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The host-guest complexations of fifteen protonated azaspirocyclic, oxa,azaspirocyclic, and diazaspirocyclic guests, three-dimensional analogues of morpholinium, piperidinium, and piperazinium catio...

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’ pKa and/or pKa* 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 pKa 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.

Chapter 3 describes the supramolecular host–guest chemistry of unmodified cucurbit[n]urils (single-cavity CB[n], n=5–8, 10, and twisted tCB[n], n=13–15). The ranges of host–guest complexes formed with the single-cavity and twisted CB[n] hosts are surveyed, and their applications, notably in the field of drug and biomolecule recognition, are described. With inner cavity volumes ranging from 68 to 691 Å3, the single-cavity CB[n] hosts exhibit unique selectivity for differently sized guest molecules and ions: the CB[5] can bind small gas molecules, CB[6] binds aliphatic chains, CB[7] can include aromatic and polycyclic guests, CB[8] allows for the binding of two complementary guests, while CB[10] can bind other small host molecules, as well as transition metal complexes. The host–guest complexation is driven primarily by the hydrophobic effect in terms of the release of high-energy waters from the cavity upon guest inclusion, along with favorable ion–dipole interactions between the polar portals and charged centers on cationic guests. The ultra-high stability constants (up to 1017 M−1) observed with certain dicationic guests and CB[7] result from optimal packing of the hydrophobic cavity with the guest core and the placement of an ammonium group adjacent to each portal.

The cucurbit[7]uril (CB[7]) host–guest complexations of a series of zwitterionic “Good's” biological pH buffers have been investigated in aqueous solution by means of 1H NMR spectroscopy. The cyclohexylammonium buffers bind very strongly (KCB[7] = 107 to 108 dm3 mol−1), while the morpholinium (102 to 103 dm3 mol−1) and piperazinium (103 to 104 dm3 mol−1) buffers have binding constants several orders of magnitude smaller. The binding constants increase as the distance between the ammonium and sulfonate groups increases. The pKa of 2-(cyclohexylammonio)ethanesulfonate (CHES) increases by 3.1 units upon complexation by CB[7].

The inclusions of 1-methyl-3-alkylimidazolium cations (ICn+, n = 4, 6, and 8) and 3,3′-bis(3-(1-methylimidazolium))-1,n-alkane (DICn2+, n = 4, 6, and 8) in the macrocyclic cucurbit[7]uril result in a decrease (up to 25-fold) of the C(2)-H/D exchange rate constants and an increase in the C(2)-H pKa values (ΔpKa = 0.34 to 1.45). The alkyl chain lengths were found to play an important role in the extent of C(2)-H activity inhibition, upon complexation with cucurbit[7]uril.

A pharmaceutically and biologically relevant molecule, pyridoxine hydrochloride (vitamin B6), was encapsulated inside the cavity of a molecular container, cucurbit[7]uril (CB[7]), in aqueous solution. The CB[7] based “nanocapsule” of vitamin B6has been investigated for the first time, via1H NMR and UV-visible spectroscopic titrations (including Job’s plot) andab initiomolecular modeling. The results have demonstrated that vitamin B6forms stable host-guest complexes within CB[7] in 1 : 1 stoichiometry, with a binding affinity of(4.0±0.5)×103 M−1. Such a nanocapsule could potentially find application in vitamin B6formulation for the purpose of enhancing the stability, absorption, and delivery of this important vitamin.

The macrocyclic molecular container cucurbit[7]uril (CB[7]), the most water-soluble homologue in the cucurbit[n]uril family (n = 5–8, 10, 14), has been evaluated for its in vivo toxicity profile, including its developmental toxicity such as its effect on hatching, growth and survival, as well as its potential organ-specific toxicities such as cardiotoxicity, hepatotoxicity, and locomotion and behavioral toxicity, using zebrafish models. The results revealed that CB[7] has measureable cardiotoxicity and locomotion and behavioral toxicity at concentrations of ∼500 μM or higher, and negligible developmental and hepatotoxicity at concentrations up to 750 μM, although extended exposure to CB[7] in the 500–750 μM concentration range induced the mortality of tested fish. These results demonstrate for the first time with live in vivo animal models that CB[7] has relatively low developmental and organic specific toxicity, and support further exploration of the use of CB[7] in biomedical research at sub-toxic concentrations.

A general anesthetic is a drug that brings about a reversible loss of consciousness, during a surgical or therapeutic procedure to render the patient free of pain and anxiety. However, the effect of anesthetics may linger far beyond the necessary time required and induce adverse effects. In addition, many surgical patients need to recover to a conscious state that allows them to make important decisions soon after their surgery. Unfortunately, there are currently no clinically-available anti-dotes to reverse the effects of anesthetics. In this study, we demonstrate the in vitro supramolecular host–guest complexations between macrocyclic cucurbit[7]uril (CB[7]) and a commonly used general anesthetic in fish, tricaine mesylate (TM), and we report for the first time the in vivo reversal effect of CB[7] to general anesthesia induced by TM with zebrafish models. These findings might lead to a new approach that may allow patients to regain lucidity much faster than their natural recovery from general anesthesia, and may also be used to reverse potentially life-threatening toxic effects encountered by some patients in response to general anesthesia.

