Calixarenes in analytical and separation chemistry

Discovered in the 1940's, [1n]metacyclophanes with the common name calix[n]arenes which is derived from for the molecule's shape enjoyed a remarkable interest in almost all fields of chemistry since the 1980's, which is highlighted by several books [1-8]. Over 50 reviews concerning their synthesis, properties and applicabilities were published, many of those with emphasis on organic synthesis and structural properties are cited in [P. 5-6 in 2]. Of interest for analytical chemists are reviews on calixarenes and the structurally related resorcin[n]arenes (or calix[n]resorcarenes) and calixpyrroles concerning potentiometric sensors [9-12], chromo- and fluorophores [13, 14], molecular switches [15], metal ion binding in solution [16-19], redox properties [20] and anion binding [21-24]. Other recent reviews deal with thermodynamic aspects [25], organometallic compounds [26], P-containing calixarenes [27-29], as well as molecular dynamics modeling [30-33]. It is a vital field with over 200 publications per year. Therefore, this article presents only selected results on complexation, solvent extraction and membrane transport with the emphasis on ion and molecular recognition which can be used for analytical purposes, without attempting to cover all available references.     

Uranium(IV) complexes of calix[n]arenes (n = 4, 6 and 8)

Reaction of UCl4 with calix[n]arenes (n = 4, 6 and 8) in THF or pyridine gave the mononuclear [UCl2(calix[4]arene--2H)(THF)2], bis-binuclear [U2Cl2(calix[6]arene--6H)(THF)3]2 and trinuclear [Hpy]6[U3Cl11(calix[8]arene--7H)] complexes, respectively, which are the first U(IV) complexes of O-unsubstituted calixarenes.     

Facile synthesis of oligophenylene-substituted calix[4]arenes and their enhanced binding properties

[reaction: see text] A facile and efficient protocol for the synthesis of oligophenylene OPP(n)-substituted calix[4]arenes (with n up to 4) via iodo-substituted oligoarylcalix[4]arenes has been developed. The cooperation effect of the proximate fluoroionophores in hexylsulfanyl end-capped OPP(n)-substituted calix[4]arene assemblies leads to metal ion binding enhancement.     

Direct access to upper rim substituted mono- and diaryloxy calix[4]arenes via bis(spirodienone) route

A seemingly ipso-like nucleophilic substitution of the upper rim of p-tert-butylcalix[4]arene is accomplished by an indirect method involving calix[4]arene derived bis(spirodienone). This method not only provides both mono and 1,3-diaryloxy calixarenes but also enables the synthesis of upper rim monothio substituted calix[4]arenes. A modification of the methodology can be successfully extended for the selective synthesis of mono- and 1,3-diquinone calix[4]arenes having free hydroxyl groups at the lower rim, in fewer steps.     

Upper rim appended hybrid calixarenes via click chemistry

We report the application of "click" chemistry for the synthesis of hybrid calixarenes appended on the upper rim with carbohydrate and N,C-protected alpha-amino acids. The chemoselective N- or C-deprotection of the alpha-amino acids and their subsequent transformation into dipeptides is described. The first example of a chemo-enzymatic synthesis on upper rim derived calix[4]arenes using trans-sialidase affords sialylated lactose calix[4]arenes. Our innovative chemo-enzymatic process paves the way for further applications.     

Complexation of fullerenes by calix[n]arenes: molecular dynamic simulations and benesi-hildebrandequilibrium constants

MD simulations using a combination of AMI and AMBER are performed to elucidate the origin of complexation between fullerenes and calix[n]arenes (n = 4,6,8). Only calix[6]arenes and calix[8]arenes are suitable for complex formation. By introducing benzyl substitutents on the upper rim of the calixarenes the interaction energy between host and guest is even improved. Analysis of the data also reveals a strong stabilization by t-butyl or benzyl substitutents beside π-π interactions between the arene units of the calixarene and fullerenes. The calculated data perfectly correlate with the experimentally observed equilibrium constants.     

para‐Sulfonated Calixarenes Used as Synthetic Receptors for Complexing Photolabile Cholinergic Ligand

The water‐soluble tetra‐, hexa‐ and octasulfonated calix[4]arenes, calix[6]arenes, and calix[8]arenes 1 – 3 , respectively, were investigated as potential synthetic receptors for photolabile cholinergic ligand A , a photolytic precursor of choline. Ligand A is a bifunctional molecule carrying a photolabile 2‐nitrobenzyl group at one end and a choline moiety at the other end. Results from NMR studies have shown that calixarenes 1 – 3 form stable 1 : 1 complexes with A , having similar binding potential to that observed with the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase. Further studies have suggested that calix[8]arene forms a ditopic complex by binding concomitantly to both the cationic choline moiety and the aromatic photolabile group of A , whereas calix[4]arene and calix[6]arene form monotopic complexes with A . The ditopic complex between calix[8]arene and A results from mutually induced fitting process, while the monotopic complexes between calix[4]arene and A can be regulated by pH: at neutral pH, calix[4]arene specifically binds the cationic choline moiety, while, at acidic pH, it complexes unselectively both the cationic choline moiety and the aromatic group of A . Our results show that para‐sulfonated calixarenes are versatile artificial receptors which bind in various ways to the bifunctional photolabile cholinergic ligand A , depending on their size, geometry, and state of protonation.     

