Cucurbit[7]uril Inclusion Complexes with Benzimidazole Derivatives: A Computational Study

Molecular dynamics (MD) simulations were carried out to study the host–guest complexation in aqueous solution between cucurbit[7]uril (CB7) and the neutral and protonated forms of benzimidazole derivatives. Complexation occurs via encapsulation of the hydrophobic part (benzene ring) of the guest within the CB7 hydrophobic cavity, and the interactions of the amine group(s) of the imidazole ring of the guest with the CB7 carbonyl portals. The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method is used to estimate the host–guest Gibbs energy of binding. The results indicate that CB7 binds the protonated form more strongly than the neutral one, and that the dominant contribution to the Gibbs energy of complexation for the neutral and protonated guests is associated, respectively, with the host–guest van der Waals and electrostatic interactions. Quantum chemical calculations using dispersion-corrected density functional theory (DFT) are used to calculate the binding affinities and to predict the pK_a values of the free and complexed guests. The calculated pK_a values for the free guests reveal excellent agreement with the experimental values, while for the complexed guests, general trends are obtained.     

SAMPL6 host–guest challenge: binding free energies via a multistep approach

In this effort in the SAMPL6 host–guest binding challenge, a combination of molecular dynamics and quantum mechanical methods were used to blindly predict the host–guest binding free energies of a series of cucurbit[8]uril (CB8), octa-acid (OA), and tetramethyl octa-acid (TEMOA) hosts bound to various guest molecules in aqueous solution. Poses for host–guest systems were generated via molecular dynamics (MD) simulations and clustering analyses. The binding free energies for the structures obtained via cluster analyses of MD trajectories were calculated using the MMPBSA method and density functional theory (DFT) with the inclusion of Grimme’s dispersion correction, an implicit solvation model to model the aqueous solution, and the resolution-of-the-identity (RI) approximation (MMPBSA, RI-B3PW91-D3, and RI-B3PW91, respectively). Among these three methods tested, the results for OA and TEMOA systems showed MMPBSA and RI-B3PW91-D3 methods can be used to qualitatively rank binding energies of small molecules with an overbinding by 7 and 37 kcal/mol respectively, and RI-B3PW91 gave the poorest quality results, indicating the importance of dispersion correction for the binding free energy calculations. Due to the complexity of the CB8 systems, all of the methods tested show poor correlation with the experimental results. Other quantum mechanical approaches used for the calculation of binding free energies included DFT without the RI approximation, utilizing truncated basis sets to reduce the computational cost (memory, disk space, CPU time), and a corrected dielectric constant to account for ionic strength within the implicit solvation model.     

Complexation of N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation and its neutral analogue by cucurbit[7]uril and β-cyclodextrin: a computational study

In this work, molecular dynamics (MD) simulations have been conducted to study the inclusion complexes between cucurbit[7]uril (CB7) and β-cyclodextrin (β-CD) with N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation, and N-methyl-4-(p-methyl benzoyl)-pyridine in aqueous solutions to gain detailed information about the dynamics and mechanism of the inclusion complexes. The obtained MD trajectories were used to estimate the binding free energy of the studied complexes using the molecular mechanics/Poisson Bolzmann surface area (MM–PBSA) method. Results indicate preference of CB7 to bind to the cationic guest more than the neutral guest, whereas β-CD exhibits more or less the same affinity to complex with either species. Furthermore it was interesting to note that β-CD forms more stable complexes with both guests than CB7. Average structure of each complex and the distances between the center of masses of the guest and the host were also discussed.     

Formation of aqua and tetraammine Cu(II) complexes inside the cavities of cucurbit[6,8]urils: A DFT forecast