This report describes, for the first time, cucurbit[7]uril-assisted quantitative in vitro and in vivo uptake of a hydrophobic model drug, coumarin-6, by both an epithelial cell model and a zebrafish model. The transcellular delivery pathway study suggested multiple mechanisms involved, including macropinocytosis, clathrin and lipid raft-mediated endocytosis/exocytosis.

A biologically- and pharmaceutically-relevant bis(thiazolium) dication model compound, α,α′-bis(thiazolium)-p-xylene (BTX2+), forms a strong 1 : 1 host–guest inclusion complex with cucurbit[7]uril (CB[7]). The complexation stoichiometry, binding affinity and geometry were studied via 1H NMR and UV-visible titrations, ESI-MS, and molecular modeling (ab initio calculations). The hydrogen/deuterium exchange reactions of the C(2)-proton of BTX2+ were conducted in the absence and presence of CB[7] in D2O at 25 °C and at an ionic strength of 0.20 M. The inhibition of C(2)-H/D exchange of the guest bis(thiazolium) dication upon complexation with CB[7] exhibited a second-order rate constant that decreased by more than four-fold in the presence of CB[7]. The supramolecular-controlled stability of thiazolium cations through complexation with CB[7] host molecules is anticipated to have applications for stability enhancement of thiazolium based drugs and to potentially draw interest in the application of CB[n] host molecules with regard to the formulation and delivery of these drugs.

The ideal neuromuscular blocking agent (NMBA) is regarded as being a non-depolarizing equivalent of succinylcholine, having a rapid onset and short duration of action, with minimal side effects. In the absence of a single drug, the administration of an aminosteroid NMBA, such as rocuronium, followed by reversal using an acetylcholinesterase inhibitor, such as neostigmine, is commonly employed. A different and safer approach to rapidly reversing the action of the NMBA, by encapsulating it with a macrocyclic or acyclic host molecule, such as the cyclodextrin sugammadex or more recently, cucurbituril-type hosts such as cyclic cucurbit[7]uril and the acyclic glycoluril tetramer calabadion 1, is described.

The host–guest complexations of a series of biguanidinium cations (metformin and phenformin) and bis(biguanidinium) dications (chlorhexidine and alexidine) by the host molecule cucurbit[7]uril (CB[7]) in aqueous solution have been investigated by 1H NMR spectroscopy and ESI mass spectrometry. Metformin forms both 1:2 and 1:1 host–guest complexes, whereas phenformin forms only a 1:1 complex. The two bis(biguanidinium) dications both form sequential 1:1, 2:1 and 3:1 host–guest complexes, however, the mechanism is different in each case. With chlorhexidine, the first CB[7] binds to the central hexamethylene chain, followed by sequential complexation of the terminal 4-chlorophenyl groups. With alexidine, the two terminal 2-ethylhexyl groups are bound first, with the third CB[7] adding only with a concomitant relocation of one CB[7] to the central hexamethylene binding site. The stability constants of the various host–guest complexes were determined by 1H NMR titrations and competitive binding experiments, as well as by the application of a statistical binding model.

The cucurbit[ n ]urils, a family of cyclic host molecules comprised of n glycoluril units bridged by 2 n methylene bridges, and their acyclic analogues form very stable supramolecular host–guest complexes with neutral and cationic drug molecules in aqueous solution, which can be applied to drug binding, targeted delivery and controlled release, and drug reversal. The abilities of the cucurbiturils to modulate the solubility, acidity (p K a ), and chemical reactivity of included drug molecules will discussed in the context of these applications.

Cucurbit[7]uril selectively binds the epigenetic mark N(ε),N(ε),N(ε)-trimethyllysine (LysMe(3), K(CB[7]) = (1.8 ± 0.6)× 10(6) dm(3) mol(-1)) by 3500-fold over lysine ((5.3 ± 0.7) × 10(2) dm(3) mol(-1)) in aqueous solution, using ion-dipole interactions and the hydrophobic effect, rather than cation-π interactions, as in the "aromatic cages" of p-SO(3)-calix[4]arene hosts or chromodomain proteins which recognize LysMe(3). The trend in K(CB[7]) of LysMe(3)LysMe(2)LysMeLys follows the recognition pattern of the chromodomain HP1 and other LysMe(n) protein readers. With CB[6], protonation of the guest carboxylate group is required for the formation of inclusion complexes with the LysMe(n) series. The CB[7] host also displays modest selectivity between the asymmetric ((2.0 ± 0.3) × 10(3) dm(3) mol(-1)) and symmetric ((6.1 ± 0.6) × 10(3) dm(3) mol(-1)) dimethylarginines, both of which bind more strongly than the parent arginine or monomethylarginine.

The effects of the encapsulation of drugs and other molecules of biomedical interest by cucurbit[n]uril (n=5–8, 10) host molecules on the chemical properties of the drugs in aqueous solution are reviewed. The cucurbituril complexation of drug molecules has been shown to generally increase the guests’ pKa values through preferential inclusion of the protonated species, modulate other equilibria involving the guest, improve the solubility in aqueous solution, reduce the toxicity and other side effects, as well as enhance the stability and targeted delivery of the drug molecule. These benefits have led to an increasing interest in the applications of cucurbit[n]urils in novel drug formulations.

