Water inside a hydrophobic cavitand molecule

The structure and dynamics of water inside a water-soluble, bowl-shaped cavitand molecule with a hydrophobic interior are studied using molecular dynamics computer simulations. The simulations find that the number of inside water molecules is about 4.5, but it fluctuates from being completely empty to full on a time scale of tens of nanoseconds. The transition from empty to full is energetically favorable and entropically unfavorable. The water molecules inside have fewer hydrogen bonds than the bulk and in general weaker interactions; the lower energy results from the nearest-neighbor interactions with the cavitand atoms and the water molecules at the entrance of the cavitand, interactions that are lost upon dewetting. An analysis of translational and rotational motion suggests that the lower entropy of the inside water molecules is due to decreased translational entropy, which outweighs an increased orientational entropy. The cavitand molecule acts as a host binding hydrophobic guests, and dewetting can be induced by the presence of a hydrophobic guest molecule about 3 A above the entrance. At this position, the guest displaces the water molecules which stabilize the inside water molecules and the empty cavitand becomes more stable than the full.     

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.     

Cavitands with introverted functionality stabilize tetrahedral intermediates

The synthesis and characterization of two deepened cavitand hosts with introverted functionality--functional groups directed into the cavity--is described. Two functions can be introverted, alcohol and aldehyde, and they show the formation of hemiacetals and hemiketals on binding small guests with complementary functional groups. The structures of the bound hemiacetals are determined by 1D and 2D NMR studies. The arrangements of the guests in the cavitands enhance the equilibrium constants of carbonyl additions, K/K(ctrl), between 13- and 10(5)-fold, compared to their counterparts in solution. The stabilization of the addition products is due to the prior complexation of the guests and the organized solvation provided to the tetrahedral intermediates by a network of secondary amides at the cavitand rim.     

A deep cavitand catalyzes the Diels-Alder reaction of bound maleimides

A deep cavitand catalyzes Diels-Alder reactions of bound maleimides via activation of the dienophile by interaction with the organized hydrogen bonding network at the cavitand rim. Rapid in-out exchange of reactant and product allows efficient turnover. The increase in steric bulk of the reaction product lessens its binding affinity, reducing (and in some cases completely eliminating) product inhibition.     

Cooperative Binding of Divalent Diamides by N‐Alkyl Ammonium Resorcinarene Chlorides

N‐Alkyl ammonium resorcinarene chlorides, stabilized by an intricate array of hydrogen bonds leading to a cavitand‐like structure, bind amides. The molecular recognition occurs through intermolecular hydrogen bonds between the carbonyl oxygen and the amide hydrogen of the guests and the cation–anion circular hydrogen‐bonded seam of the hosts, as well as through CH ??? π interactions. The N‐alkyl ammonium resorcinarene chlorides cooperatively bind a series of di‐acetamides of varying spacer lengths ranging from three to seven carbons. Titration data fit either a 1:1 or 2:1 binding isotherm depending on the spacer lengths. Considering all the guests possess similar binding motifs, the first binding constants were similar (K₁: 10² M ^?1) for each host. The second binding constant was found to depend on the upper rim substituent of the host and the spacer length of the guests, with the optimum binding observed with the six‐carbon spacer (K₂: 10³ M ^?2). Short spacer lengths increase steric hindrance, whereas longer spacer lengths increase flexibility thus reducing cooperativity. The host with the rigid cyclohexyl upper rim showed stronger binding than the host with flexible benzyl arms. The cooperative binding of these divalent guests was studied in solution through ¹H NMR titration studies and supplemented by diffusion‐ordered spectroscopy (DOSY), X‐ray crystallography, and mass spectrometry.     

Recent Advances in the Applications of Water-soluble Resorcinarene-based Deep Cavitands

We review here the use of container molecules known as cavitands for performing organic reactions in water. Central to these endeavors are binding forces found in water, and among the strongest of these is the hydrophobic effect. We describe how the hydrophobic effect can be used to drive organic molecule guests into the confined space of cavitand hosts. Other forces participating in guest binding include cation−π interactions, chalcogen bonding and even hydrogen bonding to water involved in the host structure. The reactions of guests take advantage of their contortions in the limited space of the cavitands which enhance macrocyclic and site-selective processes. The cavitands are applied to the removal of organic pollutants from water and to the separation of isomeric guests. Progress is described on maneuvering the containers from stoichiometric participation to roles as catalysts.     

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.     

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.     