Results of DFT calculations of the structure and thermodynamics of formation of aqua and tetraammine Cu(II) complexes inside CB[n] (n = 6,8) are presented in this study. Formation thermodynamics of the complexes in the cavitands was evaluated by taking into account the most probable number of water molecules inside CB[n]. In this methodology, the complexation was first considered as a substitution reaction in which the guest complex displaces partially or completely the water molecules that are located inside the cavity. The water molecules present in the cavitand were shown to play an important role in the fixation of the guest complex inside the cavity due to the hydrogen bonds with the oxygen portals. The hydration of Cu(II) ion inside CB[6] leads to the formation of an inclusion compound with the formula {[Cu(H₂O)₄]²⁺·2H₂O}@CB[6] while in CB[8] {[Cu(H₂O)₆]²⁺·4H₂O}@CB[8] is formed. For the binding of tetraammine Cu(II) complex, CB[8] was determined to be a significantly more suitable “container” than CB[6]. Both a direct embedding of this complex into the CB[8] and another mechanism in which ammonia molecules replace the water molecules in the Cu(II) aqua complex, preexisting in CB[8] were determined to be thermodynamically possible. Both these lead to the formation of the resultant inclusion compound described by the formula {[Cu(NH₃)₄(H₂O)₂]²⁺·4H₂O}@CB[8].     

Almost Enclosed Buckyball Joints: Synthesis,Complex Formation,and Computational Simulations of Pentypticene‐Extended Tribenzotriquinacene

We report the synthesis of a tribenzotriquinacene‐based (TBTQ) receptor ( 3 ) for C₆₀ fullerene, which is extended by pentiptycene moieties to provide an almost enclosed concave ball bearing. The system serves as a model for a self‐assembling molecular rotor with a flexible and adapting stator. Unexpectedly, nuclear magnetic resonance spectroscopic investigations reveal a surprisingly low complex stability constant of K₁=213±37 M ^?1 for [C₆₀? 3 ], seemingly inconsistent with the previously reported TBTQ systems. Molecular dynamics (MD) simulations have been conducted for three different [C₆₀?TBTQ] complexes to resolve this. Because of the dominating dispersive interactions, the binding energies increase with the contact area between guest and host, however, only for rigid host structures. By means of free‐energy calculations with an explicit solvent model it can be shown that the novel flexible TBTQ receptor 3 binds weakly because of hampering entropic contributions.     

Encapsulation of a β-carboline in cucurbit[7]uril

Inclusion of a biological photosensitizer and prototype of β-carbolines, norharmane (NHM), into the cavity of cucurbit[7]uril (CB[7]) has been investigated for the first time, by using ¹H NMR and UV–visible spectroscopy, and ab initio calculations. Protonated NHM forms a very stable host–guest complex with CB[7] in aqueous solution, with a binding constant of (9.0 ± 0.5) × 10⁴ M^?1. The encapsulation of NHM into CB[7] has driven the prototropic equilibrium of NHM to protonated NHM (NHMH⁺) at neutral pH. A pH titration for the host–guest complex revealed a moderate shift of the acid–base equilibrium in the ground-state (from 7.2 to 7.9), which may be caused by the low polarity microenvironment of the CB[7] cavity. The CB[7] provides a binding pocket for the hydrophobic molecule, and the polar, carbonyl-lined portals offering an anchoring site for the positive charge of the cationic species NHMH⁺.     

α‐Cyclodextrin Host–Guest Binding: A Computational Study of the Different Driving Forces

Free‐energy differences govern the equilibrium between bound and unbound states of a host and its guest molecules. The understanding of the underlying entropic and enthalpic contributions, and their complex interplay are crucial for the design of new drugs and inhibitors. In this study, molecular dynamics (MD) simulations were performed with inclusion complexes of α‐cyclodextrin (αCD) and three monosubstituted benzene derivatives to investigate host–guest binding. αCD Complexes are an ideal model system, which is experimentally and computationally well‐known. Thermodynamic integration (TI) simulations were carried out under various conditions for the free ligands in solution and bound to αCD. The two possible orientations of the ligand inside the cavity were investigated. Agreement with experimental data was only found for the more stable orientation, where the substituent resides inside the cavity. The better stability of this conformation results from stronger Van der Waals interactions and a favorable antiparallel host–guest dipole–dipole alignment. To estimate the entropic contributions, simulations were performed at three different temperatures (250, 300, and 350 K) and using positional restraints for the host. The system was found to be insensitive to both factors, due to the large and symmetric cavity of αCD, and the nondirectional nature of the host–guest interactions.     