Pseudorotaxanes may be assembled in aqueous solution using dicationic acetylcholinesterase inhibitors, such as succinylcholine, BW284c51, and alpha,omega-bis(trialkylammonium)alkane dications (or their phosphonium analogues), as bolaform axles and cucurbit[7]uril (CB[7]) as the wheel. With the exceptions of the shorter [(CH(3))(3)N(CH(2))(n)N(CH(3))(3)](2+) (n = 6, 8) dications, the addition of a second CB[7] results in the translocation of the first CB[7], such that the hydrophobic -NR(3)(+) and -PR(3)(+) end groups (R = Me or Et) are located in the cavities of the wheels, while the central portion of the axles extend through the CB[7] portals into the bulk solvent. In the case of the [Quin(CH(2))(10)Quin](2+) (Quin = quinuclidinium) dication, the CB[7] host(s) resides only on the quinuclidinium end group(s). The 1:1 host-guest stability constants range from 8 x 10(6) to 3 x 10(10) M(-1) and are dependent on both the nature of the end group as well as the length and hydrophobicity of the central linker. The magnitude of the stability constants for the 2:1 complexes closely follow the trend observed previously for CB[7] binding with the NR(4)(+) and PR(4)(+) cations.

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+.

The stability of the 4,4′-bis(dimethylamino)diphenylmethane carbocation is significantly enhanced in aqueous solution by its inclusion in the cucurbit[7]uril host cavity. The formation of the host–guest complex (KCB[7] = 2.0 × 104 M−1) shifts the carbinol–carbocation equilibrium, maximizing the formation of the intensely blue carbocation to 90% at pH 5.2.

Vitamin B1 (1) and its phosphate derivatives, thiamine monophosphate (2) and thiamine pyrophosphate (3), are shown to form stable 1:1 host-guest complexes with cucurbit[7]uril (CB[7]) in aqueous solution. The binding sites of CB[7] on these guests shift from the ethylthiazolium region of 1 to the pyrimidine moiety of 2 and 3 due to the presence of phosphate groups, leading to variations of binding affinities as well as C(2)-H/D exchange rate constants and C(2)-H pKa values with these guest molecules.

The novel asymmetric dicationic ligands [Quin(CH2)10tbp]2+, [Quin(CH2)10bpy]2+, and [Lut(CH2)10bpy]2+ (Quin+ = quinuclidinium, Lut = 3,5-lutidinium, tbp+ = 4-tert-butylpyridinium, and bpy+ = 4,4′-bipyidinium) form [2]semirotaxanes with α- and β-cyclodextrins in aqueous solution, with the cyclodextrin passage possible only over the 4-tert-pyridinium or bipyridinium end groups to yield two orientational isomers. The kinetics of the formation and dissociation of the kinetically and thermodynamically preferred orientational isomers of the [Quin(CH2)10tbp]2+[2]semirotaxane with α-CD have been investigated by 1H NMR spectroscopy. Complexation of the free nitrogen on the 4,4′-bipyridinium end groups of the [R(CH2)10bpy]2+ ligands by the aquapentacyanoferrate(II) ion results in the formation of the corresponding [2]rotaxanes.

The kinetic parameters for the axial-ligand-substitution reactions of [Ru 2 (μ-O 2 CCH 3 ) 4 (MeCN) 2 ]+ in acetonitrile (MeCN) with PCy 3 and PCy 2 Ph (Cy = cyclohexyl and Ph = phenyl) were investigated under pseudo first-order conditions of excess phosphane. The rate-determining formation of [Ru 2 (μ-O 2 CCH 3 ) 4 (MeCN)(PCy 2 R] + appears independent of the nature of the incoming phosphane with an average k 1 (25.0 °C) = (1.25 ± 0.06) × 10 3 M -1 s -1 . A dissociatively activated mechanism is proposed for substitution of the axially coordinated acetonitrile, and the rate parameters are compared to earlier measurements carried out on [Rh 2 (μ-O 2 CCH 3 ) 4 (MeCN) 2 ]. Variable-temperature magnetic susceptibility measurements were carried out on the two phosphane diadducts, [Ru 2 (μ-O 2 CCH 3 ) 4 (PCy 3 ) 2 ]PF 6 , (1) and [Ru 2 (μ-O 2 CCH 3 ) 4 (PCy 2 Ph) 2 ]-PF 6 (2), and showed behaviour unique to a Boltzmann distribution of states over the temperature range 2-300 K. To support the magnetic measurements, the single-crystal X-ray structure of 1 was redetermined at various temperatures down to -150 °C and showed a distinct decrease in the Ru-Ru bond length with decreasing temperature, consistent with a σ 2 π 4 δ2π* 3 configuration at low temperature (ground state) and a σ 2 π 4 δ 2 π* 2 δ* 1 configuration at room temp. In addition, the structure redeterminations of 1 were better resolved than the earlier reported structure and also corrected a minor error in that the molecule of solvation was found to be 1,2-dichloroethane instead of dichloromethane.

