The inverted cucurbit[n]uril family

We report the isolation, characterization, and recognition behavior of iCB[6] and iCB[7], which are diastereomers of CB[6] and CB[7], respectively, containing a single inverted glycoluril unit. Product resubmission experiments establish that these inverted CB[n] are intermediates in the mechanism of CB[n] formation. As a consequence of the inverted glycoluril ring, these inverted cucurbiturils possess a permanent dipole moment, are slightly smaller than their diastereomers, show distinctive selectivity in their recognition behavior, and report directly on the contents of their hydrophobic cavity.     

The cucurbit[n]uril family

In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was dubbed "cucurbituril" by Mock and co-workers because of its resemblance to the most prominent member of the cucurbitaceae family of plants--the pumpkin. In the intervening years, the fundamental binding properties of CB[6]-high affinity, highly selective, and constrictive binding interactions--have been delineated by the pioneering work of the research groups of Mock, Kim, and Buschmann, and has led to their applications in waste-water remediation, as artificial enzymes, and as molecular switches. More recently, the cucurbit[n]uril family has grown to include homologues (CB[5]-CB[10]), derivatives, congeners, and analogues whose sizes span and exceed the range available with the alpha-, beta-, and gamma-cyclodextrins. Their shapes, solubility, and chemical functionality may now be tailored by synthetic chemistry to play a central role in molecular recognition, self-assembly, and nanotechnology. This Review focuses on the synthesis, recognition properties, and applications of these unique macrocycles.     

The cucurbit[n]uril family: prime components for self-sorting systems

We determined the values of Ka for a wide range of host-guest complexes of cucurbit[n]uril (CB[n]), where n = 6-8, using 1H NMR competition experiments referenced to absolute binding constants measured by UV/vis titration. We find that the larger homologues--CB[7] and CB[8]--individually maintain the size, shape, and functional group selectivity that typifies the recognition behavior of CB[6]. The cavity of CB[7] is found to effectively host trimethylsilyl groups. Remarkably, the values of Ka for the interaction of CB[7] with adamantane derivatives 22-24 exceeds 10(12) M(-1)! The high levels of selectivity observed for each CB[n] individually is also observed for the CB[n] family collectively. That is, the selectivities of CB[6], CB[7], and CB[8] toward a common guest can be remarkably large. For example, guests 1, 3, and 11 prefer CB[8] relative to CB[7] by factors greater than 10(7), 10(6), and 3000, respectively. Conversely, guests 23 and 24 prefer CB[7] relative to CB[8] by factors greater than 5100 and 990, respectively. The high levels of selectivity observed individually and collectively for the CB[n] family renders them prime components for the preparation of functional biomimetic self-sorting systems.     

Binding modes of cucurbit[6]uril and cucurbit[7]uril with a tetracationic bis(viologen) guest

Binding behaviors of two cucurbit[n]urils (CB[n]) hosts with the [CH3bpy(CH2)6bpyCH3]4+ (bpy = 4,4'-bipyridinium) guest were investigated by 1H NMR and MALDI-TOF-MS experiments. While the CB[6] and CB[7] form [2]pseudorotaxanes with the host located over the hexamethylene chain of the guest, only the CB[7] forms a [3]pseudorotaxane with both host molecules residing over the bipyridinium groups. The initial CB[7] host vacates the inclusion of the hexamethylene chain as a result of the electrostatic and steric repulsions that would arise in simultaneous binding of adjacent aliphatic and aromatic portions of the guest.     

Binding modes of cucurbit[6]uril and cucurbit[7]uril with a series of bis-pyridinium compounds

Binding behaviors of cucurbit[6]uril (CB[6]) and cucurbit[7]uril (CB[7]) with a series of bis-pyridinium compounds N, N’-hexamethylenebis(1-alkyl-4-carbamoyl pyridinium bromide) (HBPB-n) (alkyl chain length, n = 6, 8 and 10) guests were investigated using ¹H-NMR, ESI–MS and single crystal X-ray diffraction methods. The results show that CB[6] and CB[7] can form [2]pseudorotaxanes with HBPB-n easily. When increasing the length of tail alkyl chain, the binding site of CB[6] at guest molecules changed from the tail to the middle part, while CB[7] remained located over the tail chain. As CB[6] and CB[7] were added in HBPB-8 aqueous solution, a [3]pseudorotaxane was formed by the inclusion of the internal middle site in CB[6] and the tail chain in CB[7].     