Electron Density Shift in Imidazolium Derivatives upon Complexation with Cucurbit[6]uril

In this study, we have investigated the supramolecular interaction between series of 1‐alkyl‐3‐methylimidazolium guests with variable alkyl substituent lengths and cucurbit[6]uril (CB6) in the solution and the solid state. Correct interpretation of ¹H NMR spectra was a key issue for determining the binding modes of the complexes in solution. Unusual chemical shifts of some protons in the ¹H NMR spectra were explained by the polarization of the imidazolium aromatic ring upon the complexation with the host. The formation of 1:1 complex between 1‐ethyl‐3‐methylimidazolium and CB6 is in disagreement with previously reported findings describing an inclusion of two guest molecules in the CB6 cavity.     

DFT-B3LYP and SMD study on the interactions between aza-, diaza-, and triaza-12-crown-4 (A n -12-crown-4, n = 1, 2, 3) with Na+ in the gas phase and acetonitrile solution

B3LYP/6-311G level of theory is used to study the interactions between aza-, diaza-, and triaza- 12-crown-4 ligands as host molecules and Na⁺ ion as a guest species. Minimum energy structures, complexes binding energies, basis set superposition errors, and various thermodynamic parameters of free ligands, ion, and complexes have been calculated based on the proposed level of theory. A simple thermodynamic cycle with and without different acetonitrile cluster sizes inside the cavity of Na⁺, has been used to calculate the stability constants of aza-12-crown-4 complex. All solvation free energy estimations have been done with using SMD model. Results show that with introducing more acetonitrile molecules in the cavity of guest species, the absolute deviation is reduced. In addition, a good linear correlation between experimental complex formation constants and binding energies of complexes has been obtained. Calculated results, which are in agreement with the experimental data, predict that the interaction energy of triaza- is more than diaza-12-crown-4, which in turn is greater than aza-12-crown-4 with Na⁺ ion.     

Stereoselective inclusion mechanism of ketoprofen into β-cyclodextrin: insights from molecular dynamics simulations and free energy calculations

The host–guest inclusion mechanism formed between β-cyclodextrin and those poorly water-soluble drug molecules has important applications in supramolecular chemistry, biology and pharmacy. In this work, the chiral recognition ability of β-cyclodextrin to one of nonsteroidal anti-inflammatory drugs, ketoprofen, has been systematically investigated using molecular dynamics and free energy simulation methods. The R- and S-enantiomers of ketoprofen were explicitly bound within the cyclodextrin cavity in our simulations, respectively. In consistent with experimental observations, tiny structural difference between two isomers could be observed. Calculated absolute binding free energies using adapted biasing force (ABF) method and MM/GBSA approach for both isomers are comparable to experimental values. Significant binding fluctuations along the MD trajectory have been observed. The free energy profiles calculated using two different approaches reveal that the ketoprofen prefers binding in the cavity with the carboxylate group facing the wider edge of β-cyclodextrin. Similar free energy profiles for two enantiomers obtained using ABF calculations indicate that it is very hard to separate and identify the chiral conjugates within the framework of the natural β-cyclodextrin.     

First Principles Investigation of Noncovalent Complexation: A [2.2.2]‐Cryptand Ion‐Binding Selectivity Study

A first principles methodology, aimed at understanding the roles of molecular conformation and energetics in host–guest binding interactions, is developed and tested on a system that pushes the practical limits of ab initio methods. The binding behavior between the [2.2.2]‐cryptand host (4,7,13,16,21,24‐hexaoxa‐1,10‐diaza‐bicyclo[8.8.8]hexacosane) and alkali metal cations (Li⁺, Na⁺, and K⁺) in gas, water, methanol, and acetonitrile is characterized. Hartree–Fock and density functional theory methods are used in concert with crystallographic information to identify gas phase, energy‐minimized conformations. Gas phase free energies of binding, with vibrational contributions, are compared to solution‐state binding constants through relative binding selectivity analysis. Calculated relative binding free energies qualitatively correlated with solution state experiments only after gas phase metal desolvation is considered. The B3LYP exchange–correlation functional improves theoretical correlations with experimental relative binding free energies. The relevance of gas phase calculations towards understanding binding in condensed phases is discussed. Natural bond orbital methods highlights previously unidentified intramolecular and intermolecular M⁺(222) chemistries, such as an intramolecular n′_O→σ*_CH hydrogen bond.     