The blue fluorescence of acridizinium bromide (ADZ+) and the green fluorescence of 9-aminoacridizinium bromide (AADZ+) in aqueous solutions can be almost entirely switched off upon the double inclusion of these guests in the cavity of cucurbit[8]uril (CB[8]) owing to the formation of a nonfluorescent, noncovalent dimer complex, and then fluorescence can be effectively restored by adding cucurbit[7]uril (CB[7]) to the complex because it competitively extracts the fluorophores out of the CB[8] cavity.

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.

The protonated forms of the chiral molecules ( S )- and ( R )- N -benzyl-1-(1-naphthyl)ethylamine (BNEAH + ) form very stable 1:1 guest–host complexes with cucurbit[7]uril in aqueous solution. The stoichiometry and stability constants for the guest–host complexes were determined by 1 H NMR, UV–visible and circular dichroism spectroscopy and electrospray mass spectrometry. The molecular optical rotations of the guests increase in magnitude by about 5-fold upon formation of the {BNEAH·CB[7]} + species. Energy minimized structures of the guests and guest–host complexes indicate changes in the dihedral angles about the stereogenic centre upon ion-dipole and H-bonding interactions between the ammonium hydrogens of the guest and the carbonyl groups of the cucurbituril portals. The increases in the optical rotations are discussed in terms of restricted rotations of the naphthyl groups and in preferential solvation of benzylamine in the cucurbit[7]uril cavity.

The host–guest interactions between cucurbit[7]uril and a series of novel cationic bis(4,5-dihydro-1H-imidazol-2-yl)arene and 1-(4,5-dihydro-1H-imidazol-2-yl)- and 1,3-bis(4,5-dihydro-1H-imidazol-2-yl)-adamantane guests have been investigated in aqueous solution using UV–vis and NMR spectroscopy, and electrospray mass spectrometry. With the exception of the 1,3-bis(4,5-dihydro-1H-imidazol-2-yl)adamantane (which binds externally to the CB[7]), these guests form very stable inclusion complexes with slow exchange on the 1H NMR timescale. The direction and magnitude of the complexation-induced shifts (CIS) in the proton resonances of the guests are indicative of the residence of the hydrophobic core of the guest within the CB[7] cavity and the charged 4,5-dihydro-1H-imidazol-2-yl units outside the cavity adjacent to the carbonyl-lined portals of the host. The CIS values and the inclusion stability constants have been correlated with the nature of the guest core and with the distance between the charges on the terminal 4,5-dihydro-1H-imidazol-2-yl rings.Key words: cucurbit[7]uril, host–guest complex, dihydroimidazolyl, inclusion stability constants.

The (E)-1-ferrocenyl-2-(1-methyl-4-pyridinium)ethylene cation, (E)-FcMPE+, forms a very stable guest−host complex (KCB7 = (1.3 ± 0.5) × 1012 M-1) in aqueous solution with cucurbit[7]uril (CB[7]). The 1H NMR, ES-MS, and UV−visible spectra are consistent with 1:1 {(E)-FcMPE·CB[7]}+ species formation, in which the CB[7] encapsulates the ferrocenylethylene portion of the guest. The reduction potential of the (E)-FcMPE2+/+ couple increases slightly (+0.03 V) in the presence of CB[7], while the rate constant for the oxidation of (E)-FcMPE+ by Co(dipic)2- (dipic2- = 2,6-pyridinedicarboxylate) decreases significantly. UV−visible spectra of (E)-FcMPE+ in the absence and in the presence of CB[7] during photoirradiation demonstrate that the photoisomerization to (Z)-FcMPE+ is fully inhibited and photostabilization of (E)-FcMPE+ is dramatically enhanced upon inclusion in CB[7].

A series of dinuclear platinum(II) complexes, [(dien)Pt(NH2(CH2)nNH2)Pt(dien)]Cl4 (dien = diethylenetriamine, n = 8, 9, 10, and 12) and their corresponding [2]rotaxanes with α-cyclodextrin (α-CD), [(dien)Pt{NH2(CH2)nNH2·α-CD}Pt(dien)]Cl4, have been synthesized and characterized by 1H, 13C, and 195Pt NMR spectroscopy and electrospray mass spectrometry. The rotaxanes were prepared by reacting the {NH2(CH2)nNH2·α-CD} pseudorotaxanes with [Pt(dien)]Cl, to stopper the included linear α,ω-diaminoalkane chains with the inert Pt(II) end groups. The kinetics of the self-assembly and dissociation of the β-CD rotaxane, [(dien)Pt{NH2(CH2)10NH2·β-CD}Pt(dien)]4+, were investigated by using 1H NMR and are indicative of a slippage mechanism, owing to the comparable sizes of the β-CD cavity and the [Pt(dien)]+ end group. A relatively weak inclusion of the end group in the β-CD cavity precedes a thermally promoted passage of the β-CD over the [Pt(dien)]+ end group onto the hydrophobic polymethylene chain of the bridging ligand of the thread. Key words: rotaxanes, pseudorotaxanes, cyclodextrin, platinum complexes, slippage mechanism.