Daisy chain assembly formed from a cucurbit[6]uril derivative

The building block synthesis of a derivative of CB[6] that bears a reactive propargyloxy group and its functionalization by click chemistry to yield 1 which contains a covalently attached isobutylammonium group is presented. Compound 1 undergoes self-assembly to yield a cyclic [c2] daisy chain assembly (1(2)) in water. The behavior of 1(2) in response to various stimuli (e.g., guests and CB[n] receptors) is described.     

Diastereoselective formation of glycoluril dimers: isomerization mechanism and implications for cucurbit[n]uril synthesis

Cucurbit[6]uril (CB[6]) is a macrocyclic compound, prepared in one pot from glycoluril and formaldehyde, whose molecular recognition properties have made it the object of intense study. Studies of the mechanism of CB[n] formation, which might provide insights that allow the tailor-made synthesis of CB[n] homologues and derivatives, have been hampered by the complex structure of CB[n]. By reducing the complexity of the reaction to the formation of S-shaped (12S-18S) and C-shaped (12C-18C) methylene bridged glycoluril dimers, we have been able to probe the fundamental steps of the mechanism of CB[n] synthesis to a level that has not been possible previously. For example, we present strong evidence that the mechanism of CB[n] synthesis proceeds via the intermediacy of both S-shaped and C-shaped dimers. The first experimental determination of the relative free energies of the S-shaped and C-shaped dimers indicates a thermodynamic preference (1.55-3.25 kcal mol(-)(1)) for the C-shaped diastereomer. This thermodynamic preference is not because of self-association, solvation, or template effects. Furthermore, labeling experiments have allowed us to elucidate the mechanism of this acid-catalyzed equilibrium between the S-shaped and C-shaped diastereomers. The equilibration is an intramolecular process that proceeds with high diastereoselectivity and retention of configuration. On the basis of the broad implications of these results for CB[n] synthesis, we suggest new synthetic strategies that may allow for the improved preparation of CB[n] (n > 8) and CB[n] derivatives from functionalized glycolurils.     

Cucurbit[n]uril analogues

[structure: see text] Cucurbits come in a variety of sizes, shapes, and colors. We present a building block approach that allows the tailor-made synthesis of CB[5], CB[6], and CB[7] analogues whose sizes, shapes, and colors differ from those of the known CB[n].     

Templated synthesis of glycoluril hexamer and monofunctionalized cucurbit[6]uril derivatives

We report that the p-xylylenediammonium ion (11) acts as a template in the cucurbit[n]uril forming reaction that biases the reaction toward the production of methylene bridged glycoluril hexamer (6C) and bis-nor-seco-CB[10]. Hexamer 6C is readily available on the gram scale by a one step synthetic procedure that avoids chromatography. Hexamer 6C undergoes macrocylization with (substituted) phthalaldehydes 12, 14, 15, and 18-in 9 M H(2)SO(4) or concd HCl at room temperature to deliver monofunctionalized CB[6] derivatives 13, 16, 17, and 19-that are poised for further functionalization reactions. The kinetics of the macrocyclization reaction between hexamer and formaldehyde or phthalaldehyde depends on the presence and identity of ammonium ions as templates. p-Xylylenediammonium ion (11) which barely fits inside CB[6] sized cavities acts as a negative template which slows down transformation of 6C and paraformaldehyde into CB[6]. In contrast, 11 and hexanediammonium ion (20) act as a positive template that promotes the macrocyclization reaction between 6C and 12 to deliver (±)-21 as a key intermediate along the mechanistic pathway to CB[6] derivatives. Naphthalene-CB[6] derivative 19 which contains both fluorophore and ureidyl C═O metal-ion (e.g., Eu(3+)) binding sites forms the basis for a fluorescence turn-on assay for suitable ammonium ions (e.g., hexanediammonium ion and histamine).     

Cucurbit[n]uril formation proceeds by step-growth cyclo-oligomerization

In contrast to the high yield formation of cucurbit[n]uril (CB[n]) from a 1:2 ratio of glycoluril to formaldehyde, the condensation of glycoluril with less than 2 equiv of formaldehyde delivers a reaction mixture that contains glycoluril oligomers (2-6) and CB[n] compounds that lack one or more methylene bridges known as nor-seco-cucurbit[n]urils (ns-CB[n]). In this paper we report the chromatographic purification of C-shaped glycoluril oligomers (dimer-hexamer), their characterization in solution, and their X-ray crystal structures. Quite interestingly, despite being acyclic glycoluril pentamer 5 and hexamer 6 retain the ability to bind to guests typical of CB[6] but are also able to expand their cavity to accommodate larger guests like cationic adamantane derivatives. We performed product resubmission experiments with glycoluril oligomers 2-6 and found preferences for the formation of specific ring sizes during CB[n] formation. A comprehensive mechanistic scheme is proposed that accounts for the observed formation of 2-6 and ns-CB[n]. Overall, the experiments establish that a step-growth cyclo-oligomerization process operates during CB[n] formation.     