The SAMPL5 host–guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method

The absolute binding free energies and binding enthalpies of twelve host–guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R²) of 0.8 and root-mean-squared error of 1.7 kcal/mol using the TIP3P water model. The binding enthalpy calculations achieve moderate correlations, with R² of 0.5 and RMSE of 2.5 kcal/mol, for TIP3P water. Calculations using the newly developed OPC water model also show good performance. Furthermore, the present calculations semi-quantitatively capture the experimental trend of enthalpy-entropy compensation observed, and successfully predict guests with the strongest and weakest binding affinity. The most populated binding poses of all twelve systems, based on clustering analysis of 750 ns molecular dynamics (MD) trajectories, were extracted and analyzed. Computational methods using MD simulations and explicit solvent models in a rigorous statistical thermodynamic framework, like APR, can generate reasonable predictions of binding thermodynamics. Especially with continuing improvement in simulation force fields, such methods hold the promise of making substantial contributions to hit identification and lead optimization in the drug discovery process.     

Probing Conformational Changes of Ubiquitin by Host–Guest Chemistry Using Electrospray Ionization Mass Spectrometry

We report mechanistic studies of structural changes of ubiquitin (Ub) by host–guest chemistry with cucurbit[6]uril (CB[6]) using electrospray ionization mass spectrometry (ESI-MS) combined with circular dichroism spectroscopy and molecular dynamics (MD) simulation. CB[6] binds selectively to lysine (Lys) residues of proteins. Low energy collision-induced dissociation (CID) of the protein-CB[6] complex reveals CB[6] binding sites. We previously reported (Anal. Chem. 2011, 83, 7916–7923) shifts in major charge states along with Ub-CB[6] complexes in the ESI-MS spectrum with addition of CB[6] to Ub from water. We also reported that CB[6] is present only at Lys₆ or Lys₁₁ in high charge state (+13) complex. In this study, we provide additional information to explain unique conformational change mechanisms of Ub by host–guest chemistry with CB[6] compared with solvent-driven conformational change of Ub. Additional CID study reveals that CB[6] is bound only to Lys₄₈ and Lys₆₃ in low charge state (+7) complex. MD simulation studies reveal that the high charge state complexes are attributed to the CB[6] bound to Lys₁₁. The complexation prohibits salt bridge formation between Lys₁₁ and Glu₃₄ and induces conformational change of Ub. This results in formation of high charge state complexes in the gas phase. Then, by utilizing stronger host–guest chemistry of CB[6] with pentamethylenediamine, refolding of Ub via detaching CB[6] from the protein is performed. Overall, this study gives an insight into the mechanism of denatured Ub ion formation via host-guest interactions with CB[6]. Furthermore, this provides a direction for designing function-controllable supramolecular system comprising proteins and synthetic host molecules.      

Diarylethylene guest anchored into a cyclodextrin molecular host: optical,quantum chemical studies and biological activity

The host–guest complexation between a novel guest namely; 2-(4-pyridinylbenzothiazolyl) ethane, PBE and β-cyclodextrin was studied using steady-state absorption and emission techniques. The fluorescence maximum is strongly blue-shifted with a great enhancement in the fluorescence intensity upon addition of β-CD, confirming the formation of inclusion complexes. The solid inclusion complex between PBE and β-CD has been prepared, characterised using FT-IR, X-ray diffraction and scanning electron microscope techniques. PBE is encapsulated with β-CD nanocavity and 1:1 PBE–β-CD host–guest interaction is identified. This is confirmed using semi-empirical quantum chemical calculations. PBE guest entered into the less polar cavity through the benzothiazole moiety. The negative values of enthalpy and free energy changes suggest that the encapsulation process is thermodynamically favourable. Additionally, the fluorescence is more sensitive to the micellar medium, whether it was cationic, anionic or neutral as well as metal ions like, Li⁺, Cu²⁺ and Fe³⁺. Finally, the antimicrobial activities of PBE guest and its inclusion complex with β-CD host are studied.     

