Extraction of hydrophobic species into a water-soluble synthetic receptor

A deep, water-soluble cavitand extracts a variety of neutral hydrophobic species into its cavity. Flexible species such as n-alkanes tumble rapidly on the NMR time scale inside the cavity, but this motion is slowed for bulkier guests. Long, rigid guests such as p-substituted aromatics are either static or only tumble at elevated temperatures via flexing motions of the cavitand. Strong selectivity in recognition of long rigid guests is seen. The binding of neutral guests occurs via the classical hydrophobic effect; the process is entropically favored, as shown by isothermal titration calorimetry measurements. Binding affinities are generally on the order of 10(4)-10(5) M(-1). The extent of the hydrophobic stabilization is shown by the binding of long trimethylammonium salts, which bind the alkyl chain in the cavity, rather than the NMe3+ group. Dynamic NMR studies show that self-exchange of neutral guests is independent of guest concentration, and most likely occurs via rate-determining unfolding of the cavitand. In the absence of guests, the cavitand exists in a dimeric velcrand structure.     

Cavitands with revolving doors regulate binding selectivities and rates in water

A water-soluble self-folding cavitand has been prepared, featuring four benzoate groups attached to the open end. These benzoates act as rapidly "revolving doors" to the cavity. The cavitand shows increased selectivity for small hydrophobic guests and slower rates of guest exchange.     

Protein recognition by a self-assembled deep cavitand monolayer on a gold substrate

This paper details the first use of a self-folding deep cavitand on a gold surface. A sulfide-footed deep, self-folding cavitand has been synthesized, and its attachment to a cleaned gold surface studied by electrochemical and SPR methods. Complete monolayer formation is possible if the cavitand folding is templated by noncovalent binding of choline or by addition of space-filling thiols to cover any gaps in the cavitand adsorption layer. The cavitand is capable of binding trimethylammonium-tagged guests from an aqueous medium and can be deposited in 2 × 2 microarrays on the surface for characterization by SPR imaging techniques. When biotin-labeled guests are used, the cavitand:guest construct can recognize and immobilize streptavidin proteins from aqueous solution, acting as an effective supramolecular biosensor for monitoring protein recognition.     

Detection of reactive tetrahedral intermediates in a deep cavitand with an introverted functionality

Labile hemiaminal intermediates are stabilized by binding in a deep cavitand with an introverted aldehyde functionality. The aldehyde is attached to the cavitand via an anthracene spacer that rotates rapidly about the cavitand rim. The half-lives of these hemiaminals vary from 30 min to over 100 h at ambient temperature, due to hydrogen bonding with the organized peptide-like framework at the cavitand rim. The intermediates are sufficiently long-lived to allow study by 2D NMR techniques requiring many hours of acquisition time. Mechanistic analysis of the dehydration step shows first-order kinetics. The analogous "extroverted" reaction was also performed, where the addition took place outside the cavitand, displaying standard steady-state kinetics; no hemiaminal was observed. The cavitand shows strong selectivity based not on binding affinity but upon the rate of the product-forming step. A 10:1 ratio of product imines was obtained, while the initial binding ratio was 1:1. The cavitand acts as a mimic of enzymes in that it uses weak binding forces to stabilize reactive intermediates and isolates them from the medium. The synthetic environment allows direct detection and analysis of the intermediates, as opposed to natural systems that must be analyzed indirectly.     

Recognition of Hydrophilic Cyclic Compounds by a Water-Soluble Cavitand

A water-soluble deep cavitand bearing amides on the upper rim and trimethyl ammonium groups on the feet was synthesized. The open-ended cavity is stabilized by the intramolecular hydrogen bonds formed between the adjacent amides, and the introduction of trimethylammonium imparts to the cavitand good solubility in water. The cavitand exhibits high binding affinity and selectivity to hydrophilic molecules in water. With certain guests, such as cyclohexyl alcohols, amines and acids, the recognition involves the synergistic action of hydrogen bonding with hydrophobic effects. The binding phenomena are interpreted in terms of a fixed solvent cage presented by the host to the guest.     

A light controlled cavitand wall regulates guest binding

Here we report a cavitand with a photochemical switch as one of the container walls. The azo-arene switch undergoes photoisomerization when subjected to UV light producing a self-fulfilled cavitand. This process is thermally and photochemically reversible. The reported cavitand binds small molecules and these guests can be ejected from the cavitand through this photochemical process.     