A general and efficient method to form self-assembled cucurbit[n]uril monolayers on gold surfaces

A general protocol based on spontaneous adsorption of cucurbit[n]uril (CB[n]) molecules through a strong multivalence interaction between CB[n] and gold is described, by which the formation of self-assembled CB[n] monolayers on gold surfaces can be efficiently achieved.     

pH-Triggered dethreading-rethreading and switching of cucurbit[6]uril on bistable [3]pseudorotaxanes and [3]rotaxanes

A series of water-soluble [3]rotaxanes-(n+2) and [3]pseudorotaxanes-(n+2) with short (propyl, n=1) and long (dodecyl, n=10) aliphatic spacers have been prepared in high yields by a 1,3-dipolar cycloaddition reaction catalyzed by cucurbit[6]uril (CB6). The pH-triggered dethreading and rethreading of CB6 on these pseudorotaxanes was monitored by 1H NMR spectroscopy. A previously reported [3]rotaxane-12 that is known to behave as a bistable molecular switch has two recognition sites for CB6, that is, the diaminotriazole moieties and the dodecyl spacer. By changing the pH of the system, it is possible to observe more than one state in the shuttling process. At low pH values both CB6 units are located on the diaminotriazole moieties owing to an ion-dipole interaction, whereas at high pH values both of the CB6 units are located on the hydrophobic dodecyl spacer. Surprisingly, the CB6 units shuttle back to their initial state very slowly after reprotonation of the axle. Even after eighteen days at room temperature, only about 50 % of the CB6 units had relocated back onto the diaminotriazole moieties. The rate constants for the shuttling processes were measured as a function of temperature over the range from 313 to 333 K and the activation parameters (enthalpy, entropy, and free energy) were calculated by using the Eyring equation. The results indicate that this [3]rotaxane behaves as a kinetically controlled molecular switch. The switching properties of [3]rotaxane-3 have also been studied. However, even under extreme pH conditions this rotaxane has not shown any switching action, which confirms that the propyl spacer is too short to accommodate CB6 units.     

Preparation and recognition property of an acyclic cucurbit[n]uril dimer

Journal of Inclusion Phenomena and Macrocyclic Chemistry - A new acyclic cucurbit[n]uril (CB[n]) dimer is synthesized by copper-catalyzed azide-alkyne cycloaddition or “click” reaction....     

Inclusion complexation of diquat and paraquat by the hosts cucurbit[7]uril and cucurbit[8]uril

The binding interactions in aqueous solution between the dicationic guest diquat (DQ(2+)) and the cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8) hosts were investigated by (1)H NMR, UV/Vis, and fluorescence spectroscopy; mass spectrometry; single-crystal X-ray diffraction; and electrochemical techniques. The binding data were compared with previously reported results for the related paraquat guest (PQ(2+)). DQ(2+) was found to bind poorly (K=350 m(-1)) inside CB7 and more effectively (K=4.8 x 10(4) m(-1)) inside CB8. One-electron reduction led to increased binding affinity with both hosts (K(r)=1 x 10(4) m(-1) with CB7 and K(r)=6 x 10(5) m(-1) for CB8). While (1)H NMR spectroscopic data revealed that DQ(2+) is not fully included by CB7, the crystal structure of the CB8DQ(2+) complex-obtained from single-crystal X-ray diffraction-clearly establishes its inclusion nature. Overall, both diquat and its one-electron reduced radical cation are bound more effectively by CB8 than by CB7. In contrast to this, paraquat exhibits selectivity for CB7, but its radical cation forms a highly stable dimer inside CB8. These differences highlight the pronounced sensitivity of cucurbit[n]uril hosts to guest features such as charge, charge distribution and shape.     