Deep cavitand receptors with pH-independent water solubility

Pendant oligoethyleneglycol groups confer water solubility to a cavitand over a wide pH range. The kinetic stability of the host-guest complexes reveals an effective stabilization through hydrogen bonding even in the highly competitive aqueous environment.     

A new imidazolium cavitand for the recognition of dicarboxylates

[structure: see text] A new cavitand bearing four imidazolium groups was synthesized for the recognition of anions through (C-H)+...X- hydrogen bond formation. The binding properties toward various anions including dicarboxylates were examined on the basis of 1H NMR spectroscopic experiments.     

酰胺水化作用的富里埃红外光谱研究及其SCFPPP计算

本文用富里埃红外光谱仪研究了酰胺水化作用引起的红外光谱变化。用SCFPPP方法对五种酰胺进行了计算。含水酰胺的羰基伸缩振动频率向低波数的位移与酰胺和水分子间的氢键强度成正比。其氢键强度与羰基上氧原子的净电荷密度成正比,与酰胺分子的HOMO轨道能量成反比。     

Structural Studies of Self‐Folding Cavitands

Resorcinarene‐based cavitands 1a – c fold into a deep open‐ended cavity by means of intramolecular hydrogen bonds in both apolar solutions and the solid state. The X‐ray crystal‐structure analysis of cavitand 1a features a seam of secondary amide C=O⋅⋅⋅H−N interactions that bridge adjacent rings and are held in place by intra‐annular hydrogen bonds. This results in a cavity of 9.2×7.0 Å dimensions. The arrangement of the amides in 1a – 1c is cycloenantiomeric, with clock‐ and counterclockwise orientation of the head‐to‐tail amide sequence. Interconversion rates of the two enantiomers are controlled by solvent polarity: the rate is slow on the NMR time‐scale in aromatic solvents and CDCl₃, but fast in (D₆)acetone. The ¹H‐ and ¹³C‐NMR‐spectral analysis is in agreement with the crystallographic data. Chiral cavitand 1b with eight HN−C(O)−C*HMeEt ((+)‐(S)) groups on its upper rim exists as two cyclodiastereoisomers (in a ca. 3 : 1 ratio) in apolar solution. A `library' of 512 diastereoisomeric cavitands 1c is obtained as a mixture by using the corresponding racemic acid chloride.     

Metal-free synthesis of calixsalen-type cavitands for the recognition of fluoride ion

Novel calixsalen-type cavitands have been synthesized using metal-free synthesis from simple and inexpensive materials, such as ethylenediamine and 5,5′-methylene-bis-salicylaldehyde derivatives. The cavitand 1 containing salen functionality recognizes fluoride ion. Fluoride ions switch on fluorescence on binding with the cavitand 1. Substitution on bis-salicylaldehyde part of calixsalen-type cavitand shows change in recognition behavior. On the attachment of electron withdrawing substituent, such as nitro group, the cavitand lost its fluorescence properties but proved to be a better colorimetric probe showing marked color change from pale yellow to red on addition of tetrabutyl ammonium salt of fluoride ion to the solution of cavitand. The nitro substituted cavitand is highly sensitive and selective for fluoride anion and hence is a promising candidate for development of colorimetric chemosensor. The binding of the cavitands with fluoride ion is investigated using ¹H NMR-titration experiments.     

A fluorescence enhancement-based sensor for hydrogen sulfate ion

Sugar-aza-crown ether-based cavitand 1 can act as a selective turn-on fluorescence sensor for hydrogen sulfate ion in methanol among a series of tested anions. Spectroscopic studies, particularly NMR spectroscopy, revealed that the C-H hydrogen bonding between 1,2,3-triazole ring of cavitand 1 and hydrogen sulfate ion is crucial for the high selectivity of the receptor for hydrogen sulfate.     

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.     

Hydrogen reduction of the Cu(acac)2 complex sorbed by cucurbit[8]uril

The hydrogen reduction of bis(2,4-pentanedionato)copper(II) sorbed by the cavitand cucurbit[8]uril has been studied. After sorption of the complex at 180°C, the crystal structure of the resulting phase differs from the structure of the individual compounds. EPR shows that the reduction of the complex with hydrogen at 250°C for 15 min leads to the loss of one of the ligands and formation of the coordination bond between the Cu²⁺ ion and a nitrogen atom of cucurbit[8]uril and the oxygen atom of the water molecule or OH^? group located in the cavitand cavity. The molecular structure of the resulting supramolecular compound has been optimized by density functional theory quantum-chemical calculations with the exchange-correlation functional with the use of the PRIRODA program package. EPR, EXAFS, and XANES show that an increase in the reduction time or temperature (to 280°C) leads to the formation of copper clusters.     