Kinetics and Mechanism of Cation-Induced Guest Release from Cucurbit[7]uril

The release of two organic guests from cucurbit[7]uril (CB7) was selectively monitored by the stopped-flow method in aqueous solutions of inorganic salts to reveal the mechanistic picture in detail. Two contrasting mechanisms were identified: The symmetric dicationic 2,7-dimethyldiazapyrenium shows a cation-independent complex dissociation mechanism coupled to deceleration of the ingression in the presence of alkali and alkaline earth cations (Mⁿ⁺) due to competitive formation of CB7–Mⁿ⁺ complexes. A much richer, unprecedented kinetic behaviour was observed for the ingression and egression of the monocationic and non-symmetric berberine (B⁺). The formation of ternary complex B⁺–CB7–Mⁿ⁺ was unambiguously revealed. A difference of more than two orders of magnitude was found in the equilibrium constants of Mⁿ⁺ binding to B⁺–CB7 inclusion complex. Large cations, such as K⁺ and Ba²⁺, also promoted B⁺ expulsion from the ternary complex in a bimolecular process. This study reveals a previously hidden mechanistic picture and motivates systematic kinetic investigations of other host–guest systems.     

From Packed “Sandwich” to “Russian Doll”: Assembly by Charge‐Transfer Interactions in Cucurbit[10]uril

As the host possessing the largest cavity in the cucurbit[n]uril (CB[n]) family, CB[10] has previously displayed unusual recognition and assembly properties with guests but much remains to be explored. Herein, we present the recognition properties of CB[10] toward a series of bipyridinium guests including the tetracationic cyclophane known as blue box along with electron‐rich guests and detail the influence of encapsulation on the charge‐transfer interactions between guests. For the mono‐bipyridinium guest (methylviologen, MV ²⁺), CB[10] not only forms 1:1 and 1:2 inclusion complexes, but also enhances the charge‐transfer interactions between methylviologen and dihydroxynaphthalene ( HN ) by mainly forming the 1:2:1 packed “sandwich” complex (CB[10] ? 2 MV ²⁺ ?HN ). For guest 1 with two bipyridinium units, an interesting conformational switching from linear to “U” shape is observed by adding catechol to the solution of CB[10] and the guest. For the tetracationic cyclophane‐blue box, CB[10] forms a stable 1:1 inclusion complex; the two bipyridinium units tilt inside the cavity of CB[10] according to the X‐ray crystal structure. Finally, a supramolecular “Russian doll” was built up by threading a guest through the cavities of both blue box and CB[10].     

A Nexus between Theory and Experiment: Non‐Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions

A training set of eleven X‐ray structures determined for biomimetic complexes between cucurbit[n]uril (CB[7 or 8]) hosts and adamantane‐/diamantane ammonium/aminium guests were studied with DFT‐D3 quantum mechanical computational methods to afford ΔG_calcd binding energies. A novel feature of this work is that the fidelity of the BLYP‐D3/def2‐TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[n] ? guest complex binding energy subcomponents [for example, ΔE_dispersion, ΔE_{electrostatic}, ΔG_solvation, binding entropy (?TΔS), and induced fit E_{deformation(host)}, E_{deformation(guest)}] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[n]uril (n=5, 6, 7, 8) isolated host molecules were also explored by means of the DFT‐D3 method. A high ρ²=0.84 correlation coefficient between ΔG_exptl and ΔG_calcd was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for ΔG_calcd predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [‐(CH₂)_nNH₃]⁺ amino loops attached to N,N‐dimethyl‐adamantane‐1‐amine and N,N,N′,N′‐tetramethyl diamantane‐4,9‐diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra‐high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.     

