s could have a strong impact. The effects of these molecular containers on photoactivity are discussed and new interesting work is highlighted.     

Quinoline-Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action

The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η⁶-p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC₂B₉H₁₀] ( 4 ) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas.     

Research on extraction of Cr(III) by D2EHPA/n-octanol/sulphonated kerosene

Chromium is an important industrial raw material. As far as China is concerned, chromium is in great demand, which is dependent on imports and large emissions. So recovery of chromium has important economic and environmental protection value. The extraction and back extraction of Cr(III) from solution by the extractant diisooctyl phosphate (di-2-ethylhexylphosphoric acid [D2EHPA]) with n-octanol as assistant and sulphonated kerosene as diluent was studied. The effects of saponification rate, phase ratio, temperature, condensation of extract, aging of extractant, and pH of aqueous phase on extraction equilibrium were discussed, and the formulation of extractant was optimized. The coordination number of the extraction reaction under specific conditions was discussed by the saturation capacity method. The extraction reaction kinetics were mathematically characterized by binary linear regression. The advantages and disadvantages of back extraction with H₂SO₄ or NaOH were compared. At last, a process to realize the recycling of extractant was obtained.     

Cucurbituril: At the Interface of Small Molecule Host–Guest Chemistry and Dynamic Aggregates

The remarkable guest binding behavior of the synthetic receptors, cucurbit[n]uril, has gained tremendous attention over the past few decades. The stronger and more selective encapsulation of small guests has opened up the possibility to develop multi-component, dynamic yet controlled supramolecular aggregated architectures for a wide variety of applications. Isolation of larger homologues and derivatives have expanded the scope further, and interest has grown exponentially. Applications of these unique synthetic receptors presently range from polymeric smart materials and wet nanotechnology to sensing and protein conjugation. This review highlights such examples from recent literature on the development of new dynamic supramolecular aggregates and composites using cucurbituril host–guest chemistry.     

Synthesis,extraction, and adsorption properties of calix[4]arene‐poly(ethylene‐glycol) crosslinked polymer

Novel calix[4]arene‐poly(ethylene glycol) crosslinked polymer (CCP) has been synthesized by the polycondensation reaction between a p‐tert‐butylcalix[4]arene derivative and dihydroxyl capped poly(ethylene glycol) (DHPEG, M_n = 1000) catalyzed by neodymium tosylate. The hydrogel, consisted of 66.9% water and 33.1% CCP, can selectively extract aromatic organic molecules from aqueous solution according to the diameter of the guest molecules, which infers that the diameter of the calix[4]arene cavity is about 5.4 Å and the conformation of calix[4]arene units altered from cone conformation to 1,3‐alternate conformation during the polycondensation reaction. Furthermore, CCP can also adsorb naphthalene from gas phase, showing much higher capacity than active carbon does, which may have some potential applications in the field of separation and environment protection. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Reduction electrochimique de molecules dimeres du paraquat en milieu aqueux

This paper gives a detailed study of the electrochemical reduction of some paraquat dimer molecules PQ²⁺ (CH_2nPQ²⁺, with n = 2, 3 and 4, in aqueous solution. As previously observed in DMF solution, these molecules are reduced by two successive bieletronic transfers, the first one leading to the PQ^√+ (CH_2nPQ^√+ species, the second to the neutral species PQ(CH₂)_nPQ. It appears that the intramolecular association of PQ^√+ is favoured in aqueous solution, this association was only observed for n = 3 in DMF solution. On the other hazd, cyclic voltammetry shows that covering of the electrode occurs during the reduction of PQ^√+(CH₂)_nPQ^√+ into the neutral species PQ(CH_2nPQ. This phenomena is also observed for the first step of reduction for the molecule with n = 2.     

TDO structure investigation in aqueous solution by TOF-MS,UV, Raman and quantum chemistry calculations

ABSTRACT

Time of flight-mass spectroscopy (TOF-MS), ultraviolet (UV) absorption and Raman spectroscopy, and quantum chemistry calculations were used to investigate the thiourea dioxide (TDO) structure in aqueous solution. TOF-MS with the direct injection sample method was used to get molecular weight information of TDO in solution. The two structural models, (NH₂)₂CSO₂ (I) and NH₂NHCSO₂H (II), were used for the TDO single molecule, and all the methods lead to a consistent conclusion that TDO water solution is a mixture of In-cyc clusters (cyclic structures containing n molecules of TDO) and II single molecule. This work reveals the existence state of TDO in aqueous solution and supplies systematic method to explore the molecular structure of liquid solution.     

Portal Effects on the Stability of Cucurbituril Complexes

This work is concerned with the properties of cucurbit[n]uril (CBn) host portals. The carbonyl oxygens lining each of the cavity openings on these hosts give rise to a rim of negative charge density, which often has strong effects on guest binding processes. The negative effect that carboxylates exert on guest binding to cucurbit[7]uril (CB7) is described in detail, as well as the fact that the protonation state of terminal −COO⁻/COOH groups can be utilized to control CB7 shuttling on suitably designed pseudorotaxanes. Carboxylates can also slow down the kinetics of CB7 complex formation and dissociation. Finally, the electrostatic properties of the portals are useful -with suitable molecular design- to develop strong cooperativity effects, resulting from attractive side-by-side interactions, on the assembly of multi-component supramolecular complexes.     

Hydraulic and Mass-Transfer Performance of a 20-Mm-Diameter Annular Centrifugal Contactor for the Solvent Extraction of Cesium by Bis(2-Propyloxy)Calix[4]-Crown-6 in n-Octanol

A calixcrown extraction process using bis(2-propyloxy)calix[4]-crown-6 (iPr-C[4]C-6) as extractant and n-octanol as diluent for the separation of cesium from Chinese High Level Liquid Waste (HLLW) has been developed at INET. Chinese HLLW is acidic defense waste with high salt content, which is now stored in underground stainless steel tanks. The intention is to use a process to extract cesium from HLLW conducted on multistage 20-mm-diameter annular centrifugal contactors (ACCs), so it is necessary to study the hydraulic and mass-transfer performance of a 20-mm-diameter ACC for the extraction system. In this work, the effects of the parameters such as the rotor speed, the diameter of heavy weir, and the acid concentration on the hydraulic performance were investigated. An operational envelope of the 20-mm-diameter ACC for the n-octanol/aqueous solution system was identified. The mass-transfer efficiency of the single stage 20-mm-diameter ACC for the extraction and stripping of cesium with iPr-C[4]C-6 in n-octanol was studied by varying several parameters, such as the rotor speed, the total flow rate, and the flow ratio. The extraction stage efficiency is greater than 95% at suitable operating conditions for extracting Cs⁺ with 0.025 mol/L of iPr-C[4]C-6 in n-octanol from HNO₃ solution containing Cs⁺. The stripping stage efficiency of Cs⁺ (< 90%) is lower than the extraction stage efficiency of Cs⁺.     

Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules

Cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) are two key members of the cucurbit[n]uril (CB[n]) family of macrocycles. Because of the good water solubility of CB[7] and the unique ternary binding properties of CB[8], these two macrocycles have attracted increasing attentions in recent years. In particular, many promising reports of exciting applications regarding CB[7] and CB[8] have emerged in the pharmaceutical sciences and complexations of biomolecules, which has become one of the most important areas of potential applications of CB[n]s. This review summarizes the applications of macrocyclic CB[7], CB[8] and their derivatives as supramolecular platforms that have been developed in recent years within the field of pharmaceutical sciences and biomolecular sciences, and discusses the current challenges and future prospects of this area.