Facile synthesis of cucurbit[n]uril derivatives via direct functionalization: expanding utilization of cucurbit[n]uril

A long-standing problem in cucurbituril chemistry is answered through the first direct functionalization of cucurbit[n]uril (CB[n]; n = 5-8)) leading to perhydroxyCB[n] which can be further modified to provide tailored CB[n] derivatives with desired functional groups and good solubility. Anchoring a CB[6] derivative on the surface and its potential application as a sensor are demonstrated. A CB[6] derivative forms nanospheres with possible use in protein and peptide drug delivery.     

A study of binding interactions between terpyridine derivatives and cucurbit[10]uril

The binding interactions of a series of 2,2′:6′,2″-terpyridine (TPY) derivatives and their metal complexes with cucurbit[10]uril (CB[10]) were investigated by ¹H NMR, UV/Vis, emission spectroscopy, and ESI mass spectrometry. ¹H NMR titrations revealed CB[10] could encapsulate methylated TPY (MTPY), and the binding ratio between guest MTPY and host was 1:1 and 2:1 via ESI-MS characterization. For the transition metal complexes composed of Fe(II) or Ru(II) or Rh(III) and TPY derivatives, the octahedral TPY?metal?TPY core can be included in the cavity of CB[10]. Three binding modes (1:1, 1:2 and 1:3) have been detected for the binding of the metal?MPTY complexes with CB[10] by ESI-MS.     

Interaction between cucurbit[8]uril and viologen derivatives

The interaction between cucurbit[8]uril (Q[8]) and a series of symmetric viologen derivatives having aliphatic substituents of variable length [N,N′-dialkyl-4,4′-bipyridinium dianions; alkyl = CH₃(CH₂) _n –, n = 0 (MV²⁺), 1 (EV²⁺), 2 (PV²⁺), 3 (BV²⁺), 4 (FV²⁺), 5 (HV²⁺) or 6 (SV²⁺); BPY²⁺ = diprotonated 4,4-bipyridine], determined by ¹H NMR and electronic absorption spectroscopy methods, is described. Some different binding models were observed in this work when compared to the interactions between cucurbit[7]uril (Q[7]) and these guests. The experimental results revealed that the binding site of the guests by Q[8] depended strongly on the length of the aliphatic substituents on the 4,4′-bipyridinium nucleus. While a 1:2 complex was observed for Q[8]-BPY²⁺ under acidic conditions, a 1:1 complex was formed for Q[8]-viologen derivatives with chains shorter than four carbon atoms. However, multiple Q[8] molecules could be threaded on the longer-chain FV²⁺, HV²⁺ or SV²⁺ molecules to form 2:1 and even possibly 3:1 complexes.     

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.     

Sequence recognition and self-sorting of a dipeptide by cucurbit[6]uril and cucurbit[7]uril

Cucurbit[7]uril forms very strong complex with zwitterionic dipeptide Phe-Gly with affinity exceeding 10(7) M(-1) and effectively recognizes peptide sequence of Phe-Gly over Gly-Phe as well as Tyr-Gly over Gly-Tyr and Trp-Gly over Gly-Trp with relative affinities of 23 000, 18 000 and 2000, respectively.     

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.     

Supramolecular assembler based on cucurbit[8]uril: Photodimerization of a styryl dye in water

Photolysis of aqueous solutions of styryl dye 1 in the presence of cucurbit[8]uril (CB[8]) has been studied by optical spectroscopic methods for the molar ratios n = c _CB[8]/c ₁ in the range of 0 ≤ n ≤ 6. It has been found that the inclusion complexes (1)₂@CB[8] dominate in the solution at n ≤ 0.5, whereas the complexes 1@CB[8] dominate at n ≥ 1. The stability constants have been determined for the 1: 1 (log K ₁ = 6.2 (L mol^?1)) and 2: 1 (log β = 11.9 (L² mol^?2)) complexes. The fluorescence decay kinetics of dye 1 in the presence of CB[8] is two-exponential, with the average lifetime increasing substantially at n ≥ 1. It has been shown that the system can operate in the cyclic mode as an assembler (or supramolecular catalyst) in the photodimerization reaction of dye 1 to form cyclobutane derivative 2. The stability constant of the complex 2@CB[8] (log K ₃ = 5.9 (L mol^?1)) and the quantum yield of cycloaddition (? ≈ 0.07 at n ≈ 0.5) have been determined.     

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.     

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].     