Ion binding to cucurbit[6]uril: structure and dynamics

Molecular dynamics simulations are used to study the microscopic structure and dynamics of cations bound to cucurbit[6]uril (CB[6]) in water and in aqueous solutions of sodium, potassium, and calcium chloride. The molarities are 0.183 M for the salts and 0.0184 M for CB[6]. The cations bind only to CB[6] carbonyl oxygens. They are never found inside the CB[6] cavity. Complexes with Na(+) and K(+) mostly involve one cation, whereas with Ca(2+) single- and double-cation complexes are formed in similar proportions. The binding dynamics strongly depends on the type of cation. A smaller size or higher charge increases the residence time of a cation at a given carbonyl oxygen. When bound to CB[6], sodium and potassium cations jump mainly between nearest or second-nearest neighbors. Calcium shows no hopping dynamics. It is coordinated predominantly by one CB[6] oxygen. A few water molecules (zero to four) can occupy the CB[6] cavity, which is limited by the CB[6] oxygen faces. Their residence time is hardly influenced by sodium and potassium ions. In the case of calcium the residence time of the inner water increases notably. A simple structural model for the cation activity as "lids" over the CB[6] portal cannot, however, be identified. The slowing of the water exchange by the ions is a consequence of the generally slower dynamics in their presence and of their stable solvation shells.     

Probing guest compounds enabling the facile isolation of cucurbit[10]uril

A large set of commercially available amino compounds were assessed toward binding with cucurbit[10]uril(CB[10]),with the purpose of facilitating the isolation of pure CB[10].We found that the addition of a specific guest into a relevant mixture of CB[n]allowed the displacement of CB[5]from CB[10]?CB[5].Subsequent washing of the resulting(G=guest)with dimethyl sulfoxide(DMSO),enabled to get pure CB[10]in a facile and highly efficient way.     

Bromination of N-phenyloxypropyl-N'-ethyl-4,4'-bipyridium in cucurbit[8]uril molecular reactor

CB[n](n=6-8) is a family of synthetic macrocyclic host molecules composed of n glycoluril units, which can be employed as molecular reactor. N-phenyloxypropyl-N'-ethyl-4,4'-bipyridium (1) was designed to form a host-guest inclusion complex with CB[n](n=6-8), subsequently, the bromination reaction of 1 and its corresponding inclusion complexes was investigated in this work. In the case of 1/CB[8], the folded including mode is quite helpful to acquire 1-bormination product completely through intramolecular charge transfer (ICT), and CB[8] can provide a safe bromination environment for 1.     

Cucurbit[n]uril analogues: synthetic and mechanistic studies

[reaction: see text] The synthesis of cucurbit[n]uril analogues (18, 19, (+/-)-20, 33, 34, 35, 36, and 37) is presented. These CB[5], CB[6], and CB[7] analogues all contain bis(phthalhydrazide) walls that are incorporated into the macrocycle. The tailor-made synthesis of these CB[n] analogues proceeds by the condensation of the appropriate bis(electrophile) (4, 7, or 9) with bis(phthalhydrazide) (17), which delivers the CB[6] and CB[7] analogues in good yield, whereas the CB[5] analogue is formed in low yield. To improve the solubility characteristics of the CB[n] analogues for recognition studies in water or organic solution, the CO2Et groups were transformed to CO2H and CO2(CH2)9CH3 groups. On the basis of the results of product resubmission experiments, we conclude that these macrocycles are kinetic products. To help rationalize the good yields obtained in the CB[6] and CB[7] analogue macrocyclization reactions, we performed mechanistic studies of model methylene bridged glycoluril dimers, which suggest an intramolecular isomerization during CB[n] analogue formation.     

pH-responsive movement of cucurbit[7]uril in a diblock polypseudorotaxane containing dimethyl beta-cyclodextrin and cucurbit[7]uril

[Structure: see text] A polypseudorotaxane consisting of cucurbit[7]uril (CB[7])/N,N'-(3-phenylenebis(methylene)dipropargylamine (PMPA), [2]pseudorotaxane, and 2,6-O-dimethyl beta-cyclodextrin (DM-beta-CD)/alpha,omega-bisazidopropylene glycol 400 [2]pseudorotaxane was synthesized using the "click" reaction. The polypseudorotaxane structure was maintained in aqueous solution over a wide range of pH values with the DM-beta-CD units contributing to increased solubilization of the polypseudorotaxane without dethreading. The pH-responsive movement of the CB[7] units in the polypseudorotaxane was also observed.     

A hemicyanine and cucurbit[n]uril inclusion complex: competitive guest binding of cucurbit[7]uril and cucurbit[8]uril

The interaction between the hemicyanine indole derivative H and the cucubit[n]urils Q[7] and Q[8] has been studied using ¹H NMR and UV spectroscopy as well as by fluorescence experiments. Competitive studies on the inclusion of H by Q[7] and Q[8] have also been conducted, and reveal that on changing the size of the Q[n] cavity, the binding behaviour can be very different.