A series of novel bischelate bridging ligands, CH3NH(CH2)2N(CH3)(CH2)nN(CH3)(CH2)2NHCH3 (n = 9, 10, 11, and 12) were synthesized as hydrochloride salts and characterized by elemental analyses, electrospray mass spectrometry, and 1H and 13C NMR spectroscopy. These ligands form [2]pseudorotaxanes with α-cyclodextrin (α-CD) and the stability constants have been determined from 1H NMR titrations in D2O. The kinetics and mechanism of the assembly and dissociation of a [2]pseudorotaxane in which α-CD has been threaded by the CH3NH2(CH2)2N(CH3)(CH2)12N(CH3)(CH2)2NH2CH32+ ligand were determined in aqueous solution using 1H NMR spectroscopy. A weak inclusion of the dimethylethylenediamine end group precedes the passage of the α-CD onto the hydrophobic dodecamethylene chain.

[2]Pseudorotaxanes have been prepared by threading N,N′-bis(4-pyridinylmethylene)-1,2-ethanediimine (L2), -1,4-butanediimine (L4), and -1,6-hexanediimine (L6) ligands through α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD), and have subsequently been converted to the corresponding [2]rotaxane species by coordinating bulky [Fe(CN)5]3– end groups. The stability constants for the [2]pseudorotaxanes were determined by 1H NMR chemical shift titrations and increase with the polymethylene chain length n. The rate constants for both the formation of the [Fe(CN)5(Ln)]3– complexes from the [Fe(CN)5OH2]3– ion and Ln, and the rate constants for the dissociation of Ln from the metal complexes, exhibit significant diminutions in the presence of α- and β-CD, owing to inclusions of the free and coordinated ligands, respectively. The lability of the iron(II)–pyridine bonds also permits the spontaneous self-assembly of the [2]rotaxane upon the addition of cyclodextrin to the iron dimer complexes. The mechanism for this process involves the rate-determining dissociation of a [Fe(CN)5]3– unit from [(NC)5Fe(Ln)Fe(CN)5]6–, followed by CD inclusion of the Ln ligand to form a semirotaxane, and subsequent recomplexation by the [Fe(CN)5OH2]3– ion. Key words: cyclodextrins, rotaxanes, pentacyanoferrate(II), ligand substitution, kinetics.

The effects of β-cyclodextrin on the kinetics of the oxidation of three novel bisferrocenyl cationic complexes; [(η 5 -C 5 H 5 )Fe(η 5 -C 5 H 4 CH 2 N(CH 3 ) 2 CH 2 ( p -C 6 H 4 )CH 2 N(CH 3 ) 2 CH 2 η 5 -C 5 H 4 )Fe(η 5 -C 5 H 5 )] 2+ ( 1 ), [(η 5 -C 5 H 5 )Fe(η 5 -C 5 H 4 CH 2 N(CH 3 ) 2 (CH 2 ) 12 N(CH 3 ) 2 CH 2 η 5 -C 5 H 4 )Fe(η 5 -C 5 H 5 )] 2+ ( 2 ), and [(η 5 -C 5 H 5 )Fe(η 5 -C 5 H 4 CH 2 N(CH 3 ) 2 CH 2 η 5 -C 5 H 4 )Fe(η 5 -C 5 H 5 )] + ( 3 ), by bis(pyridine-2,6-dicarboxylato)cobaltate(III) have been investigated in aqueous media. 1 H NMR and electrospray ionization mass spectroscopy revealed that these compounds form 1:1 and 2:1 host–guest complexes with β-cyclodextrin. The respective stability constants, K CD and K 2CD , of 3700±400 and 1500±200 M −1 for 1 , 6800±800 and 1600±200 M −1 for 2 , and 4000±500 and 1500±200 M −1 for 3 , were determined from fits of the kinetic data. The electron transfer rate constants were observed to decrease significantly upon the formation of a 1:1 host–guest complex with β-CD (890±30 to 260±40 M −1 s −1 for 1 , 870±50 to 300±65 M −1 s −1 for 2 , and 520±40 to 350±50 M −1 s −1 for 3 at 25.0°C). The 2:1 host–guest complexes were found to be unreactive to oxidation (0±50 M −1 s −1 ). The decreased reactivities of the inclusion complexes are attributed to decreased thermodynamic driving forces and steric hindrances to the approach of the oxidant. The molecular structure of compound 3 was determined by X-ray structure analysis.

The kinetics and thermodynamics of the self-assembly of a series of [2]pseudorotaxanes comprised of α-cyclodextrin (α-CD) and racemic 1,12-bis(4-(α-alkyl-α-methylmethanol)pyridinium)dodecane dications (L(CH2)12L2+) in aqueous solutions have been investigated using 1H NMR spectroscopy. The mechanism of assembly involves inclusion of the α-methyl-α-alkylmethanol substituent groups (−C(CH3)(OH)R, where R = Me, Et, Pr, Bu, allyl, and 4-butenyl) by α-CD, followed by a rate-determining passage of the cyclodextrin over the pyridinium group onto the dodecamethylene chain. Dicationic threads containing end groups with R = Ph or i-Pr or where L = 4-(α,α-diethylmethanol)pyridinium did not form α-cyclodextrin pseudorotaxanes, even after prolonged heating. The trends in the rate and activation parameters may be related to the size, shape, and hydrophobicity of the alkyl substituents and are compared with several other systems from the literature. An increase in the length and hydrophobicity of the alkyl group increase...

