Gold and Silver Chains from Tetrahydrothiophenocucurbit[6]uril as Au or Ag-Nanoparticles.

Tetrahydrothiophenocucurbit[5 and 6]uril has been synthesized from tetrathiophenoglycoluril diether, providing thioether functionality at the exterior equatorial position of the cucurbituril cage. This functionality has been investigated for chemical modification through sulfoxide formation and subsequent Pummerer rearrangement to the acetoxy derivative of the tetrahydrothiophenocucurbit[5]uril. Nanoparticles of Au and Ag were prepared in the presence of tetrahydrothiophenocucurbit[6]uril, which curiously led to the formation of nanoparticle chains, growing in length over days to weeks.

Microwave Synthesis of Au Nanoparticles in the Presence of Tetrahydrothiophenocucurbituril.

The preparation of gold nanoparticles (AuNPs) from tetrachloroauric acid in the presence of tetrahydrothiophenocucurbit[n]uril (THTmQ[n]) has been effectively achieved in a microwave reactor. The reaction was performed in the presence of an excess of the tetrahydrothiopheno function in a partial reductant role, while the remainder formed AuNP-THTmQ[n] conjugates after the reduction was completed with formic acid. An affinity for the AuNPs by the THTmQ[n] was observed in the purification of the NPs via centrifugation, removal of the supernatant and resuspension of the conjugate.

The Cyclobutanocucurbit[5-8]uril Family: Electronegative Cavities in Contrast to Classical Cucurbituril while the Electropositive Outer Surface Acts as a Crystal Packing Driver.

The structural parameters for the cyclobutanoQ[5-8] family were determined through single crystal X-ray diffraction. It was found that the electropositive cyclobutano methylene protons (CH2) are important in forming interlinking crystal packing arrangements driven by the dipole-dipole interactions between these protons and the portal carbonyl O of a near neighbor. This type of interaction was observed across the whole family. Electrostatic potential maps also confirmed the electropositive nature of the cyclobutano CH2 but, more importantly, it was established that the cavities are electronegative in contrast to classical Q[5-8], which are near neutral.

Photophysical Activity and Host-Guest Behavior of Ruthenium Polypyridyl Catalysts Encapsulated in Cucurbit[10]uril.

This work outlines a strategy to combine the use of visible light and confined spaces to form a supramolecular photocatalyst system. Polypyridyl ruthenium(II) complexes [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine), [Ru(bpy)2(bpm)]2+ (bpm = 2,2'-bipyrimidine), and [Ru(bpy)2(bpz)]2+ (bpz = 2,2'-bipyrazine) are encapsulated in cucurbit[10]uril to form host-guest systems in aqueous solution. The photophysical properties of the complexes are altered by encapsulation, with improved emissive behavior for the heteroleptic complexes. Oxidative quenching of the photocatalyst's excited state via intermolecular charge transfer to methyl viologen can occur within the internal cavity, which acts to preorganize the reagents. The host-guest system containing [Ru(bpy)3]2+ can bind suitable substrates, and essential criteria for its use as a supramolecular photocatalyst are investigated.

Interaction of the Large Host Q[10] with Metal Polypyridyl Complexes: Binding Modes and Effects on Luminescence.

Aqueous solution state host-guest systems have been studied, comprising the large host cucurbit[10]uril with luminescent cationic tris(polypyridyl) (PP) metal complexes [Ru(PP)3]2+ and [Ir(PP)3]3+. All complexes bind strongly with the host, with the overall complex charge and size having a minor effect on affinity but influencing the association dynamics and contribution from higher-order (1:2) host-guest species. The 1:2 species contributes more significantly to the binding equilibrium in the case of [Ru(phen)3]2+. The effect of the host upon emission is highly variable and depends on the electronic structure of the guest. The metal-to-ligand charge transfer (MLCT) emission of [Ru(PP)3]2+ is strongly quenched, in contrast to the large enhancements seen previously for MLCT emission of iridium cyclometalated complexes, while the ligand-centered emission of [Ir(PP)3]3+ is little affected. The mechanisms of quenching and enhancement are discussed, together with the implications for the design of larger supramolecular assemblies based on these archetypal emitters.

Glycoluril derived cucurbituril analogues and the emergence of the most recent example: tiarauril.

Cucurbituril analogues can bear some of the chemical and physical characteristics of their parental origin and are derived wholly or in part from glycolurils (including homologues). The development of analogues is discussed from their earliest origins to the most recent developments, which includes deviations in binding properties and the inclusion of alternative molecular units in conjunction with glycolurils. Examples of alternative guest binding are discussed and compared to the behaviour of conventional cucurbituril.