Trapping of bulky guests inside dimeric molecular capsules formed by a deep-cavity cavitand

The inclusion of three bulky guests, adamantyl(ferrocenylmethyl)amine (2), adamantylferrocenecarboxylamide (3), and 1,1'-bis(adamantylaminomethyl)ferrocene (4), inside dimeric molecular capsules formed by an octaacid deep-cavity cavitand (1) was investigated using (1)H NMR spectroscopy and voltammetric techniques. Guests 2 and 3 were encapsulated inside 1(2) assemblies, as evidenced by (1)H NMR spectroscopic data. Although both guests are electroactive, the supramolecular complexes 2@1(2) and 3@1(2) showed no voltammetric current responses in the potential window corresponding to the electrochemical oxidation of their ferrocenyl groups. In contrast, each of the adamantyl ends of compound 4 is bound by the cavitand 1, but the central ferrocene residue was not fully encapsulated in this supramolecular assembly and the voltammetric behavior of 4·1(2) was clearly detected. In marked contrast with the experimental results obtained with guests 2 and 3, we could not obtain any evidence for the simultaneous encapsulation of free ferrocene and adamantane inside the 1(2) capsular assembly.     

Metal-switching and self-inclusion of functional cavitands

Cavitands bearing both eight (5) and two (13) metal-ligating carboxymethylphosphonate groups on their rims were synthesized by Arbuzov reaction of the corresponding bromoacetamido cavitands with trialkyl phosphites. These exist in the vase conformation in CDCl(3) and are stabilized by a cyclic seam of hydrogen bonds. This structure was also found in the solid state for the octabromoacetamide 4a and diphosphonate cavitand 13 by single-crystal X-ray analysis. Cavitands 5 and 13 form caviplexes in CDCl(3), CD(2)Cl(2), and alcohol solutions with adamantane derivatives 15a,b, quinuclidine 15d, ammonium and phosphonium salts 14, and drugs like ibuprofen 15c, all of which are stable on the NMR time scale at 295 K. NMR spectroscopy reveals that at 223 K octaphosphonate 5b exists in two forms: the major C(4)-symmetrical compound is filled with solvent while the minor species shows intramolecular inclusion of a dialkoxyphosphoryl group. In methanol-d(4) 5 and 13 exist in a lower symmetry vase conformation with self-inclusion of one alkyl group. Interaction of these complexes with La(OTf)(3) results in a change in the conformation of the cavitand from vase to kite with concomitant and quantitative release of the encapsulated guests. Two to three equivalents of the lanthanide salt per equivalent of cavitand 5a-d is necessary for the complete decomplexation of the included guest. The kite and the vase conformers equilibrate slowly on the NMR time scale at 295 K. The addition of good ligands for metal cations (nitrate or CMPO calixarene 16) shifts the equilibrium to the vase-shaped caviplex and allows quantitative control of the binding and release of the guest. The lanthanide complexes of octaphosphonates 5 in methanol-d(4) are velcraplex-like dimers held together by four metal cations.     

A carbohydrate-conjugated deep cavitand permits observation of caviplexes in human serum

A deep cavitand was covalently modified with carbohydrates to provide solubility in biologically relevant environments and to investigate its receptor function. Specifically, a tetrakis(β-D-glucosyl) cavitand (1) that was soluble in neutral water or acid/base-buffered solutions was synthesized, and it formed complexes with hydrophobic small molecules. Extraction of the cavitand into aqueous sodium dodecyl sulfate micelles as simple membrane mimetics increased the scope of guests bound by 1 beyond that observed in only aqueous media. Complex formation was also detected in human serum. The findings show the functional compatibility of the receptor in both micelle-bound and serum-soluble forms.     

Guest recognition with micelle-bound cavitands

We report that a benzimidazole cavitand is incorporated in aqueous phosphocholine (PC) micelles, folds into the vase conformation, and functions as small-molecule host. As a micelle-bound host it has the ability to sequester selective hydrophobic guest "anchors" into its interior. These anchors include cycloalkanes, adamantanes, and nitrogen heterocycles that compete favorably with the large excess of PC alkyl side-chains that make up the micelle interior. The adamantyl anchor was further functionalized with a fluorophore, and in another instance a dipeptide and both guests retain their recognition properties with the micelle-bound cavitand. Additionally, we report that variations in the cavitand periphery and rim are well-tolerated under our experimental conditions. We find that enhanced binding toward certain guests in both micelles as well as in solution occurs in response to titration with base; this previously unknown property of benzimidazole cavitands is reported in detail.     

A functionalized, deep cavitand catalyzes the aminolysis of a choline derivative

The aminolysis of choline p-nitrophenyl carbonate is catalyzed with turnover by a deep cavitand bearing an introverted pyridone function. The synergy of action between the recognition of the guest in the binding pocket and the catalytic activity brought to bear by the pyridone is responsible for the high substrate specificity observed.     