The kinetics and mechanism of the formation and dissociation of a series of [2]pseudorotaxanes, comprised of α -cyclodextrin (α -CD) as the cyclic component and the ([Me3N(CH2)nNMe3]2+ (n = 8-12), [Me2EtN(CH2)10NEtMe2]2+, and [Me3P(CH2)10PMe3]2+) dications as the threads, were determined by means of 1H and 31P NMR in aqueous solution. The length of the polymethylene chain (n) of the thread, which has a minor effect on the rate constant for pseudorotaxane formation, is important in the kinetics of the dissociation reactions, with the longer, more hydrophobic chains resulting in slower pseudorotaxane dissociation. The replacement of one methyl substitutent by an ethyl group in each of the end groups on the [Me3N(CH2)10NMe3]2+ thread results in a 30-fold decrease in the formation rate constant. Replacements, by ethyls, of two or all of the methyl substitutents prevent the formation of the pseudorotaxane, even after prolonged heating. The pseudorotaxane containing the {Me3P(CH2)10PMe3.; α-CD}2+ thread forms only at elevated temperatures by a slippage mechanism, and the rate constant for its self-assembly at 75°C (8 x 10-5 M-1 s-1) is more than 106 smaller than the rate constant at 75°C (200 M-1 s-1) extrapolated for the corresponding {Me3N(CH2)10NMe3 . α -CD}2+complex. The enthalpies and entropies of activation for the formation and dissociation of the [2]pseudorotaxanes decrease with an increase in the size and hydrophobicity of the end groups, suggesting a reduced role of desolvation of the quaternized atoms in the threading or dethreading processes.Key words: pseudorotaxane, α -cyclodextrin, kinetics, self-assembly, slippage, supramolecular.

The 1:1 and 2:1 host–guest complexation of a series of 1,n-bis(isoquinolinium)alkane dications (Iq(CH2)nIq2+, n = 2, 4, 5, 6, 8, 9, 10 and 12, and Iq(p-xylene)Iq2+) by cucurbit[7]uril (CB[7]) in aqueous solution has been investigated by 1H NMR spectroscopy and ESI mass spectrometry. The site of binding of the first CB[7] is dependent on the nature of the central linker group, with encapsulation of the p-xylene group or the polymethylene chain when n = 6–10.With shorter (n = 2–5) or longer (n = 12) chains, the first CB[7] binds over an isoquinolinium group. With a second CB[7], the binding of the central group is abandoned in favour of the CB[7] hosts encapsulating the two cationic isoquinolinium termini. The 1:1 and 2:1 host–guest stability constants are related to modes of binding and the nature of the central linkers, and are compared with dicationic guests bearing different terminal groups.

This report describes the synthesis and characterization of Pt(II)-bis(guanosine)(R-phen) complexes (where R=H (phen) or 2,9-dimethyl (dmphen)), as a model for bifunctional covalent adduct formation between antitumor (dichloro)Pt(II)amine complexes and DNA bases. The 1 H and 13 C NMR spectra (in D 2 O) of the isolated product in the reaction of the corresponding [(dichloro)(R-phen)Pt(II)] complex, with 2 mole equivalents of guanosine, reveal formation of a cis -bis(guanosine)(phen)Pt(II) ( 1 ) and a trans -bis(guanosine)-(dmphen)(Cl)Pt(II) ( 2 ). The 1 H NMR spectrum of 1 reveals a mixture of head-to-tail ( htt ) and head-to-head ( hth ) rotamers that do not interconvert on the NMR time scale (200 and 400 MHz, 298–343 K). For complex 2 the formation of a trans -bis(guo) complex with monocoordinated dmphen ligand is in accord with recent findings in analogous reactions of [Pt(dmphen)Cl 2 ] with alkenes, alkynes and aryl phosphine ligands. It is noteworthy that the room-temperature 1 H NMR spectrum of 2 in D 2 O showed no intramolecular process due to ‘flipping’ of the mono-coordinated dmphen ligand; this is in contrast to observations with trans -bis(PPh 3 ) complex (in CD 2 Cl 2 ,RT) previously reported. The NMR spectral data of the two complexes have been re-examined and the different behavior is discussed.

[2]Pseudorotaxanes have been prepared by threading linear chains of the type [R(CH2)nR]2+ (where R = 3- or 4-cyanopyridine and n = 9 or 10) through α-cyclodextrin (α-CD), and subsequently converted to the corresponding [2]rotaxane species by coordinating bulky [Fe(CN)5]3- end groups. The lability of the iron(II)-cyanopyridinium bonds also permits the spontaneous rotaxane self-assembly upon cyclodextrin addition to the iron dimer complexes. The mechanism for this process involves the rate-determining dissociation of a [Fe(CN)5]3- unit ((7 ± 1) × 10-2 s-1 at 25 °C for [(NC)5Fe(4CNpyr(CH2)94CNpyr)Fe(CN)5]4-). The stability constants for the α- and β-CD inclusion complexes; {AD-CNpyr·CD}+ and [Fe(CN)5{AD-CNpyr·CD}]2- (AD-CNpyr+ = 1-adamantan-1‘-yl-3- and -4-cyanopyridinium), have been determined by 1H NMR spectroscopy and ligand substitution kinetic studies. The rate constants for the ligand substitution reactions of the [Fe(CN)5(AD-CNpyr)]2- and [Fe(CN)5(CNpyr(CH2)nCNpyr)]- complexes exhibited significant di...