A new convergent strategy for the synthesis of calixarenes via a triple annulation of Fischer carbene complexes

A new method for the synthesis of unsymmetrical calix[4]arenes is described which involves the reaction of a diyne with a bis-carbene complex of chromium. This synthesis of calixarenes is unique in that it involves the formation of two of the four benzene rings of the calixarene and the macrocyclic ring of the calixarene in the same step. Thus, two of the four benzene rings of the calixarene are identical, but the other two rings may each be different, giving a general method for the synthesis of calixarenes in which there are either two or three differently substituted benzene rings. This protocol gives access to a large family of unsymmetrical calixarenes by the proper choice of arene substitution in the starting diyne and the starting carbene complex. Nine examples are presented in which the yields in the key triple annulation step range from 22 to 41%. The overall yields of calixarenes from commercially available starting materials compare favorably with those from existing methods for the synthesis of unsymmetrical calix[4]arenes.     

Linked Supramolecular Building Blocks for Enhanced Cluster Formation

Methylene‐bridged calix[4]arenes have emerged as extremely versatile ligand supports in the formation of new polymetallic clusters possessing fascinating magnetic properties. Metal ion binding rules established for this building block allow one to partially rationalise the complex assembly process. The ability to covalently link calix[4]arenes at the methylene bridge provides significantly improved control over the introduction of different metal centres to resulting cluster motifs. Clusters assembled from bis‐calix[4]arenes and transition metal ions or 3d‐4f combinations display characteristic features of the analogous calix[4]arene supported clusters, thereby demonstrating an enhanced and rational approach towards the targeted synthesis of complex and challenging structures.     

DNA condensation and cell transfection properties of guanidinium calixarenes: dependence on macrocycle lipophilicity, size, and conformation

Calix[n]arenes functionalized with guanidinium groups at the upper rim and alkyl chains at the lower rim bind to DNA, condense it, and in some cases, promote cell transfection depending on their structure and lipophilicity. Atomic force microscopy (AFM) studies indicate that upon DNA binding the hydrophobic association of the lipophilic chains of cone guanidinium calix[4]arenes drives the formation of intramolecular DNA condensates, characterized by DNA loops emerging from a dense core. Furthermore, hexyl and octyl chains confer to these calixarenes cell transfection capabilities. Conversely, larger and conformationally mobile calix[6]- and calix[8]arene methoxy derivatives form intermolecular aggregates characterized by "gorgonlike" structures composed of multiple plectomenes. These adducts, in which interstrand connections are dominated by electrostatic interactions, fail to promote cell transfection. Finally, calix[4]arenes in a 1,3-alternate conformation show an intermediate behavior because they condense DNA, but the process is driven by charge-charge interactions.     

Synthesis and Extractive Properties of Hexaphosphorylated Calix[6]arenes

A series of calix[6]arenes substituted with phosphoryl functional groups were prepared by the Arbuzov reaction of hexakis(chloromethyl)calix[6]arene hexamethyl ether with isopropyl esters of trivalent phosphorus acids, followed by appropriate chemical transformations. Molecular modeling and NMR data show that phosphorylated calix[6]arenes exist in the stereochemically labile 1,2-alternate conformation. The extractive power of these compounds with respect to americium and europium was studied. Due to the cooperative binding of the metal cation with phosphoryl groups, the phosphorylated calixarenes are more effective extractants than their acylcic analogs and commercial organophosphorus extractants.     

Calix[4]arenes as molecules for second order nonlinear optics

Abstract

The synthesis of a novel class of molecules for second order nonlinear optics, i.e. calix[4]arenes with extended π-systems, is described. These compounds are obtained via Wittig-Horner reactions of the formylated calix[4]arenes 5 and 6 to give the stilbene derivatives 7–9, or by diazotization of calix[4]arene, 1, followed by alkylation to give the phenylazocalix[4]arenes 11 and 12. The molecular second order nonlinear optical properties (β_z) of these calix[4]arenes have been measured by electric field-induced second harmonic generation. The influence of different acceptors as well as the influence of the different conformations of the calix[4]arenes on β_z values were determined. Surprisingly, the wavelength of the charge-transfer band λ_max is lower when β_z increases upon increasing the number of acceptors.     