Recognition of glycine by cucurbit[5]uril and cucurbit[6]uril: A comparative study of exo- and endo-binding

Recognition features of glycine (Gly) with cucurbit[5]uril (Q[5]) and cucurbit[6]uril (Q[6]) both in aqueous solution and solid state were investigated by ¹H NMR spectroscopy and X-ray crystallography. ¹H NMR data indicate that the Gly is located outside of the portals of the Q[5], exhibiting exo binding with the Q[5]. In the case of the Q[6], the Gly shows endo binding or a dual binding mode (endo and exo binding) with the host, which depends on the amount of the host in the aqueous solution. X-ray crystallography clearly display that the Gly forms 2:1 exclusion complex with the Q[5], and 2:1 inclusion complex with the Q[6]. Interestingly, hydrogen bondings between the encapsulated Gly molecules in the Q[6] were observed.     

Cyclodextrin-driven movement of cucurbit[7]uril

The movement of cucurbit[7]uril (CB[7]) driven by alpha-cyclodextrin (alpha-CD) is investigated by various experimental techniques including NMR, ESI-MS, UV-vis, and ITC. CB[7] can form stable pseudorotaxanes with N-methyl-N'-octyl-4,4'-bipyridinium (MVO2+) and N,N'-dioctyl-4,4'-bipyridinium (OV2+) dication in aqueous solution. CB[7] shuttles between the octyl and bipyridinium moieties in MVO2+, but docks at one of the octyl moieties in OV2+. The addition of alpha-CD pushes CB[7] from the octyl moiety of MVO2+ or OV2+ to the bipyridinium moiety. Thermodynamically, the movement of CB[7] is mainly driven by exothermic enthalpy changes coming from the complexation of the octyl moiety of MVO2+ or OV2+ with alpha-CD.     

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).     

Size selective supramolecular cages from aryl-bisimidazolium derivatives and cucurbit[8]uril

A series of bisimidazolium salts were synthesized as novel guests for the macrocyclic host molecule cucurbit[8]uril (CB[8]). These bisimidazolium-CB[8] binary complexes exhibited a unique cage structure with the imidazolium rings acting as lids, leading to a size-dependent binding selectivity by altering the hydrophobic linker between the two imidazolium moieties. This new class of CB[8] complexes was also capable of binding small solvent molecules, including acetone, acetonitrile, diethyl ether, and tetrahydrofuran (THF) in an aqueous environment.     

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.     

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.     

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.     

Controllable fabrication of a supramolecular polymer incorporating twisted cucurbit[14]uril and cucurbit[8]uril via self-sorting

A linear supramolecular polymer with controllable features based on twisted cucurbit[14]uril (tQ[14]) and cucurbit[8]uril (Q[8]) was firstly fabricated via an effective self-sorting strategy. Herein we designed a monomer, 1?butyl?1′-(naphthalen- 2-ylmethyl)-4,4′-bipyridinium bromide (BNB), that contains bipyridyl, aliphatic butyl and aromatic naphthyl groups, simultaneously. Two host molecules, tQ[14] and Q[8] were employed to develop an effective strategy for constructing a linear supramolecular polymer with controllable features. The alkyl groups on both sides of BNB could insert into the two cavities of tQ[14], the naphthyl part of BNB via π-π stacking in Q[8] cavity, serving as the driving force for supramolecular polymerization. Through self-sorting of the monomer, tQ[14] and Q[8], led to the formation of the linear supramolecular polymer. Depolymerization could be achieved by addition of adamantane hydrochloride (AH) which driven two BNB guest molecules out of the Q[8] cavity. This self-sorting strategy has great potential, not only for designing supramolecular polymer materials with different controllable structures through introduction of multiple functional groups, but also for broadening the application of twisted cucurbit[14]uril in supramolecular chemistry.     

Scope of amino acid recognition by cucurbit[8]uril

This paper describes the molecular recognition of amino acids by cucurbit[8]uril (Q8) and by the 1:1 complex between Q8 and methyl viologen (MV) in purely aqueous solution. These hosts are known to bind aromatic peptides with high affinity and sequence specificity, but prior work has focused on only a small subset of amino acids. In an effort to elucidate the scope and limitations of amino acid recognition by Q8 and Q8?MV, a comprehensive examination of the 20 genetically encoded amino acids was carried out by ¹H NMR spectroscopy and isothermal titration calorimetry. We find that both Q8 and Q8?MV bind measurably to only tryptophan, phenylalanine, and tyrosine. These results demonstrate that Q8 and Q8?MV are highly selective in the context of all genetically encoded amino acids and are therefore promising for the development of recognition-intensive applications involving peptides, proteins, and proteomes.     

pH-Switched fluorescent pseudorotaxane assembly of cucurbit[7]uril with bispyridinium ethylene derivatives

¹H NMR spectra and fluorescence analysis revealed that the molecular shuttle and pseudorotaxane assembly of Q[7] with guest G²⁺ can be significantly switched via protonation and deprotonation of the terminal carboxylates of the guest.