The kinetics and mechanisms of the oxidation of Nb(CN)inf8sup5−by the oxyanions S2Oinf8sup2−, BrOinf3sup−, and IOinf4sup−have been investigated in alkaline aqueous media (pH 12). The second-order rate constant for the electron transfer reaction between Nb(CN)inf8sup5−and S2Oinf8sup2−at 25.0 °C, I = 0.36m (K+), is 11.1± 0.3 m−1s−1 with ΔH‡ = 30 ± 2kJmol−1 and ΔS‡ = - 125 + 7JK−1 mol−1. The rate constant for the oxidation of Nb(CN)inf8sup5−by BrOinf3sup−at 25.0 °C, I = 0.20m (Na+), is 2.39 ± 0.08m−1s−1 with ΔH‡ = 28 ± 2kJmol−1 and ΔS‡ = -139 ± 7JK−1mol−1. The oxidation of Nb(CN)inf8sup5−by IOinf4sup−proceeds by two parallel pathways involving the monomeric IOinf4sup−ion and the hydrated dimer H2I2Oinf10sup4−. The second-order rate constant for the oxidation of Nb(CN)inf8sup5−by monomeric IOinf4sup−at 5.0 °C, I = 0.050m (Na+), is (3.3 ± 0.6) × 103m−1s−1 with ΔH‡ = 75 ± 6 kJ mol−1 and ΔS‡ = 94 ± 15 J K−1 mol−1, while the rate constant for the oxidation by H2I2Oinf10sup4−is (1.8 ± 0.1) × 103m−1s−1 with ΔH‡ = 97 ± 5 kJ mol−1 and ΔS‡ = 166 ± 16 J K−1 mol−1 under the same reaction conditions. The rate constants for each of the oxidants employed display specific cation catalysis with the order of increasing rate constants: Li+ < Na+ < NHinf4sup+< K+ < Rb+ < Cs+, in the same direction as the electronic polarizability of the cations. The results are discussed in terms of the outer-sphere electron-transfer processes and compared with the corresponding data and mechanisms reported for other metal-cyano reductants.

The kinetics and thermodynamics of the self-assembly of a [2]pseudorotaxane comprised of α-cyclodextrin and the 1,10-bis[1-(4-tert-butylpyridinium)]decane dication, by means of a slippage procedure, have been measured in aqueous solutions using 1H NMR spectroscopy. The very slow threading of the α-cyclodextrin [k1=(4.2 ± 0.3)× 10–4 s–1 at 25 °C] is preceded by a weak inclusion of the tert-butylpyridinium end group (KCD= 18 ± 3 dm3 mol–1). The dissociation of the [2]pseudorotaxane occurs with a rate constant of (4.2 ± 0.2)× 10–6 s–1 at 25 °C, yielding a pseudorotaxane stability constant of (1.8 ± 0.2)× 103 dm3 mol–1.

Metal rotaxane complexes of a-cyclodextrin (a-CD), [ (NC)~F~(~~Z(CH~),R.~-CD)F~(CN)~]~-, have been prepared by the reactions of labile [Fe(CN)50H2I3- ions with pre-threaded dicationic bridging ligands [pyz(CH2),RI2+ (pyz = pyrazinium, R = pyrazinium or 4,4'-bipyridinium (bpy), and n = 8-12) in aqueous solution. The stability constants for the a-CD inclusion of the ligands, as determined by 'H NMR spectroscopy, increase with the chain length n and are slightly larger for R = 4,4'-bipyridinium than for pyrazinium head groups. The thermodynamic parameters for the pseudorotaxane equilibria may be correlated in terms of an enthalpy-entropy compensation effect, suggesting that substantial conformation changes and desolvation are involved in the inclusion and dissociation processes. The inclusion of the free ligand by a-CD decreases the rate constants for the formations of the monomeric and dimeric metal complexes from the [Fe(CN)50H2I3- ion. The rate constants for ligand dissociation of [pyz(CH2),RI2+ from the metal complexes also decrease upon inclusion of the coordinated bridging ligand. The kinetics of the spontaneous self-assembly of the rotaxane upon mixing the dimer [(NC)5Fe(pyz(CH2),R)Fe(CN)sl4- and a-cyclodextrin are consistent with a rate-determining dissociation of a [Fe(CN)5I3unit, followed by a-CD inclusion of the semirotaxane and rapid recomplexation by a [Fe(CN)50H2I3- ion to form the rotaxane.

The stability constants for the inclusions of the [FeCp(CpCH2N(CH3)3]+ cation in α- (150±10 M−1), β- (4810±600 M−1), dmβ- (5010±800 M−1) and γ-cyclodextrins (500±50 M−1) have been determined at 25 °C by means of 1H NMR chemical shift titrations. The effects of cyclodextrin inclusion of the substituted ferrocene couple on the kinetics of its electron-transfer reactions have been investigated in aqueous solution at 25.0 °C. The inclusions of [FeCp(CpCH2N(CH3)3]+ by cyclodextrins decrease the rate constant for its oxidation by bis(pyridine-2,6-dicarboxylato)cobaltate(III) (from 930 to 20 M−1 s−1 upon β-CD inclusion). The rate constants for the oxidations of ascorbic acid by [FeCp(CpCH2N(CH3)3]2+ increase (from 640 to 2600 M−1 s−1 for β-CD) upon inclusion of the oxidant by α- (KCD=10±5 M−1), β- (150±15 M−1) and dmβ-cyclodextrin (140±30 M−1) inclusions of the oxidant. The γ-cyclodextrin has a negligible effect on the electron-transfer rate constant. The effects of cyclodextrin inclusion on the kinetics of these electron-transfer reactions are discussed in terms of changes in the thermodynamic driving force of the reaction and shielding of the reactants.