Tiara[ n]uril: A Glycoluril-Based Macrocyclic Host with Cationic Walls.

The synthesis of new cationic macrocyclic host molecules is described. These macrocycles are comprised of glycoluril oligomers linked to two pyrazolium groups, which form part of a cationic wall facing into their cavities. A number of derivatives have been prepared with an objective to increasing the cavity size, and each new product has been fully characterized. Preliminary investigations of p Kas of Me10Tu[3]2+ and an interaction of L-glutamine indicate a potential for binding anionic molecules that also carry H-bond donor groups.

Eukaryotic Cell Toxicity and HSA Binding of [Ru(Me4phen)(bb7)]2+ and the Effect of Encapsulation in Cucurbit[10]uril.

The toxicity (IC50) of a series of mononuclear ruthenium complexes containing bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (bbn) as a tetradentate ligand against three eukaryotic cell lines-BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma)-have been determined. The results demonstrate that cis-α-[Ru(Me4phen)(bb7)]2+ (designated as α-Me4phen-bb7, where Me4phen = 3,4,7,8-tetramethyl-1,10-phenanthroline) showed little toxicity toward the three cell lines, and was considerably less toxic than cis-α-[Ru(phen)(bb12)]2+ (α-phen-bb12) and the dinuclear complex [{Ru(phen)2}2{µ-bb12}]4+. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). The binding of α-Me4phen-bb7 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. Large upfield 1H NMR chemical shift changes observed for the methylene protons in the bb7 ligand upon addition of Q[10], coupled with the observation of several intermolecular ROEs in ROESY spectra, indicated that α-Me4phen-bb7 bound Q[10] with the bb7 methylene carbons within the cavity and the metal center positioned outside one of the portals. Simple molecular modeling confirmed the feasibility of the binding model. An α-Me4phen-bb7-Q[10] binding constant of 9.9 ± 0.2 × 106 M-1 was determined by luminescence spectroscopy. Q[10]-encapsulation decreased the toxicity of α-Me4phen-bb7 against the three eukaryotic cell lines and increased the binding affinity of the ruthenium complex for HSA. Confocal microscopy experiments indicated that the level of accumulation of α-Me4phen-7 in BHK cells is not significantly affected by Q[10]-encapsulation. Taken together, the combined results suggest that α-Me4phen-7 could be a good candidate as a new antimicrobial agent, and Q[10]-encapsulation could be a method to improve the pharmacokinetics of the ruthenium complex.

Modelling the luminescence of iridium cyclometalated complexes encapsulated in cucurbituril.

Iridium(iii) cyclometalated complexes in aqueous solution often display relatively weak luminescence. It has been shown in previous work that this emission can be significantly enhanced (by up to two orders of magnitude) by encapsulation in cucurbit[10]uril (Q[10]). Luminescence lifetime measurements suggest a dynamic self-quenching mechanism is active, possibly due to displacement of an excited guest complex via collision with an unbound complex. We devise a model for the association of a group of iridium(iii) cyclometalated complexes with Q[10]. The model parameters are then fitted to steady-state emission titration curves. The excellent agreement of experimental data with the model provides valuable mechanistic information relating to the way this class of metal complexes interact and associate with the Q[10] host.

The Inheritance Angle: A Determinant for the Number of Members in the Substituted Cucurbit[n]uril Family.

Two new glycoluril diethers have been prepared, bearing strained cyclobutene and cyclobutane rings at the fused junction of the two imidazolidinone rings. The wide angle of the concave face of the cyclobutano derivative enabled the synthesis of cyclobutanocucurbit[5-8]uril, the largest member being the most significant achievement. A limited binding affinity study compared the new substituted family to classical cucurbit[5-8]uril. Surprisingly lower affinities were found, except for cyclobutanocucurbit[6]uril, which was 3.3-fold higher.

Molecular Snuggle and Stretch of a Tetraammonium Chain in the Construction of a Hetero-[4]pseudorotaxane with CyclopentanoQ[6] and Classical Q[7].

A hetero-[4]pseudorotaxane was designed to perform a molecular machine function of contraction and expansion utilizing the binding features of CyP6Q[6] and classical Q[7]. First, the effect on guest binding of equatorial substitution on Q[6]'s was examined by comparing Me4Q[6] and CyP6Q[6] against classical Q[6] using eight guest molecules varying in shape, size, neutrality, or cations. Second, the binding data provided optimal structural features for the design of a tetraammonium ion chain to effect the synthesis of the hetero-[4]pseudorotaxane. Finally, the hetero-[4]pseudorotaxane was constructed, and the order of component placement was examined for function and thermodynamic stability in relation to component order on the molecular axle.