Bridge-disubstituted calix[4]arenes obtained via a new preparative route. Synthesis and structural study

A series of calix[4]arenes bearing various substituents including alkyl, p-bromobenzyl, carboxy and allyl at opposite methylene bridges has been synthesized via successive metallation followed by nucleophilic substitution. In a first step, mono-lithiated calix[4]arenes react with terminal bromoalkanes to give 2-alkylated calix[4]arenes or with CO₂ the respective calixarene-2-carboxylic acid in good yields. A second lithiation step of the monosubstituted products with subsequent attachment of both polar and non-polar substituents yields several new diametrally bridge-disubstituted calix[4]arenes. 2D-NMR measurements establish the disubstituted calixarenes to predominantly adopt the 1,2-alternate conformation in solution. First examples of X-ray crystal structures of the new type of disubstituted calix[4]arenes are described featuring the calix[4]arene also in the rare 1,2-alternate conformation.     

Unusual reactivity of upper-rim bridged calix[4]arenes – Friedel–Crafts alkylation via cleavage of the macrocyclic skeleton

Upper-rim bridged derivatives of calix[4]arenes, prepared by the direct introduction of mercury into the meta position of the basic skeleton followed by Pd-catalyzed intramolecular bridging, represent a novel type of calixarenes bearing an additional single bond between the meta positions of neighboring aromatic units. Due to the presence of this short bridge, these compounds exhibit extremely distorted cavities when compared with common calix[4]arenes. As a consequence of highly enhanced inner strain, the bridged compounds can be cleaved under acidic conditions to form open oligomeric species (benzylic type carbocation) that can be used for the Friedel–Crafts alkylation of aromatic compounds. This behavior, never observed in common calix[4]arenes, demonstrates a reasonably amended reactivity invoked by the additional bridge.     

Synthesis, fluorescent properties and aggregation of 2,3-dihydroisoindolenylcalix[4]arenes

New derivatives of calix[4]arenes, containing two isoindole fragments in distal positions of the macrocycle upper rim were synthesized. According to NMR and molecular modeling data, the obtained calixarenes exist in “flattened cone” conformation with inclination angles of benzene rings to the macrocycle plane equal to 133–140° and 92–100°. Fluorometric studies showed the presence of self-aggregation of isoindolenylcalixarenes in acetone solutions starting from micromolar concentrations.     

The study of spectrosgraphic properties and molecular recognition of cali

The absorption spectrum and fluorescence spectrum of calix[n]arenes are studied systematically. The self-association of calix[n]arenes is proposed and the self-association constant is also obtained. The recognition properties of calix[n]arenes are studied and the inclusion constant is calculated.     

Halo-derivatised calix[4]tubes

Halo functionalisation of calix[4]tubes has been investigated through both derivatisation of individual calix[4]arenes and calix[4]tubes, using classical synthetic methods, to allow preparation of a series of novel derivatives. The solution and solid state properties are in accordance with the constituent[4]arenes adopting flattened cone arrangements which on complexation with potassium simplify to a regular cone. Electrospray and 1H NMR studies, combined with molecular modelling have been used to ascertain the metal binding of this new series of cryptand like ionophores, demonstrating their retained selectivity for binding potassium over other Group 1 metals and the dependence on counter anion in the weak binding of silver.     

Calixarenes. 23. the complexation and catalytic properties of water soluble calixarenes

A series of-water-soluble calixarenes containing dialkylamino groups and carboxyl groups have been prepared by the p-quinonemethide route of functionalization. The formation of host-guest complexes between these calixarenes and nine aromatic hydrocarbons ranging in size from durene to decacyclene has been investigated, and a correlation between the dimensions of the hydrocarbons and the “lower rim” of the calixarene, containing the array of OH groups, has been made. A study of the effect on the acid-catalyzed hydration of N-benzyl-1,4-dihydronicotinamide by p-(carboxy-ethyl) calix[n]arenes (n = 4,5,6,7,8) has shown that the calix[6]arene is more effective than either its larger or smaller analogs.     

New Wide Rim Phosphomethylated Calix[4]arenes in Extraction of Americium and Europium

A new series of the cone-shaped tetraalkoxycalix[4]arenes substituted at the wide rim with four phosphomethyl groups have been synthesized by the Arbuzov, Michaelis–Becker and Aterthon–Todd reactions of the chloromethyl or phenylhydrophosphinylmethylcalix[4]arenes. Their binding properties towards Eu³⁺ and Am³⁺ cations were investigated by the liquid–liquid extraction method. Due to the ‘calixarene effect’ the tetraphosphorylated calixarenes are more effective extractants for the metal cations than their acyclic analogs or some industrial extractants such as trialkylphosphinoxides, carbamoylphosphinoxide, bis-2-diethylhexyl phosphoric acid.