Reorganization of highly preorganized hosts upon cation complexation: Ab initio study of fluorospherands

Fluorospherands (F‐spherands) are highly preorganized hosts composed of fluorobenzene or 4‐methylfluorobenzene units attached to one another at their 2,6‐positions. To understand the intrinsic factors affecting cation complexation, we investigated the complexation behavior between F‐spherands and cations using density functional theory (DFT) at the level of B3LYP/6‐31G**. The F6‐spherand (C₆H₃F)₆, ( 1 ) has a highly preorganized spherical cavity, which can encapsulate Li⁺ and Na⁺. Its cavity is not big enough for K⁺ and NH, which prefer external binding. Plausible conformations were studied for F8‐spherand (C₆H₃F)₈. Conformer of D_2d symmetry ( 2b ) is more stable than that of D_4d ( 2a ), in agreement with NMR experiments. The cavity size of F8‐spherand is big enough to encapsulate all cations studied. However, the cavity size of 2b is smaller than that of 2a , which resulted in the guest selectivity. Upon complexation, 2b conformation is more stable for Li⁺ and Na⁺, while 2a conformation is preferred for larger cations such as K⁺ and NH. Thus, the ab initio calculations over these highly preorganized fluorospherands give important insights into their host–guest chemistry. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Interaction between tetramethylcucurbit[6]uril with α-furaldehyde-isonicotinyl-hydrazone hydrochloride

Interaction between tetramethylcucurbit[6]uril (TMeQ[6], host) and the hydrochloride salt of α-furaldehyde-isonicotinyl-hydrazone hydrochloride (FIHH⁺, guest) was investigated using X-ray crystallography and spectroscopic methods. X-ray crystallography showed that the π–π stacking effect and hydrogen bonding resulted in the formation of a dumbbell-shaped supramolecule which contained two FIHH⁺@TMeQ[6] host–guest inclusion complexes. The host–guest interaction provided identifiable changes in the vibrational frequencies in the IR spectra. ¹H NMR spectral analysis established a similar interaction model and revealed that TMeQ[6] preferred to include the furan moiety over the pyridine moiety of the FIHH⁺ guest molecule. Absorption spectrophotometric analysis suggested that the host and guest interact in a ratio of 1:1 with a stability constant K _s = (3.52 ± 0.74) × 10⁶ l mol^? 1.pH titration confirmed that the host–guest interaction led to a clear change in the protonation constant of the title guest. Quantum chemical calculations were used to determine the possible mechanism of formation of the dumbbell-shaped complex.     

Kinetic and thermodynamic inclusion complexes of symmetric teramethyl-substituted cucurbit[6]uril with HCl salts of N,N′-bis(pyridylmethyl)-1,6-hexanediamine

The host–guest interaction of symmetrical α,α′,δ,δ′-tetramethyl-cucurbit[6]uril (TMeQ[6]) with the hydrochloride salts of N,N′-bis(4-pyridylmethyl)-1,6-hexanediamine (P6), N,N′-bis(3-pyridyl-methyl)-1,6-hexanediamine (M6) and N,N′-bis(2-pyridylmethyl)-1,6-hexanediamine (O6) was investigated via single crystal X-ray diffraction, ¹H NMR spectroscopy, electronic absorption spectroscopy and fluorescence spectroscopy. Single crystal X-ray diffraction showed that the hexyl moiety of P6 or M6 was incorporated in the cavity of TMeQ[6], while the two pyridylmethyl moieties of O6 were incorporated in the TMeQ[6] cavity in the solid state. The ¹H NMR results in aqueous solution revealed that the TMeQ[6]-P6 and TMeQ[6]-M6 host–guest interaction systems produce a kinetic dumbbell-shaped inclusion complex at the initial stage and then an equilibrium pseudorotaxane-shaped inclusion complex as the only product after heating. However, only the pseudorotaxane-shaped inclusion complex was observed for the TMeQ[6]-O6 host–guest interaction system. Aqueous absorption spectrophotometric analysis showed that the dumbbell-shaped inclusion complexes were stable at pH 5.6, had a host–guest ratio of 2:1 and formed quantitatively at ～10¹¹ l²/mol² for the TMeQ[6]-M6 and TMeQ[6]-O6 systems. The transformation from dumbbell to pseudorotaxane-shaped inclusion complexes for the TMeQ[6]-P6 and TMeQ[6]-M6 host–guest systems yielded activation energies of 59.35 ± 1.55 and 78.7 ± 3.45 kJ/mol, respectively. The pseudorotaxane-shaped inclusion complexes were stable at pH 5.6, had a host–guest ratio of 1:1 and formed quantitatively at ～10⁷ l/mol for the TMeQ[6]-M6 and TMeQ[6]-P6 systems.