Encapsulation of Mitoxantrone within Cucurbit[8]uril Decreases Toxicity and Enhances Survival in a Mouse Model of Cancer.

Mitoxantrone was efficiently encapsulated within cucurbit[8]uril in a 2:1 complex where the two mitoxantrone molecules were symmetrically located through both portals of a cucurbit[8]uril cage. The novel complex facilitates increased mitoxantrone uptake in mouse breast cancer cells and decreases the toxicity of the drug in healthy mice. In an orthotopic mouse model of metastatic breast cancer the complex still maintains in vivo anticancer activity compared to the free drug, yet provides a statistically significant increase in the survival of these mice compared to conventional mitoxantrone treatment. This new low toxicity formulation offers the possibility to increase mitoxantrone dose and thus maximize efficacy while managing the dose limiting side effects.

Probing the pharmacokinetics of cucurbit[7, 8 and 10]uril: and a dinuclear ruthenium antimicrobial complex encapsulated in cucurbit[10]uril.

The relatively non-toxic family of cucurbit[n]uril, Q[n], have shown considerable potential in vitro as drug delivery agents, with only a few examples of pharmacokinetic (PK) studies for drug⊂Q[n]. Drug-free Q[n] PK studies are the next step in determining the pharmacological applicability in their drug delivery potential. The results for the first PK and bio-distribution of drug-free 14C-Q[7] are described for administration via intravenous (i.v.) and intraperitoneal (i.p.) dosing. A study of oral administration of drug-free 14C-Q[8] has also been undertaken to determine the time course for the gastrointestinal tract (GIT), absorption and subsequent bio-distribution. Q[10], a potential drug carrier for larger drugs, was evaluated for its effect on the PK profile of a dinuclear ruthenium complex (Rubb12), a potential antimicrobial agent. The Rubb12⊂Q[10] complex and free Rubb12 were administered by i.v. to determine differences in Rubb12 plasma concentrations and organ accumulation. Interestingly, the PK profiles and bio-distribution observed for Q[7] showed similarities to those of Rubb12⊂Q[10]. Drug-free Q[7] has a relatively fast plasma clearance and a generally low organ accumulation except for the kidneys. Drug-free Q[8] showed a low absorption from the GIT into the blood stream but the small percentage absorbed reflected the organ accumulation of Q[7]. These results provide a better understanding of the probable PK profile and bio-distribution for a drug⊂Q[n] through the influence of the drug delivery vehicle and the positive clearance of drug-free Q[n] via the kidneys supports its potential value in future drug delivery applications.

Iridium Cyclometalated Complexes in Host-Guest Chemistry: A Strategy for Maximizing Quantum Yield in Aqueous Media.

The weaker emission typically seen for iridium(III) cyclometalated complexes in aqueous medium can be reversed via encapsulation in cucurbit[10]uril (Q[10]). The Q[10] cavity is shown to effectively maximize quantum yields for the complexes, compared to any other medium. This may provide significant advantages for a number of sensor applications. NMR studies show that the complexes are accommodated similarly within the host molecule, even with cationic substituents attached to the ppy ligands, indicating that the hydrophobic effect is the dominant driving force for binding. Cavity-encapsulated 1:1 host-guest species dominate the emission, but 1:2 species are also indicated, which also give some enhancement of intensity. Results demonstrate that the enhancement is due primarily to much lower rates of nonradiative decay but also suggest that the encapsulation can cause a change in character of the emitting state.

Rapid degradation of cyclic peroxides by titanium and antimony chlorides.

First responders face extraordinary risks when dealing with organic peroxides such as TATP due to the extreme sensitivity of this class of explosives, and to a lack of a robust chemical means of safe and rapid neutralisation. The Lewis acids TiCl4 and SbCl3 have been found to demonstrate a novel degradation mechanism, with TiCl4 degrading a model cyclic peroxide in minutes when used in a two-fold excess, or ∼3 hours at half equivalence. The products cannot re-form peroxide compounds as is the case with acid degradation, suggesting the two mechanisms are fundamentally different. The Lewis acids mediate a rearrangement reaction in the cyclic peroxide backbone leading to relatively innocuous products through deactivation of oxidising O. Sub-stoichiometric TiCl4 reactions highlight a secondary reaction pathway that also leads to some oxidative chlorination products, possibly mediated by an unconfirmed titanium-oxychloride species. SbCl3 was found to exhibit similar reactivity to TiCl4, although at a slower rate. A mechanism is proposed, consistent with the observations for both stoichiometric and sub-stoichiometric quantities of TiCl4.