The rapid, quantitative complexation reactions of labile [Fe(CN)5-OH2]3- ions with α-cyclodextrin (α-CD) threaded 1,1″-(α,ω-alkanediyl)-bis(4,4′-bipyridinium) dicationic ligands yield stable, self-assembled metal rotaxane complexes, [(NC)5Fe{bpy(CH2) n bpy•α-CD}Fe(CN)5]4- (n=8–12), in aqueous solution. The {bpy(CH2)nbpy•α-CD}2+ inclusion complexes and the metal rotaxanes have been characterized by their 1H and 13C NMR spectra, which display pairs of proton and carbon resonances for symmetry-related nuclei upon inclusion in the asymmetric α-CD cavity. The stability constants and the associated thermodynamic parameters for the {bpy(CH2) n bpy•α-CD}2+ inclusion complexes have been determined by 1H NMR. The kinetics of the ligand substitution processes involved in the self-assembly of the metal rotaxane complexes from α-CD and [(NC)5Fe(bpy(CH2) n bpy)Fe(CN)5]4- have been measured using visible and 1H NMR spectroscopy. The kinetic and activation parameters are consistent with a rate-limiting dissociat...

Three series of N-heterocyclic dicationic ligands, [R(CH 2 ) n R] 2+ , [R(o-xyl)R] 2+ , and [R(p-xyl)R] 2+ , where R= pyrazine (pyz, n=3-8), 4,4'-bipyridine (bpy, n=1-8), and trans-1,2-bis(4-pyridyl)ethylene (bpe, n=1-8), have been synthesized by the reaction of the N-heterocycle with the appropriate α,ω-dibromoalkane, α,α'-dibromo-o- xylene, or α,α'-dibromo-p-xylene. In addition, ligands with R=3-methyl- and 3-aminopyrazine, in which the free N donor atom is sterically hindered, have been prepared

The stability constants for the inclusion complexes of a series of neutral aromatic N-heterocyclic ligands (substituted pyridines and symmetrical dipyridyls) and their pentacyanoferrate(II) complexes, Fe(CN) 5 L 3- with α- and β-cyclodextrin have been determined from 1 H NMR chemical shift and visible spectrophotometric titrations an from the kinetics of their ligand substitution reactions.

The effects of α- and β-cyclodextrin inclusion of 4-tert-butylcatechol on the kinetics of its outer-sphere oxidation by hexachloroiridate(IV), diaqua(1,4,8,11-tetraazacyclotetradecane)nickel(III), and bis(1,4,7-triazacyclononane)nickel(III) in acidic aqueous media have been investigated. The time-averaged orientations of the guest reductant in the host cavities and the magnitudes of the inclusion stability complexes have been determined by 1 H and 13 C NMR spectroscopy.

The kinetics of reduction of the hexacyanoosmate(III) ion by ascorbic acid and several substituted 1,2-and 1,4-dihydroxybenzenes have been investigated in acidic aqueous media. A Marcus correlation between the cross-reaction rate constants and the semiquinone or ascorbate radical reduction potentials has been constructed, yielding a [Os(CN)6]4–/3– self-exchange rate constant of 1.7 × 104 dm3 mol–1 s–1, in good agreement with the directly measured value. The effects of β-cyclodextrin (β-cd) inclusion of 1,2-dihydroxybenzene and 4-tert-butyl-1,2-dihydroxybenzene on the kinetics of electron transfer have been investigated. The rate constant for 4-tert-butyl-1,2-dihydroxybenzene (Kcd= 2500 ± 500 dm3 mol–1) decreases from 150 to 72 dm3 mol–1 s–1 upon β-cd inclusion. There is no observed change in the rate constant for the oxidation of 1,2-dihydroxybenzene (23 ± 1 dm3 mol–1 s–1) due to very weak inclusion (Kcd= 14 ± 3 dm3 mol–1) in the β-cd cavity.

The effects of α-, β-, dmβ-(heptakis(2,6-di-O-methyl)-β-) and γ-cyclodextrins (CD) on the kinetics of the electron-transfer reaction of the ferrocenemonocarboxylate anion (FCA−) with bis(pyridine-2,6-dicarboxylato)cobaltate(III) have been investigated in aqueous solution (0.20 M Na2HPO4, pH 9.2) at 25.0°C. Substantial decreases in the rate constants for the electron-transfer reactions were observed upon cyclodextrin inclusion of the reductant, due to an increase in the FCA0/− reduction potential and to the insulation of the reductant from oxidant. The inclusion stability constants for {FCA·CD}− were evaluated from the1H NMR and kinetic data, and the order of the stability constants was found to be β-CD≈dmβ-CD≫γ-CD>α-CD.