Diastereoselective formation of host-guest complexes between a series of phosphate-bridged cavitands and alkyl- and arylammonium ions studied by liquid secondary-ion mass spectrometry

The reactions occurring between a new class of cavitands that carry up to four dioxaphosphocin binding units and alkyl- and arylammonium ions was investigated by liquid secondary-ion mass spectrometry (LSIMS). As the cavitands existed as distinct diastereomers with different spatial orientation of their binding groups, these geometrical differences proved to have a dramatic influence on their chemical properties, including their ability to form host-guest complexes. In practice, only the cavitands that carry at least three P=O groups oriented toward the inside of the cavity were demonstrated to be strong ligands toward organic ammonium ions, whereas those with only two converging binding groups (either adjacent or opposite in the cavitand structure) still formed host-guest complexes, but they were much weaker. Adjacent binding sites proved to be more effective in interacting with organic ammonium ions than those lying in opposite positions. The isomers with no converging P=O groups did not act as molecular receptors. Even the isomer with one group oriented toward the inside of the cavity did not form host-guest complexes, as the absence of synergistic hydrogen bonding made the interaction from inside the cavity energetically equivalent (or even less favorable) to the outside binding. The presence in the cavitand structure of substituents with an electron-donating character proved to increase the proton affinity of the P=O binding groups and, consequently, their binding energy. The strong proton affinity of the cavitands led to the formation of stable host-guest complexes, as confirmed by the collisionally activated dissociation experiments. Effects of steric hindrance were weak, at least for the cavitands with three converging P=O groups. This confirmed that the cavity has a wide and readily accessible opening. The relative complexation constants were measured for the various guests, yielding scales of relative affinity toward each cavitand. These relative constants may represent thermodynamic values referred to the matrix used in LSIMS experiments, namely 3-nitrobenzyl alcohol (NBA), provided that kinetically controlled selvedge processes are negligible. Absolute complexation constants could not be obtained on account of the unknown pH and the protonation constant in the NBA matrix.     

Selective steroid recognition by a partially bridged resorcin[4]arene cavitand

The partially bridged resorcin[4]arene cavitand featuring a cleft-shaped recognition site formed by two anti-quinoxaline bridges and four convergent HO-groups was prepared in three steps and characterised by X-ray crystallography; cavitand was found to be a selective receptor for steroidal substrates in CDCl3, with the best binding observed for steroids with a flat A-ring and two H-bonding sites on rings A and C/D.     

On the relative strengths of amide…amide and amide…water hydrogen bonds

We have performed Hayes—Stone intermolecular perturbation theory (IMPT) calculations on amide…water and amide…amide complexes in order to estimate the change ΔW in intermolecular interaction energy associated with the hydrogen bond exchange process amide(NH)…water+water…(OC)amideamide(NH)…(OC)amide+water…water. ΔW is found to be small and varies by almost 5 kJ/mol and in sign for the amides formamide, acetamide, N-methyl formamide and N-methyl acetamide. The main variations in the amide hydrogen bond energies occur in the electrostatic and exchange-repulsion contributions. This reflects the variation in the charge distributions of the hydrogen bonding groups between the different amides. Thus, we cannot quantify an isolated hydrogen bond strength with any great accuracy, and care must be used in extrapolating model potentials based on small model systems to peptides and proteins.     

Anion binding by a tetradipicolylamine-substituted resorcinarene cavitand

Anion binding has been achieved with a resorcinarene substituted with four 2,2'-dipicolylamine moieties on the upper rim. The four dipicolylamine groups reside in proximity on one rim of the cavitand. The dipicolylamine groups were protonated with triflic acid to provide the cationic ammonium sites for anion binding. This anion receptor binds strongly to anions of different geometries, such as H(2)PO(4)(-), Cl(-), F(-), CH(3)CO(2)(-), HSO(4)(-), and NO(3)(-). The association constants for binding these anions are large, on the order of log K = 5 in CD(3)CN, a solvent of intermediate dielectric constant. These values represent significant binding compared to other cavitands with nitrogen pendant groups. Evidence suggests that the cavitand provides two identical receptor sites formed by two dipicolylamine groups, facilitating the simultaneous binding of two anions. Intramolecular binding of anions between two protonated dipicolylamine groups is indicated on the basis of the comparison to a structurally similar monomeric analogue and by semiempirical PM3 molecular modeling. Titrations with the analogue result in much weaker anion association, even at high concentrations, indicating the importance of proximity and preorganization of sites on the cavitand upper rim.