Cucurbituril: chiral applications.

This review brings together the past and current methods for synthesizing the classical cucurbit[n]uril (Q[n]), structural variants, and derivatives. Here we refer to the first family of Q[n] as " classical," where the cavity is spheroidal and carry no substituents at any of the equatorial methine carbons or the methylene bridging carbons. The synthetic background and general physical and chemical properties of the Q[n] as molecular hosts is discussed. Particular attention is drawn to the synthesis of structural variants that have significance for chiral recognition properties such as (±)-bis-nor-seco-Q[6] and (±)-bis-nor-seco-Q[10]. Furthermore, examples of chiral recognition, enantio- and stereoselectivity using the achiral Q[n] as supramolecular structures with a chiral function directly or indirectly via another chiral agent are also discussed.

Cyclic pentanone peroxide: sensitiveness and suitability as a model for triacetone triperoxide.

Research to counter the threat of organic peroxides such as triacetone triperoxide (TATP) is at times hampered by their inherent extreme sensitiveness and volatility. This work describes an approach to lowering some risks associated with the handling of TATP in the laboratory through the use of an analog species, tripentanone triperoxide (TPTP). Sensitiveness has been tested via standard methods. GCMS analysis has shown that TPTP degrades via similar mechanisms to TATP under a range of conditions. Slight differences in product composition were traced to side reactions which may also affect impurities present in homemade TATP synthesis. A pilot field trial was conducted to evaluate TPTP as a substitute for TATP in explosive detection dog (EDD) scent training. The degradation studies have yielded insights into the complexities of the acidic degradation of cyclic peroxides with potential forensic application, and TPTP's inadequacy as a TATP pseudoscent is a valuable example of the limitations of such training aids.

Fe(OTf)3 versus Bi(OTf)3 as mild catalysts in epoxide oxidative ring-opening, urea α-diketone condensation, and glycoluril diether synthesis.

The salt Fe(OTf)3 has been shown to function as an effective catalyst in three different reactions, epoxide oxidative ring-opening to an α-hydroxy ketone, urea α-diketone condensation to form glycolurils, and glycoluril diether synthesis by formaldehyde condensation. In each of these reactions, Fe(OTf)3 was compared to Bi(OTf)3, a viable alternative catalyst with few or no prior examples of this type. Differences and advantages are highlighted but in most cases yields were generally high, and both catalysts outperformed conventional acid catalyzed methods.

Strong enhancement of luminescence from an iridium polypyridyl complex via encapsulation in cucurbituril.

An exceptional, temperature-dependent enhancement of luminescence is reported upon encapsulation of an iridium(III) polypyridyl complex in cucurbit[10]uril (Q[10]). This is the first demonstrated example of a luminescent transition metal complex occupying the Q[10] cavity with this type of differential response.

Protein binding by dinuclear polypyridyl ruthenium(II) complexes and the effect of cucurbit[10]uril encapsulation.

The effect of human serum on the minimum inhibitory/bactericidal concentrations of the potential antimicrobial agents ΔΔ-[{Ru(phen)2}2(µ-bb(n))](4+) {ΔΔ-Rubb(n); where phen = 1,10-phenanthroline, bb(n) = 1,n-bis[4(4'-methyl-2,2'-bipyridyl)]-alkane for n = 12 and 16} against four strains of bacteria--Gram positive Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli and Pseudomonas aeruginosa--has been determined. The results demonstrated that the ruthenium(ii) complexes have significantly decreased in vitro activity in serum. Fluorescence spectroscopy was used to confirm that the decrease in antimicrobial activity was due to the strong binding of the ruthenium complexes with the serum proteins human serum albumin (HSA) and transferrin. A series of ruthenium complexes showed stronger binding to HSA than apo-transferrin but comparable or less than with holo-transferrin, with the binding affinity to all three proteins decreasing in the order trinuclear > dinuclear > mononuclear. The dinuclear complex ΔΔ-Rubb12 displaced warfarin from HSA, tentatively suggesting that the ruthenium complexes bind at or near the warfarin-binding site, Sudlow's site 1. The binding of ΔΔ-Rubb12 and ΔΔ-Rubb16 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. The large upfield (1)H NMR chemical shift changes observed for the methylene protons in the bridging ligands upon addition of Q[10], coupled with the observation of a range of intermolecular ROEs in ROESY spectra, indicated that the dinuclear complexes bound Q[10] with the bridging ligand within the cavity and the metal centres positioned outside the portals. NMR and fluorescence spectroscopy demonstrated that the Q[10]-encapsulated ruthenium complexes directly bound HSA, and with similar affinity to the corresponding free metal complexes.