Reaction of isonitriles with carboxylic acids in a cavitand: observation of elusive isoimide intermediates

A deep cavitand with an inwardly directed carboxylic acid function reacts with small aliphatic isonitriles to form N-acyl formamides inside the cavity. The unique isolation and stabilization of covalently bound guests within the structured environment of the cavitand allows for observation of the labile O-acyl isoimide intermediate using conventional spectroscopic methods.     

A deuterated deep-cavity cavitand confirms the importance of C-H...X-R hydrogen bonds in guest binding

A deuterated cavitand host was examined for its affinity to a series of guests; for halogenated, preorganized guests binding was significantly stronger than the corresponding protium host.     

Electrochemically controlled formation/dissociation of phosphonate-cavitand/methylpyridinium complexes

The phosphorus-bridged cavitand 1 self-assembles very efficiently in CH2Cl2 with either the monopyridinium guest 2+ or the bispyridinium guest 3(2+). In the first case a 1:1 complex is obtained, whereas in the second case both 1:1 and 2:1 host-guest complexes are observed. The association between 1 and either one of the guests causes the quenching of the cavitand fluorescence; in the case of the adduct between 1 and 3(2+), the fluorescence of the latter is also quenched. Cavitand complexation is found to affect the reduction potential values of the electroactive guests. Voltammetric and spectroelectrochemical measurements show that upon one-electron reduction both guests are released from the cavity of 1. Owing to the chemical reversibility of such redox processes, the supramolecular complexes can be re-assembled upon removal of the extra electron from the guest. Systems of this kind are promising for the construction of switchable nanoscale devices and self-assembling supramolecular materials, the structure and properties of which can be reversibly controlled by electrochemical stimuli.     

Non-conventional coordination of cavity-confined metal centres

WIDEPHOS, a β-cyclodextrin cavitand bearing two introverted P(III) donor atoms, readily accommodates two converging Au-X fragments (X = Cl, Br, I). In the corresponding [(WIDEPHOS)(AuX)(2)] complexes, severe steric crowding within the cavity results in one of the P-Au-X rods deviating from linearity, as revealed by an X-ray diffraction study and unusual (31)P magnetic shielding of one of the two phosphorus signals. The cavitand ligand is also suited for hosting strained dipalladium moieties with a single chlorido bridge, thereby forming dynamic complexes in which ligand coordination to one of the metal centres occurs via an oschelating P,O-subunit.     

Electronic and steric effects in binding of deep cavitands

A deep, self-folding cavitand responds to minor electronic differences between suitably sized adamantane guests. Binding constants range from <0.5 to 4000 M(-1) for guests as similar as 1-bromoadamantane and 1-cyanoadamantane. The barriers to guest exchange also vary up to 3 kcal mol(-1).     

Activation of a water-soluble resorcinarene cavitand at the water-phosphocholine micelle interface

The host-guest properties of a water-soluble resorcinarene cavitand bearing four guanidines at the feet were investigated in water and dodecylphosphocholine (DPC) micelles by NMR spectroscopy. While the binding of different guests in water was generally modest, the formation of the caviplexes was significantly enhanced in the presence of micelles and reached affinities typically observed for organic solvents. The increase in binding free energies of up to 3.2 kcal mol(-1) was determined to be enthalpic in origin and was attributed to the disruption of velcrand dimers and subsequent conformational reorganization of the receptor induced by the micelles that acted as hosts for the cavitand. In agreement with the NMR data, molecular dynamics simulations reproduced the spontaneous incorporation of the cavitand into the micelle and provided a detailed picture of the positioning of the receptor at the DPC-water interface.     

Capsular complexes of nonpolar guests with octa amine host detected in the gas phase

Nanocapsules, made up of the deep cavitand octa amine and several guests, were prepared in aqueous acidic solution and were found to be stable in the gas phase as detected by electrospray ionization mass spectrometry (ESI-MS). The observed gas phase host-guest complexes contained five positive charges and were associated with several acid molecules (HCl or HBr).     

Ferrocene derivatives included in a water-soluble cavitand: are they electroinactive?

The formation in aqueous solution of kinetically stable inclusion complexes between a deep-cavity cavitand and several redox active ferrocene derivatives was demonstrated using (1)H NMR spectroscopy. The electrochemical kinetics of the inclusion complexes was strongly attenuated as compared to that observed with the free guests.     

Bent alkanes in a new thiourea-containing capsule

The synthesis of a cavitand featuring thiourea hydrogen bonding sites and its dimerization in the presence of suitable guests are reported. Dimerization creates a capsule host wider than the corresponding urea or imide structures, and longer alkanes can be accommodated. Specifically, n-C(15)H(32) is encapsulated, but this guest appears folded inside as deduced from NMR studies. Apparently, the plasticity of hydrogen bonds between thiourea groups allows a stable encapsulation complex to persist in solution even though the guest is contorted.